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NEXT 2021: A Time for Resilience and Ingenuity
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Introduction: Rare Disease in the Time of the Pandemic


In December 10, 2019, Wei Guixian was selling shrimp at her stall at the Huanan market in Wuhan, China when she began to feel ill. She felt she had developed the flu and went to a local clinic for treatment before returning to work. She returned to the clinic as medicine that doctors there had provided failed to make her feel better. On December 16, she went to the Wuhan Union Hospital, where other people who had been at the market had already been seen with similar symptoms. She was among 27 initial cases of COVID-19, and one of 24 that had been linked to the seafood market by year end. Wei was quarantined and eventually recovered.


By December 31, 2019, the World Health Organization had its first report of pneumonia of unknown cause detected in Wuhan. Two weeks later, Thailand’s Ministry of Public Health reported the first case of the novel virus outside of China. By the end of January, the outbreak was declared a public health emergency of international concern. The disease soon had a name: COVID-19 (short for Corona Virus Disease 2019). By March 11, 2020, as the WHO grew concerned about the spread and severity of

the disease and what it characterized as “alarming levels of inaction,” it declared COVID-19 a pandemic.


The pandemic had deep reverberations on daily life throughout the world as efforts to slow the spread of the virus led to social distancing and sheltering-in-place policies, which closed businesses and schools, sent unemployment soaring, and had office workers doing their jobs from home. The pandemic delivered a protracted economic wallop that was expected to cut global economic growth by 3 to 6 percent, according to the Congressional Research Service.


The human toll also grew with troubling speed as many countries struggled to bring the spread of the virus under control. By December 31, 2020, the virus had spread to at least 191 countries and regions, infected more than 83.4 million people, and killed 1.8 million, according to the Johns Hopkins Coronavirus Resource Center. By year-end, the United States saw nearly 20 million cases and suffered more than 345,000 deaths. The pandemic created an urgency to find treatments that was familiar to the estimated 400 million rare disease patients around the globe.


The pandemic also had profound and lasting impacts on the world of rare disease. It disrupted research, halted clinical trials, and upended the delivery of care and the daily lives of people with rare conditions. Though much of this has had a negative effect on the rare disease community—delaying scientific progress, derailing fundraising efforts, and exacerbating isolation while forestalling access to care—there have also been some positive developments. The pandemic has accelerated the use of technology for remote care, advanced efforts to decentralize clinical trials, and demonstrated the benefits of tearing down barriers to collaboration and data sharing.

Halting Research

As shelter-in-place policies took hold in March of 2020, academic research labs began to shut down to prevent the spread of the virus. Institutions sent staff to work from home and, in many cases, researchers were forced to suspend any non-essential work. Some researchers studying rare diseases pivoted to take on COVID-19-related work if there was an overlapping expertise, such as research into the immune system. But the pandemic proved cruel in its effects as it was indiscriminate in the way it forced researchers to scrap work regardless of how far along it may have been.


Terry Pirovolakis had been working to raise $3 million to fund several research projects to find potential treatments or a cure for spastic paraplegia 50, an ultra-rare and progressive neurodegenerative disease that his 3-year-old son Michael has. In March 2020, as researchers at the National Institutes of Health were 48 hours away from seeing data from a critical experiment of a possible gene therapy in cells from an SPG50 patient, the lab shut down because of COVID-19 precautions. Projects Pirovolakis was involved with at three other labs had to be stopped as well. Even a global hack-a-thon he organized to develop potential therapeutic strategies to pursue for SPG50 had to be left unfinished with its review and judging of the proposed approaches put off.


“It’s heartbreaking. We’re trying to work around this extreme nightmare that we’re all in and hope that it ends quickly so we can go back to normal. I want to cry. I felt like yelling, and wanted to punch a wall, but that’s not going to help anybody. All we can do is hope everyone comes out safe and healthy and we go back to normal,” he said in April 2020. “All of our research has been paused. What takes a month or two, or potentially three months to get up and running again, is going to delay all of us in the rare disease space by at least six months.”


Pirovolakis’ organization CureSPG50 was able to get its work back on track. At the end of September 2020, it announced a manufacturing partnership agreement with Columbus Children’s Foundation for an AAV gene therapy. The nonprofit organization uses a partner model to accelerate gene therapy treatments for programs focused on ultra-rare conditions that are often ignored by traditional commercial development programs because of economics. Pirovolakis said the partnership with Columbus Children’s Foundation, which works with the AAV manufacturing organization Viralgen Vector Core, will allow it to work toward a gene therapy for SPG50 while staying within budget.


“Due to COVID-19, many biotechnology compa- nies around the world have been impacted by serious delays and those that are available to manufacture a drug such as ours have signifi- cantly increased costs or simply lack the neces- sary expertise,” he said. “We have been given a golden opportunity to save our children with great speed rarely seen in the rare disease sector thanks to CCF and Viralgen.”


While some organizations were able to find ways to sustain ongoing projects, many organizations were left with no choice but to hit the brakes on research fundamental to advancing an understanding of their diseases and essential to setting the stage for the development of potential therapies. The situation was acute for some groups early in the process of conducting research to understand the natural history of a disease, gather biosamples, and identify biomarkers for possible clinical trials of therapeutics to treat these conditions.


As groups have come to rely on conferences as ideal places to gather people with a condi- tion for the collection of samples and testing, the cancellation of these events has had a direct impact on advancing basic research well beyond any funding they may provide. For instance, Bridge the Gap—SYNGAP Education and Research Foundation uses family gatherings to bring families together to meet with clinical experts, as well as researchers. The organiza- tion had to cancel its gathering set for early June in Edinburgh, Scotland, United Kingdom because of the pandemic.


“When you have a small number of patients, you have a hard time gathering clinical data, just to be able to translate the basic science to try to find mechanisms,” said Monica Weldon, founder, president, and CEO of Bridge the Gap, a patient advocacy organization focused on SYNGAP1 mutations, which cause learning disabilities, autism, and epilepsy. “Our organization is focused on collecting the clinical data. We had to cancel our family meetups. When that kind of stuff happens, it puts off forward progress of trying to find treatments and mechanisms. We’ve had to put that off for a year.”


Such delays were not just tied to conference settings, but clinics as well. was getting ready to recruit patients in March 2020 for a natural history study in Paris of ADCY5- related dyskinesia, a rare neurologic disorder characterized by involuntary movements. “We’re trying to gather natural history studies so that we can be more attractive to industry,” said E. Gay Grossman, an ADCY5 advocate. “Right now, people can’t travel without quarantining for a long time on the other side. It would be too expensive for people to go and then sit and wait to quarantine and then be involved in this study. We just have to wait.”


Though the pandemic caused many companies to suspend clinical trials or to delay beginning approved studies because of the risks and restrictions on bringing study participants who were not infected with the virus into clinical trial sites, steps were also taken to adapt how trials are conducted. The U.S. Food and Drug Administration encouraged clinical trial sponsors, clinical investigators, and institutional review boards to implement policies and procedures to protect trial participants and manage studies during possible disruptions due to the COVID-19 pandemic. The agency issued guidance for the conduct of clinical trials during the pandemic to minimize risk to trial participants while maintaining the integrity of studies.


The guidance recommended that sponsors consider each circumstance, focusing on the potential impact on the safety of trial partici- pants, and modify study conduct accordingly. Considerations may include whether to continue enrollment in a trial, use of an investigational product for patients already participating in a trial, and changes in patient monitoring during a trial. It said because trial participants may be unable to travel to trial sites for specified visits, sponsors should evaluate whether alterna- tive methods for safety assessments could be used. This can include phone contact, virtual visits, and the use of alternative locations for assessments. The agency said sponsors should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach.


“The need to put new processes in place or to modify existing processes will vary by the protocol and local situation,” the agency said. “For example, this assessment could include consideration of whether it is appropriate to delay some assessments for ongoing trials, or, if the study cannot be properly conducted under the existing protocol, whether to stop ongoing recruitment, or even withdraw trial participants.”


Some drug developers managed to avoid interruptions in part by adopting digital health, video conferencing, and the use of home visits from laboratory services to bring the trial to the patient. When the pandemic was beginning to take hold in the United States, Palvella Therapeutics had just completed enrollment in a phase 2/3 pivotal study of PTX-022, its experimental treatment for pachyonychia congenita, a rare, chronic, and debilitating genetic skin disorder that causes extreme pain and difficulty with walking. PTX-022 is a topical formulation of rapamycin, a drug originally approved to prevent organ rejection after transplantation.


From the beginning of the trial the company implemented home health visits to address the mobility challenges of patients in the study and the disruption to patients and caregivers who would need to travel far to reach a clinical trial site. Visits that could be performed at a patient’s home by a qualified home health worker had already been built into the protocol. The company expanded the number of visits that could be done remotely and amended the protocol to reduce the number of required site visits.


One of the advantages of Palvella’s trial design was that it used a patient-reported outcome as its primary endpoint. Patients in the study kept a diary. That meant the study wasn’t dependent on the patient being in front of an investigator to track information. For blood draws, phlebot- omists were either sent to patients’ homes, or patients went to testing labs near where they lived. The company uses electronic systems for investigator site file management and much of its monitoring capabilities could be moved to remote monitoring visits. While the company did have to make additional investments in technology, it was less than the cost of flying participants to a clinical trial site.


Kathy Goin, vice president of development operations for Palvella, expects that the clinical development changes made to the trial will have a lasting impact on the approach the company takes in future studies. She said the company is implementing more of what she called “21st century ways” of working and getting its trial teams, sites, and patients to embrace them. “We will be pandemic proofing every single trial for the rest of my career,” said Goin. “That will be a topic that will be part and parcel of every trial design that we do. If we need to change the way that we’re working on a trial, how difficult is that going to be?”

Patient Life

While the spate of announcements from drug developers made the disruption to clinical trials visible, much of the impact on rare disease patients was hidden away from public sight. New York City was one of the hardest hit areas in the United State early in the pandemic. When the city began to close schools, steps had to be taken for the many services these institutions provide beyond classroom education. For instance, children from under-resourced families rely on public schools as an important source of meals. Efforts were made to ensure kids in need continued to have access to breakfast and lunch. But one group of children who fell through the cracks created by the pandemic were children with complex medical conditions who rely on schools for ongoing physical, occupational, visual, and speech therapy. These children have detailed individual education programs that are developed in conjunction with their school system to address their needs. But when the New York City schools shut down, Luke Rosen, founder and chair of, said there was no plan put in place for how to meet the needs of children who relied on daily meetings with therapists.


“I realize there’s nothing people could have done to stop this horrible situation and prevent it, but when these executive decisions were made, there was an entire group of people who were left out of consideration and proper planning, and that was children K-12 who have significant medical complexity,” Rosen said. “Many of the them have rare genetic disorders that people don’t know enough about to cure or to treat, but what they do know that as long as we keep doing the therapy, they will keep moving along while we are trying to find that treatment.”


Rosen said there were concerns that many of these children were at risk for losing basic abilities they have struggled to develop and maintain. He likens it to a highway that needs to be well traveled to be kept up. If these lanes go unused, they begin to fall apart. Rosen’s daughter Susannah, who has the rare genetic condition KIF1A associated neurological disorder, had 25 different therapy sessions a week before the pandemic took hold. He and his wife Sally traded off working with Susannah, overseeing their son’s schoolwork, doing their day jobs, and maintaining the KIF1A.ORG foundation. They were able to get a plan from Susannah’s therapist and connect with her through video conferencing for guidance while working with their daughter, but he said other families struggled, particularly one-parent households that couldn’t easily balance the demands of work and the need for caregiving and providing therapy.


When school resumed in the fall of 2020, the situation had not improved significantly. Children with special needs not only continued to face challenges accessing needed services, but the toll of the pandemic on some of them as a result of the hours of lost physical, occupational, and speech therapy led to noticeable regression as abilities they had built showed signs of erosion. Patients also suffered from decisions to put off needed medical visits to monitor progress of their conditions and adjust medications.


“We haven’t heard how we are going to get these services back. There’s just too much uncertainty,” said Rosen, who noted there’s a risk-benefit calculation many people go through as they weigh exposure to professionals and nurses that children may rely on for therapy if work demands prevent parents from doing it themselves. “For somebody who needs that closer-than-six-feet, non-isolated care, it’s difficult, but there has to be a solution. There have to be people caucusing to come up with a solution and that’s not happening.”


The problem didn’t just affect children. Adults who were sheltering in place also lost access to needed treatments and workouts. Tara Voogel, a patient advocate with the progressive muscle disease GNE myopathy who lives near Monterey, California, said she’s been unable to keep up her exercise regimen because of the pandemic. “The condition affects our muscles, our walking, and ability to hold things. With COVID-19, not being able to go out—some of us are unable to drive and we’re afraid to use public transportation because of the infectious aspect of the disease, we are homebound and it is taking a toll on us,” she said. “I can’t go to the gym because the gyms are closed and I’m getting weaker because I can’t do my aqua therapy.”

New Game Plans

Questions remain about how lasting the effects of the pandemic on the world of rare disease will be and whether there are lessons that can be applied from it. One positive has been that the pandemic ignited unprecedented collaboration among academia, industry, and government in the race to develop vaccines and find treatments for the virus. It demonstrated when the will is there, cooperation is possible and barriers can fall. Chris Austin, director of the National Center for Advancing Translational Sciences at the National Institutes of Health, delivered a keynote address during the 2020 RARE Drug Development Symposium, an event organized by Global Genes and The Penn Medicine Orphan Disease Center. He said he has long argued for the need for greater collaboration to tackle shared problems of drug development, but often has heard excuses from one group or another why this or that couldn’t be done. Now, in the face of a global health crisis, Austin said there has been collaboration and data-sharing like he has never seen before.


“Almost overnight, the entire research ecosys- tem started working together as a single team. And what you’ve seen is incredible progress to the degree that the public is worried about the safety of these drugs, which I understand is because this is being developed so much faster and they think that shortcuts must have been taken,” said Austin. “I can tell you shortcuts are not being taken. It’s just all the stupid duplica- tive secrecy and tribalism and siloism that has gone away. And that has to be celebrated. It shows you how much more efficiency we can get if we just act the right way and we could do it tomorrow.”


Many rare disease organizations are moving from thinking about how to adapt to the changing circumstances the pandemic created to considering long-term changes. Todd Tolarico, president of The APS Type 1 Foundation, said his organization has been working through how to engage with its patient community and what it means going forward. At first, he said, his organization’s leadership was a bit overwhelmed dealing with issues their own families faced, but it soon embraced online gatherings and started a monthly Zoom series. “We’re looking at how we stay connected with our community if we can’t meet face-to-face every other year,” he said. “Now it’s, how do we help people understand what the next six months looks like? How do we support our community if there are financial needs? How do we help them to understand the latest research that’s going on for how to care for yourself?”


Many rare disease organizations fear that the financial impacts of the pandemic—one of the most immediate impacts for them—may be among the most lasting. Organizations that relied on public events as their central source of funding are rethinking how they raise money. Some are also bracing for a protracted economic downturn that can make it harder to attract donors. Jennifer Sills, president and founder of CSNK2A1, which is focused on the rare, genetic disorder Okur-Chung neurodevelopmental syndrome, said her organization was forced to cancel its annual golf tournament, its largest annual fundraiser. She had expected the organization to raise $300,000 this year through the event. People who had already signed up let the organization keep their money, which allowed them to raise about half of what was expected. Now, as she braces for an extended economic downturn, she expects the organization will face a harder time raising money.


“It’s not just the immediate impact, but it’s also the longer-term impact of having to now make up the deficit in a worse economy. We’re going to have to figure out how to work on a much leaner budget,” said Sills. “The resilience and ingenuity that rare disease organizations are going to have to employ during this time by using their boards and finding other patient groups to partner with is going to determine their success.”

Gauging the Pandemic’s Toll on Clinical Trials

Though a steady stream of press releases from drug developers made it clear that the COVID-19 pandemic was disrupting many clinical trials, it was Benjamin Gregory Carlisle who tried to quantify the actual impact. Carlisle, a research fellow at the Berlin Institute of Health, in an early draft paper of ongoing research published online, found that of 2,522 clinical trial entries on for trials that have been suspended, terminated, or withdrawn between December 1, 2019 and May 5, 2020. Of those, 1,099 (44 percent) mentioned COVID-19 in a provided explanation for why the study had stopped.


The studies that stopped due to COVID-19 had a combined actual enrollment of 39,405 patients and anticipated enrollment of more than 4 million patients. For a comparator arm, Carlisle broke down the number of stopped trials during the same period two years earlier. There was a total of 1,233 trials halted during that time.


One notable difference between the two groups is that 97 percent of the trials that had stopped because of the pandemic were suspended rather than terminated or withdrawn. That compared to just 18 percent of the trials in the comparator arm. Most of the trials stopped in the comparator arm were either terminated (47 percent) or withdrawn (34 percent). That, however, may change.


“While many clinical trials were suspended with the intention of restarting after the COVID-19 pandemic,” wrote Carlisle, “the prospect of starting again is far from certain for any clinical trial that has stopped, and even in cases where a clinical trial resumes after the pandemic, there may be reduced statistical power, more funding needed, or changes to the protocol to accommodate for the interruption.”


Carlisle doesn’t identify the number of rare disease trials affected by the pandemic, but he does offer a breakdown by broad indication. This includes 125 cardiovascular studies (11 percent), 93 neurologic studies (8.5 percent), and 308 oncology studies (28 percent). Among the clinical trials that were stopped with a reason citing Covid-19, 504 trials were testing drugs or biologics. The remainder were testing procedures, devices, behavioral interventions, laboratory analyses, diagnostic tests, or other things.


For patients who were enrolled in studies, Carlisle notes they may not receive the treatment they had anticipated, and they may not make the contribution to advancing medical knowledge as they may have hoped. He noted the pandemic has also caused a setback for entire research programs and could delay the advent of new therapies.


While the human and economic toll of the pandemic have been apparent, the impact on biomedical research has been obscured and the extent of the damage remains an open question. One reasonable bet is that the longer it takes to restore trials, the more lasting the impact will be.


“Clinical trials that were stopped and do not start again may be unable to answer the questions they set out to answer,” writes Carlisle, “and even in cases where they do start again, it may take greater resources to make up for data that can no longer be included in analysis due to the interruption.”

Solving a Research Problem with a Middle School Lab Assignment

Mutations in the SYNGAP1 gene cause learning disabilities, epilepsy, autism, behavioral challenges, and sensory processing disorder; but one aspect of
the condition that researchers are trying to understand is the way the condition slows the movement of food through the intestines.


Researchers at the University of Miami and Joe DiMaggio Children’s Hospital were embarking on a study to try to unravel the neuro-gut connection in SYNGAP1. When the pandemic hit, Bridge the Gap – SYNGAP Education and Research Foundation had to cancel a planned meetup in Miami, where the study was going to take place. The question was, how to take the study virtual.


One of the things the researchers wanted to determine was the speed at which food moved through a child with the condition, as one of the symptoms of SYNGAP1 is constipation. Using radioactive tracers wasn’t an option. That’s when Monica Weldon, founder, president, and CEO of Bridge the Gap, had an idea.


Weldon, who used to teach science in middle school, recalled a lab she had done with students that allowed them to see how quickly a cupcake that they ate moved through their system. The cupcake had icing that was colored with a blue dye that didn’t break down as it moved through the digestive track and was visible when it reached the end of the line.


Researchers liked the idea, but now the challenge was to use a dye that met FDA standards and a recipe that used a precise mixture of sugar and fat for the experiment. Mixing the dye into an icing couldn’t be done because it required the use of too much sugar. The final solution was an angel food concoction dubbed “Smurf cakes” because of their blue complexion.


Patients’ families will be equipped with an app on their cellphones to record the child eating the Smurf cakes and when it is expelled. But conducting research during a pandemic can lead to many unexpected complications.


The group had contracted a bakery to make the Smurf cakes for the experiment and ship them to participants in the study. But because of the pandemic, the bakery has since shut down and the group at the time of writing was seeking a new bakery.

Keeping Research Going During the Pandemic

While the COVID-19 pandemic forced many rare disease research projects to come to a sudden halt, some organizations found that with a little quick maneuvering they would be able to keep their work going. For Luke Rosen, founder and chairman of the KIF1A.ORG, one solution was to turn to contract research organizations to take over things academic research centers were unable to do in the face of the pandemic.


“Our research did take a hit in some ways,” said Rosen. “In other ways, we actually accelerated to a place where we would not have been had it not been for the challenges that came out of COVID and the panic surrounding that.”


KIF1A.ORG had gathered blood samples during a family conference in 2019 and researchers at Wendy Chung’s lab at the Clinical Genetics Program at New York–Presbyterian Hospital / Columbia University Medical Center in New York City were in the process of creating cell lines for therapeutic developers to use as part of the organization’s research initiatives. The group was completing its longitudinal history study with Chung’s team. It was also in the process of developing reagents, assays, and other assets that it needed to advance research into the disease.


When the pandemic hit, the research efforts at Columbia University took a hard hit being at the heart of the outbreak in New York City. Medical staff needed to be enlisted to treat patients and the lab was forced to shut down as part of precautions to contain the spread of the virus. Suddenly KIF1A’s mouse model and cell lines were all in jeopardy.


Rosen was able to reach out to the Coriell Institute for Medical Research, which operates a cell bank. The institute was able to work with the Columbia researchers to take over the cell lines and continue their work. That collaboration is ongoing as researchers at both institutions are now building out a bigger library of the cell lines.


At the same time, Cathleen Lutz, whose lab at the Jackson Laboratory develops mouse models, worked with Chung’s team at Columbia to ensure that mouse experiments continued while Chung’s team continued to work on the natural history remotely and successfully completed a manuscript about the disease. The group had also identified the need for a recombinantly expressed mutant protein underlying the disease. Because the academic labs were still trying to get back up and running fully, Rosen turned to Albany Molecular Research Institute, which went to work to produce the protein at a much greater volume than would have been possible in an academic lab.


Rosen reached out to the contract the research organization PRA Health Sciences for advice on how his organization might be able to use digital tools to maintain participation of its patient community in data collection from their homes for the organization’s longitudinal study. And, as one of the Chan Zuckerberg Initiative’s Rare As One initiative’s recipients, KIF1A.ORG was able to begin a monthly research roundtable with 19 researchers involved in working on different aspects of the disease to discuss what they were working on, what tools they had, what mouse models they were using, and what strategies they were pursuing.


“We were luckier than some,” said Rosen. “I know that there’s rare disease research that’s just set back beyond repair.”


Research: Mothers of Invention


When Sandra Bedrosian-Sermone’s son Tony in 2014 became one of the first people in the world to be diagnosed with ADNP syndrome, a complex neurodevelopmental disorder that can affect multiple systems throughout the body, there was not much known about the condition. It had only recently been discovered and there was just a single paper that existed in the medical literature. There were no doctors who knew about the disease that she could turn to for information. Medical protocols, support groups, treatments, or even a patient group with a website didn’t exist. In fact, at the time, the condition didn’t even have a name.


“They basically handed me a piece of paper with an ultra- rare genetic mutation on it and sent me on my merry way,” she said.


In July 2020, the Seaver Autism Center for Research and Treatment at Mount Sinai began recruiting participants for a phase 2a clinical trial to evaluate a low-dose of the powerful anesthetic ketamine as a treatment for children with ADNP syndrome, thanks in large part to the efforts of Sermone and Matt Davis, the father of another child with ADNP syndrome.


Sermone may seem like an unlikely rare disease researcher, having been a stay-at-home mom whose formal education culminated in her earning a GED, but the work she has done in ADNP includes creating a parent- generated patient registry that led to her collaboration with researchers. She identified the first biomarker for the condition, co-authored five papers in peer-reviewed scientific journals, has been sought out by scientific journals to review others’ papers on the condition, and has even filed for a patent for the use of ketamine as a potential treatment for ADNP syndrome. The story of how the clinical trial came about is testament to the impact people with rare diseases and their families can have on advancing research and identifying potential treatments when they are driven to do so.


Sermone had been working to get an Israeli drug company to begin testing an experimental drug as a potential treatment for ADNP. The company was exploring broader indications for the drug and delayed clinical studies of its possible use for ADNP. Sermone grew frustrated by the delays and decided to begin efforts to find candidates to repurpose as a treatment for the condition. She discussed the idea with Davis, who not only has a child with ADNP, but is a physician in the department of neurosurgery at the University of Alabama at Birmingham.


Through her effort to find a diagnosis and treatment for her son, Sermone came to know Matt Might, the father of a child with a different rare disease. Sermone’s son was diagnosed after a long odyssey when physicians at Duke University identified the gene that was driving his condition. Might’s son had been diagnosed at Duke about three months before Sermone’s son Tony, and she had run into Might at sever- al rare disease conferences where she would often prod him for advice. It so happened that Might had taken a new job and was now director of the Hugh Kaul Precision Medicine Institute at the University of Alabama, where he had been developing MediKanren, an arti- ficial intelligence system that scours millions of published research papers to find potential drugs that could be repurposed to treat rare diseases.


Repurposing, an effort to find new uses for existing drugs, is a strategy that has been embraced in the rare disease community because it offers a faster and less expensive path than traditional drug discovery and development to finding treatments for rare diseases. With Might now at the University of Alabama, Davis went to talk to him and asked if he could see what the system could turn up as potential treatments for ADNP. Might turned over a list of potential candidates and Davis and Sermone began investigating the results.


As Sermone and Davis started reading through scientific publications to explore the candidates that they had in hand, they found evidence that low-dose ketamine could be a viable candidate to treat ADNP. Ketamine at high doses destroys neuronal cells, but at low doses it is neuroprotective and increases expression of the ADP protein, something that could benefit people with ADNP. Sermone had a meeting at Mount Sinai in New York and brought up the idea of ketamine. A month earlier a new version of ketamine had won approval as a therapy for treatment-resistant depression and there was talk about other potential uses. It was suddenly being viewed as a wonder drug. When she mentioned the drug to the team at Mount Sinai, she was met with skepticism. She had not brought any data with her and she sunk into her chair.


After that experience, she and Davis did extensive research through medical literature to build a case for the drug. They spent months researching it, reading through hundreds of pages of medical literature, speaking to scientists, and collecting data. They filed for a patent on the use of ketamine in ADNP syndrome and then Sermone called Alexander Kolevzon, the director of the Seaver Autism Center at Mount Sinai, and presented their findings. Kolevzon brought it to his team, and they recognized the possibilities and moved with speed to begin a clinical trial.


“If we can replicate the increase in ADNP protein production in humans, it could be a major breakthrough to help reduce negative effects of this devastating disorder,” Kolevzon said when the trial was announced in July 2020.


The phase 2a study is the first clinical trial for ADNP syndrome. The open-label study is testing a single low-dose infusion of ketamine for 40 minutes. The Seaver Autism Center said it planned to enroll 10 participants, ages 5 to 12, at The Mount Sinai Hospital. Participants will be monitored for four weeks. At each clinic visit, participants will undergo safety monitoring, clinical evaluations, and biomarker studies using electrophysiology and eye tracking.


“I joke that I’m a top graduate of the Google school of medicine,” said Sermone. “I would tell other families, ‘There’s hope, but you have to light the fire.’ You have to continue creating and building these networks of researchers who are interested in your kids.”

Parents Driving Research

While there are several mature rare disease patient organizations that have built extensive research programs that are reshaping the therapeutic landscape for their conditions, small organizations with little resources have shown the power they can have to find therapeutic options for a rare disease by studying medical literature, challenging assumptions, and being persistent.


Sermone and Davis were not the only rare disease advocates to see their efforts result in a clinical trial in 2020. At the end of February, Harmony Biosciences initiated a clinical trial of its narcolepsy drug pitolisant as a potential treatment for patients with the rare disease Prader-Willi syndrome, a complex genetic condition characterized by obesity, excessive hunger, and low muscle tone. But it was the work of Lara Pullen and Maria Picone, mothers of children with Prader-Willi syndrome, who identified and documented that pervasive sleepiness is an often-neglected symptom of Prader-Willi. They made a scientific case for why the mechanism of action of pitolisant could potentially benefit people with the condition.


The phase 2 study to evaluate the safety and efficacy of pitolisant in patients with Prader-Willi syndrome includes an 11-week double- blind treatment phase (including a 3-week titration period and an 8-week stable dose period), and an optional open label extension phase. Investigators were readying to enroll 60 patients ages 6 to 65 years but hit the brakes on the study because of the COVID-19 pandemic. Harmony said it would begin the study once the impact of this pandemic begins to subside, to ensure the trial can be completed under the rigors required by the protocol, including completing inpatient study procedures at the investigative sites.


Pullen, founder and president of the rare disease advocacy organization Chion Foundation, holds a doctorate in immunology. When her child was diagnosed with Prader-Willi syndrome, she took a deep dive into the medical literature and found that widespread notions of the disease were incomplete when measured against the data in published studies. Endocrinologists have typically been used to treating Prader-Willi because of its hallmark associations with intense appetite, diabetes, and obesity. But it is a complex condition that involves muscle weakness, developmental and intellectual disability, sleep apnea, and daytime sleepiness. Everything Pullen read pointed her back to the nervous system. One thing that caught her attention was that the histamine 3 receptor, which is found in the brain, plays a role in regulating sleep and wake states, hunger, alertness, anxiety, and REM sleep. The more she read, the more she was taken by how role of the histamine 3 receptor aligned with different problems in Prader-Willi patients.


“There is no denying that hunger and obesity are problems in the PWS community,” said Pullen. “The thing is that the pharmaceutical community has not yet been able to deliver a drug that relieves those symptoms of PWS and improves the quality of lives of patients with PWS and their families. We think that a different strategy, tackling sleepiness, may be able to achieve all of those goals.”


Pullen believed Prader-Willi syndrome symptoms were similar to what is seen in narcolepsy with cataplexy, a rare condition involving daytime sleepiness, and sleep apnea. She reasoned that pitolisant, which targets the histamine 3 receptor and had been approved by European regulators in 2016 as a treatment for narcolepsy, might benefit people like her son.


Pullen’s case for pitolisant strengthened by the work of TREND Community, a platform for scouring patient insights from social media, which found an alignment between Prader- Willi syndrome and the symptoms of daytime sleepiness. Picone, co-founder and CEO of TREND Community, has a daughter with Prader-Willi syndrome.


“We analyzed caregiver conversations from closed Facebook groups and our findings val- idated Lara’s hypothesis. The PWS community frequently discussed issues related to sleep,” said Picone. “In fact, terms associated with sleep were used far more often than terms for hunger.”


Pullen obtained a prescription for the drug from her son’s physician, purchased it in Germany, and brought it into the United States under a personal importation route allowed at the FDA’s discretion. She enlisted other families to do the same. The families agreed to document their experience using the TREND Community platform, which allowed caregivers to track and report on their experiences using pitolisant.


Pullen, Picone, and others published on the experience with the drug in a clinical vignette in the March-April 2019 issue of the Journal of Pediatric Pharmacology and Therapeutics. They reported that pediatric patients with Prader- Willi who used pitolisant had decreased daytime sleepiness and improved cognition. They suggested the drug had the potential to relieve symptoms associated with the condition. They managed to convince Harmony Biosciences, which won FDA approval for the drug as a treatment for narcolepsy in August 2019, to study it in Prader-Willi. They did an early study to determine appropriate dosing and in December 2020 resumed enrollment in the phase 2 study.

Enabling a Breakthrough, Advancing a Treatment

For Leslie Gordon, efforts to find a treatment for Hutchinson-Gilford progeria syndrome culminated in the 2020 approval of Eiger Biopharma- ceutical’s drug Zokinvy, the first drug approved for the ultra-rare condition. Progeria is a fatal genetic condition that causes premature aging. The manifestations of progeria include growth failure, loss of body fat and hair, aged-looking skin, stiff joints, hip dislocation, and cardiovascular disease. Most patients die before the age of 15 years from heart failure, heart attack, or stroke— conditions typically associated with old age.


Gordon, a physician researcher in pediatrics, and her husband Scott Berns, an emergency room pediatrician, had never heard of the disease when doctors diagnosed their son Sam with the condition in 1998. He was less than 2 years old at the time. Doctors told Gordon and her husband that there was nothing they could do. They didn’t know what caused the disease, and they said it was fatal.


“My husband and I dropped everything as any parents would and tried to find out more about progeria. What could we do? Where was there to go? How could we, you know, find out more? What was the research out there? And essentially there was no research going on,” said Gordon. “There were very few people doing anything for this disease. There was no organization where we could even find other parents. So, we decided to start our own.”


In 1999 she and her husband founded the Progeria Research Foundation and Gordon served as its medical director. They not only set out to raise money to fund research, but to understand what researchers needed to advance an understanding of the disease and find treatments and a cure. She began by reaching out to scientists and clinicians to see what they needed to conduct research into the disease. As a result, they created an international progeria registry, developed a medical research committee, established grants to bring scientists into the field, and banked cells and tissue samples for researchers to study.


Research Foundation, which funded a series of clinical studies to explore its use in progeria.


What made lonafarnib a potential treatment for progeria is that it is a farnesyltransferase inhib- itor. In simple terms, it works by inhibiting an enzyme that is involved in the biological pathway that leads to the production of the mutated pro- tein progerin. In November 2020, the FDA grant- ed Eiger Biopharmaceuticals approval to market lonafarnib under the brand name Zokinvy.


The approval was based on a study in 62 patients from two single-arm trials that were compared to patients in a separate natural history study. It showed the lifespan of patients treated with Zokinvy increased by an average of three months through the first three years of treatment and by an average of 2.5 years through the maximum follow-up time of 11 years.


Though Zokinvy is not a cure, its approval provided the first treatment for the condition. In addition, it will help advance future research because the FDA granted the drug a Rare Pediatric Disease designation and awarded Eiger a priority review voucher when the drug was approved. The voucher allows the holder to use it to cut the review time of an application for the approval of a drug to six months from 10 months. Eiger sold the voucher for $95 million, half of which goes to the Progeria Research Foundation and will help it advance its research agenda.


Gordon’s son Sam died in 2014 at the age of 17 from complications from progeria. Even with the approval with Zokinvy, she continues to work to find better treatments and a cure. “This will be a great infusion for the Progeria Research Foundation’s efforts towards the mission,” she said.


She noted that in the case of Zokinvy, which was repurposed, there were many studies that had been done before the Progeria Research Foundation became involved and there was much known about the drug. Now, though, with funding in hand, the organization can pursue promising earlier stage opportunities. “There are other potential treatments and cure strategies that can be developed,” she said. “The Progeria Research Foundation can now make great efforts to delve into those arenas. We can invest in that science in order to bring promising drugs and drug strategies forward.”

Zeroing in on Pathogenic Genes

The diagnostic rate of large-scale sequencing programs is somewhere between 20 percent and 40 percent. The reason most rare disease patients remain undiagnosed is because the underlying genetic cause of their condition can be difficult to identify if mutations in culprit genes are not already known to cause a rare disease.


Researchers at the International Mouse Phenotyping Consortium published a study in the journal Nature Communications5 in January 2020 that suggests a way to help identify genes involved in rare diseases. They have created an open-access resource that can be used to identify genes that when mutated would be most likely to cause
a rare disease. They said this would allow clinicians and researchers to better draw connections between candidate genes and previously undiagnosed cases.


In the study, the scientists integrated measures of how essential a gene is to supporting life using viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium. They also performed screens on human cell lines to determine how essential genes were to cell survival. It created a cross- species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and showed that genes in five mutually exclusive FUSIL categories have differing biological properties.


They found Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development.

Gene Editing Method Leads to Historic Nobel Win for Two Women

The Royal Swedish Academy of Sciences in 2020 awarded the Nobel Prize in Chemistry to Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens in Berlin and Jennifer Doudna of the University of California, Berkeley for their discovery of a method for genome editing. They were the first two women to share the prize.


The two scientists discovered CRISPR/Cas9, a bacterial enzyme that can be harnessed to make precise changes to the DNA of animals, plants, and microorganisms.


The discovery has been called the most important biological advance since the discovery of the structure of DNA and is already changing the way scientific research is conducted while opening up new therapeutic approaches to treating people with rare diseases with the potential to correct the genetic errors that drive them.


“There is enormous power in this genetic tool, which affects us all. It has not only revolutionized basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” said Claes Gustafsson, chair of the Nobel Committee for Chemistry.


Charpentier, who was studying the harmful bacteria Streptococcus pyogenes, discovered a previously unknown molecule, tracrRNA. She showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/ Cas, that disarms viruses by cleaving their DNA. Charpentier published her discovery in 2011.


That same year, she initiated a collaboration with Doudna, and they succeeded in recreating the gene editing abilities in a test tube and simplified the molecular components to make them easier to use. They then reprogrammed the molecules and showed that they could be controlled so that they can cut any DNA molecule at a predetermined site. Once the DNA is cut, it is then easy to rewrite.

Harnessing Data to Advance Rare Disease Diagnosis and Treatment

A group of patient organizations, academic researchers, and other rare disease stakeholders have launched RARE-X, which is expected to become the largest data sharing initiative focused on rare disease. The grant-supported nonprofit was created to accelerate the diagnosis and treatment of diseases through collaborative efforts to gather, structure, and share critical patient data.


“Patient data is the fundamental element needed to drive innovation in rare disease, but data does little to advance progress if it’s not accessible to researchers, inadequately formatted, or incomplete,” said Nicole Boice, co-founder and executive director of RARE-X and founder of Global Genes. “RARE-X is working to remove one of the greatest obstacles to progress in the area of rare diseases by eliminating barriers for patients to gather and responsibly share research- ready data with scientists, drug developers, and clinicians.”


The RARE-X collaborative data platform provides a means for patient organizations to share patient registries, natural history studies, genomic information, electronic health records, and other data with researchers, clinicians, and drug developers. The platform and support services will be provided free of charge to patient organizations to ensure that they can gather the right data, and share it without many of the burdens that can impact patients’ willingness to participate in studies.


In addition to patient-owned data collection efforts, RARE-X is building a federated data sharing platform. Federated data systems allow users to draw results from multiple databases at once through a single query, but owners of the data store their own data and control who has access to it. Doing so will interconnect data from various sources that until now have been siloed. That is expected to accelerate discovery by providing opportunities for researchers to look across diseases, disease types, phenotypes, genes, and treatments.


“Federating Data has been desired for years within the research community. The reason it hasn’t happened yet is that it is hard to do, and industry has been trying to monetize it,” said John Wilbanks, chief commons officer at Sage Bionetworks. “Bringing forward an open federated data sharing effort is the right thing to do for rare disease patients and researchers, and having it be driven by a patient focused non-profit is the right approach. This will be transformative.”


Several patient communities are already operating on the RARE-X data collection platform and the organization is embarking on an initial set of phase I programs that are intended to demonstrate all aspects of the platform, while working on the necessary additions to scale and support the unique needs in rare disease. RARE-X’s goal is to have hundreds of rare communities and other stakeholders gathering and sharing data through the RARE-X platform by the end of 2021.


“This initiative significantly changes the outlook for patient communities wait- ing for treatments,” said Matt Might, director of the Hugh Kaul Precision Medicine Institute at the University of Alabama Birmingham. “RARE-X gives patients everywhere the opportunity to become central drivers of progress in their disease and makes every- one—researchers, drug developers, and everyone else in the system who are working on their behalf— be more effective.”

Necessity and Other Mothers

Patient advocates have not only found potential treatments for repurposing, but they also drive fundamental research in new ways. Terry Jo Bichell had been a licensed nurse and board-certified midwife when she gave birth to her fifth child Lou. She kept telling her pediatrician that there was something wrong with Lou, who had trouble feeding and communicating with her, but the doctor dismissed it. He told her she was being neurotic. “It’s your first boy,” the doctor said, “and boys are different than girls.”


As Bichell and her husband continued to search for answers about Lou, a friend who was a geneticist looked at the baby over drinks and told the couple the child had facial characteristics consistent with a genetic disorder. The couple had a book about congenital malformations in newborns and had been flipping through the pages. Every time they came to the page about Angelman syndrome they would stop. The author of the book was a geneticist who happened to live in their town, and they reached out to him. He took one look at the happy and laughing child, placed a tuning fork on the 15-month- old’s knee, and watched him explode with laughter. He ordered a single test for Angelman syndrome, which confirmed the child had the condition.


Angelman syndrome is a neurological disorder. Children with the condition often smile, laugh, and are excitable. People with the condition have developmental delays, balance issues, motor impairment, and seizures. Some people with Angelman syndrome are unable to walk and most do not speak.


Bichell became a visiting scholar at Vanderbilt University and a co-investigator and coordinator of the Rare Disease Clinical Research Network. There she had access to researchers and would try to engage them on finding therapies for Angelman syndrome. There had been a few small trials to repurpose high-dose vitamins to treat the condition, but Bichell argued for a high-throughput drug screen to find potential treatments, something she couldn’t interest anyone in doing.


“Whenever I would talk to researchers and try to get them interested in looking at treatments, most of them felt that I was just crazy,” she said. “I realized that the only way I was going to be able to get some kind of a high-throughput drug screen done was to do it myself. And that would mean that I needed to just put my money where my mouth is and go back to school and just do it.” That’s when Bichell decided to get a doctorate in neuroscience at Vanderbilt.


Though others ran the type of drug screen Bichell had hoped to do before she had her chance, and several antisense oligonucleotides entered the development pipeline, Bichell came to see another need. While potential therapies were being identified, there wasn’t a good way to figure out how to measure whether those drugs worked. Bichell was soon drafted to lead the Angelman Biomarkers and Outcome Measures Alliance (A-BOM), an effort by the Foundation for Angelman Syndrome Therapeutics and the Angelman Syndrome Foundation. That effort, which has involved patient organizations, academic institutions, and industry, has been a success. Bichell eventually left the organization, but its work continues.


Now, though, Bichell is taking the A-BOM model and broadening it to include a wide number of genetic, non- verbal neurodevelopmental disorders, and pooling efforts, studies, and data. At the start of 2020, she announced the launch of COMBINEDBrain (Consortium for Outcome Measures and Biomarkers for Neurodevelopmental Disorders). “We want to help these Angelman-like disorders pave the way to clinical trials by using similar wheels, not new wheels,” she said. “I’m against remaking wheels.”


Many of the people interested in seeing therapies for rare neurologic disorders face similar hurdles. They need help with natural history studies, they may lack an animal model for their disease, and may need to identify biomarkers and outcome measures for use in clinical trials. COMBINEDBrain, a collaboration of more than a dozen patient advocacy foundations focused on genetic neurodevelopmental disorders, seeks to address obstacles to drug development for these conditions by collaborating, and sharing resources, tools, and experts. The hope is to de-risk therapeutic development by grouping together disorders with similar symptoms, aligning questions in natural history studies so that data can be compared, getting researchers and physicians to engage across conditions, and organizing studies to address more than one condition at a time.


COMBINEDBrain’s initial efforts are focused on creating a common data management system that can be shared across these disorders. It is also making sure the people running natural history studies are asking the right questions and working to ensure there is robust translational science that will allow potential therapies to advance to the clinic. The organization is also conducting a survey of the field to understand what biomarkers and outcome measures exist for severe neurodevelopmental disorders.

“I needed to just put my money where my mouth is and go back to school and just do it.”

As with A-BOM, the model to support the operational expenses of COMBINEDBrain is through membership fees. The base membership of the consortium consists of patient organizations, but COMBINEDBrain is now expanding that to include academia and industry. Grants are expected to fund scientific work.


Diagnosis: A Move from Art to Science


Health authorities, rare disease organizations, and scientists are quick to put a number to the universe of rare diseases—typically 7,000 but often ranging between 5,000 and 8,000. The truth is there is not agreement. Even though it has also been said for many years that some 250 new rare diseases are identified each year, the oft-quoted number doesn’t seem to budge. It’s a number that’s been traced back, in part, to the debate over the Orphan Drug Act of 1983, but nearly 40 years later, it is still widely used. Though it may seem like an issue of little consequence, it highlights fundamental challenges underlying the diagnosis of people with rare diseases.


The differing definitions of what constitutes a rare disease from country to country, how individual rare diseases are characterized, and the language used to describe them reflects a lack of clarity that impedes the ability to diagnose these conditions with speed and confidence. Diseases have long been defined by a description of their clinical features. But today, they can be defined with much greater precision around a data model, according to Melissa Haendel, professor at Oregon Health & Science University in the Department of Medical Informatics and Clinical Epidemiology.


Haendel is principal investigator of the multi-institution Monarch Disease Ontology Initiative (MONDO), which is seeking to create a common language for describing and defining individual rare diseases. Not only could that help bring clarity to the often fuzzy definitions used for rare diseases today, but doing so could provide a roadmap for diagnosis of any given condition and help make the process of determining what condition a patient with a rare disease has less of an art and more of a science.


MONDO uses an algorithm to assign a probability score that different diseases are actually the same, and then researchers manually curate the information to make a determination. In looking at the five most widely used databases of rare diseases, MONDO found that there are only 347 diseases that are common to all. MONDO has found some rare diseases with different names in these databases that are describing the same condition. Perhaps more surprising is that the researchers identified many instances where diseases called by the same name in different databases are describing different diseases. Though MONDO continues to refine its work, it believes there are more than 10,000 unique rare diseases that it has identified.


“One of the reasons that there are so many more diseases than we had originally realized in MONDO is because of this problem that people have a fuzzy way of defining diseases,” said Haendel. “When you look more closely, you realize there’s a lot of ones that are actually not the same.”


Each of the rare disease databases define diseases in their own way. For instance, ClinVar captures information about rare diseases by variants, but doesn’t say anything about the phenotypic features (although it is starting to do so). The Online Mendelian Inheritance in Man (OMIM) site captures disease to gene associations. The Monarch Initiative’s Human Phenotype Ontology annotation file captures disease to phenotype associations. And the Comparative Toxicogenomics Database captures information about diseases and environmental exposures.


“Everybody’s curating a different part of this model and that’s just bonkers because it reflects each one of those sources’ idea of these diseases,” said Haendel. “If I had one disease, it means something different in the context of ClinVar than it does here because I don’t have the full picture. It’s not to say that the sources are dumb. They’re just focused on particular aspects of their view of disease because there’s no standard for how to represent the whole disease.”


While each database is capturing a view of rare disease that is important to the communities that they serve, Haendel said a holistic picture and standards are needed for diagnostic and discovery tools. While each of these sources continue to curate the information that they do, Haendel hopes they come to a common definition for each disease. For instance, when a new genetic variant is discovered to be associated with Huntington’s disease, the other forms of Huntington’s should still be defined according to the other features of the disease in a computational manner.


“At the end of the day, if you use only one of these terminologies and only parts of these models, you could end up with a different diagnosis. There’s a lot of manual due diligence on the part of clinicians to make sure that doesn’t happen, but it’s certainly not helpful in that the computational tools that you’re using  for the diagnostics are giving you different answers,” Haendel said. “I’d like to get everyone behind this idea of a shared model and a shared community resource that we all work on together so that the different groups are contributing different information, but it all fits together more neatly.”


In October, the National Institutes of Health established a new Center of Excellence in Genomic Sciences to create tools to improve the way medical information about genetic conditions are captured, stored, and exchanged. The new center is backed with $10 million in funding, led by Haendel, and includes collaborators Lawrence Berkeley National Laboratory, Johns Hopkins University, The Jackson Laboratory for Genomic Medicine, Queen Mary University of London, and the European Bioinformatics Institute, all of whom are involved in the MONDO Initiative. The Center of Excellence is being housed at the Oregon State University’s newly established Translational and Integrative Sciences Center.


The researchers will use the emerging field of phenomics, which aims to encode, integrate, and analyze the observable characteristics or traits of an organism. They will use model systems to derive insights. One of the goals of the project is to organize knowledge about rare diseases so that a doctor can access it and understand it without having to be an expert on the condition.


“Without unifying standards, the knowledge from the data that is being amassed just cannot reach its full potential,” said Julie McMurry, associate director of the center. “It can’t reach its full potential for patients. It can’t reach its full potential for doctors. And it certainly can’t reach its full potential for people trying to understand any underlying biological mechanisms.”

The Power of Sequencing

While many people with a rare disease still face a protracted diagnostic odyssey, for newborns with certain genetic diseases, a rapid diagnosis can allow for life-saving treatments and interventions before irreversible damage can occur. Rady Children’s Institute for Genomic Medicine in June 2020 completed a two-year pilot project with the state of California that demonstrated its use of rapid whole genome sequencing in real world hospital neonatal and pediatric intensive care units can improve outcomes and save money.


“There are a lot of critically ill children in the hospital who don’t have a diagnosis, and it’s not clear exactly why they’re sick,” said Lauge Farnaes, who had been assistant medical director for Rady Children’s Institute for Genomic Medicine during the study. “Traditionally, whole genome sequencing has been the testing of last resort because it’s relatively expensive. What we wanted to do was show that doing the most comprehensive test upfront to help identify if there’s a genetic cause to why these children are sick is not only the right thing to do in terms of providing better care to the patient, but it’s also the right thing to do economically.”


Rady Children’s has used whole genome sequencing to diagnose babies and children hospitalized in intensive care with rare diseases  since July 2016, but only as part of clinical trials. In 2018, the state of California committed $2 million to Project Baby Bear, a pilot project involving five hospital systems in California, to see if the use of rapid whole genome sequencing would benefit Medi-Cal infants who were critically ill. Until the initiation of Project Baby Bear, though, whole genome sequencing was not covered by insurance or Medi-Cal and was available only through clinical trials paid for by research grants or philanthropic donations.


Stephen Kingsmore, president and CEO of Rady Children’s Institute for Genomic Medicine said research studies over the past eight years have consistently shown that children in intensive care units benefit from rapid genome sequencing, but they wanted to show the technology was ready for everyday use outside of a research study at multiple sites. “That was an open question,” he said. “Sure. It’ll work at Rady Children’s where we have a highly trained staff used to using this technology, but what about the real world? That was the question that we set out to answer.”


Over the 23 months of the study, the five participating hospital systems completed rapid whole genome sequencing on 178 families and babies. Samples taken from the hospital were sent to Rady, where they were sequenced and analyzed. The effort provided a diagnosis for 76 babies (43 percent) and led to changing the management of 55 babies (31 percent) that reduced their days in the hospital, and lessened procedures or use of new therapies. The median turnaround time for provisional sequencing results was three days. Some 35 babies who were diagnosed had conditions that occur in less than 1 in a million births, according to a final report on the project.


The use of rapid genome sequencing resulted in 513 fewer days in the hospital, 11 fewer major surgeries, and 16 fewer invasive diagnostic tests. That helped to create overall savings from the pilot study of more than $2.5 million.


As an example of the power of the technology to improve outcomes for patients, Kingsmore pointed to the case of a baby who was born with a slow heartbeat at Orange County Children’s Hospital. The hospital had just begun the program and the doctor ordered the rapid whole genome sequencing and the infant was discharged. Rady sequenced the blood sample and diagnosed the child with Timothy syndrome, a genetic disease that typically leads to sudden infant death syndrome.


“That child’s slow heart rate was not just a benign finding. It actually signaled the fact that she was at high risk of developing a malignant heart disorder that would kill her,” said Kingsmore, who explained they were about to bring the infant back and implant a device that would prevent her from suffering from a life-threatening heart rhythm disorder. “The likelihood that would have been picked up is zero. It was not on anybody’s differential diagnosis list. In fact, the doctor in charge of the PICU there told us he’d never actually seen it before. They regarded this as basically a lifesaver.”


Kingsmore said he wants this to be used as part of the initial battery of tests that are ordered on critically ill babies rather than a test of last resort after everything else has failed to provide answers. “That’s a mindset change we still need to facilitate for them to bring it to the front of their mind,” he said.


While payers have been one of the obstacles to expanding the use of sequencing as a clinical diagnostic tool, that’s beginning to change. In March 2020, Blue Shield of California became the first health plan in the United States to cover rapid and ultra-rapid whole genome sequencing for critically ill babies and children in intensive care with unexplained medical conditions. “We know that uncertainty and long testing wait times can create tremendous risks for children in intensive care, and anxiety for their families, all the while creating more challenges for physicians and specialists,” said Terry Gilliland, executive vice president of Healthcare Quality and Affordability at Blue Shield of California. “By providing our members with access to Rady Children’s Institute for Genomic Medicine’s pioneering work in rapid whole genome sequencing, we’re supporting them in what is often the most difficult time in their lives.”


Outside the United States, whole exome sequencing is being used to diagnose critically ill babies and children. Whole exome sequencing looks at only the protein- coding regions of the genome. It looks for and can identify a range of potentially life- threatening conditions through a single test, rather than standard tests that usually are limited to looking for indicators of a specific condition. England’s National Health Service said it is providing whole exome sequencing to diagnose critically ill babies and children, a decision it says will double the chance of a diagnosis for a child. It is also faster than the standard practice of using multiple tests, giving parents of seriously ill children results in days rather than months.


In January 2020, the National Health Service reported that 80 babies and children have received this new test, with almost half being given a diagnosis for their rare disease. Up to 700 babies and children are expected to benefit from the testing each year. The effort is part of the NHS’ Long Term Plan, which includes a commitment to harness the power of DNA mapping. The testing can detect rare neurological, metabolic, or other conditions by identifying genetic mutations, and helps to show which patients are unlikely to respond to treatments. That, NHS said, also saves on the unnecessary use of medications and avoids potential side effects that they can cause.


“The pain for families seeking a diagnosis for their sick children is unimaginable,” said Matt Hancock, the U.K.’s secretary of health and social care. “These cutting-edge DNA tests will much more rapidly diagnose rare diseases, helping to put an end to uncertainty and allowing children to receive the best possible treatment.”

Check Back

Though the use of genomic sequencing remains a powerful tool for people suspected of having a genetic disease, it can still leave people without a diagnosis. Because the understanding of the genetic causes of rare diseases continues to evolve, it is often necessary to reanalyze the genetic data of someone who has been sequenced to check for newly identified genetic associations with particular conditions and newly discovered genetic variants. In fact, a study published in the journal Familial Cancer, led by scientists at the Murdoch Children’s Research Institute and the University of Melbourne, found great variances in practices around reanalysis of genetic data and said a better framework for doing so could improve diagnostic rates of rare diseases by as much as 32 percent.


Previous studies have shown that de- spite the high diagnostic yield associated with genomic sequencing (up to 68 percent depending on the genetic condition), a sizable proportion of patients still do not receive a genetic diagnosis at the time of the initial analysis. Even though reanalysis of genomic sequencing data could potentially change treatment or management of a patient, particularly in rare diseases and inherited cancers, there is currently no responsibility for laboratories to reanalyze data. The research- ers said this raises concerns about the responsibilities of laboratories and clinicians, as well as patients’ abilities to advocate for themselves.


“Studies show that systematic data reanalysis leads to considerable increases in genetic diagnosis rates between 4 and 32 percent. Yet it is time intensive and is not currently feasible for most laboratories to implement,” said Danya Vears, Murdoch Children’s Research’s lead researcher. “Few policies address whether laboratories have a duty to reanalyze and it is unclear until now how this has impacted clinical practice.”


The study interviewed 31 genetic counselors and clinical geneticists across Europe, Australia, and Canada about their experiences with data reanalysis and reinterpretation practices after requesting genomic sequencing for their patients. It found that a combination of patient-, clinician-, and laboratory-initiated reanalysis practice models were used to trigger reanalysis of patient data. Patient-initiated reanalysis, where clinicians instruct patients to return to the genetic service for reassessment after a period of time or if new information came to light, was the most common.


While some participants felt that the system was working well, others raised questions about patients’ abilities to request reanalysis. This could be due to their lack of understanding of what a negative result might mean, or because it places additional pressure on patients or families to remember to return when they are dealing with a complex medical situation.


Genetic health professionals felt a laboratory- initiated model would be ideal, but many acknowledged the technology to make this a reality was not yet available. Vears said, in many cases, there was no clear pathway for the initiation of reanalysis and that it could occur through multiple channels, which could lead to confusion. “Regardless of the model that a genetic service adopts,” Vears said, “roles and responsibilities need to be clearly outlined so patients do not miss the opportunity to receive ongoing information about their genetic diagnosis.”


One way to improve the process of reanalysis is to use artificial intelligence to monitor undiagnosed patients and alert them when newly available clinical information may suggest a diagnosis. Emedgene, which has developed an AI-based genomic interpretation platform used by research institutes, in February 2020 launched an initiative to help patients with undiagnosed rare diseases by applying its genomics analysis platform and new Pathorolo algorithm to re-run patient cases and identify whether they can be solved with newly available information. Pathorolo is a machine-learning algorithm developed to assess the likelihood of solving a genomic clinical case with currently available evidence.


Emedgene said it would continuously run its algorithms on the data and alert patients once cases are recognized as solvable. The recommended follow-up will be through a certified medical geneticist, who will be provided with the new evidence for the case. Emedgene will collaborate with patient advocacy groups, research institutes, and non-profit organizations to make the program available for their patients.


“Fewer than 50 percent of rare disease cases are solved on initial analysis,” said Einat Metzer, CEO of Emedgene. “But genomics knowledge is growing at a fast pace, and at re-run, an estimated 10 percent of cases can be solved with new information. We’d like to close the gap between scientific knowledge and patient care. In this era of extremely rapid discovery, ironically, computational AI approaches can demonstrate human compassion.”

A Data Challenge

Anyone who has watched the television show House will recall how the diagnostician and his team would work through a differential diagnosis by listing a patient’s symptoms on a whiteboard, consider diseases that fit, and then use diagnostic tests to eliminate or confirm their suspicions. In the case of rare diseases, where many symptoms can appear to be those associated with more common ailments, diagnosis can be challenging. But as a greater understanding of the manifestations of rare 

diseases emerge, and critical indicators can be discerned from genome sequencing, medical records, biomarkers, patient morphology, and other details, the process of diagnosing patients is becoming a computational and data challenge.


Researchers at the Berlin Institute of Health in a study published in the June 9, 2020 issue of the Orphanet Journal of Rare Diseases sought to determine the use of machine learning in diagnosing and treating rare disease through a scoping review study. The study, authored by Julia Schaefer and her colleagues, examined 211 studies from 32 countries investigating 74 different rare diseases. The studies made use of images (32.2 percent) demographic data (27 percent) and omics data (38.4 percent). They found most of the studies involved diagnosis (40.8 percent) or prognosis (38.4 percent). They said given the challenges in diagnosis and treatment in rare disease, AI and machine learning technologies have the potential to provide benefits.


“While it is virtually impossible for a physician to memorize information about thousands of rare diseases, modern computers can easily ‘memorize’ huge quantities of digital information,” they wrote. “If the computer can also extract and use this information in a meaningful way—for example, by classifying patients into disease groups or predicting outcomes—this has a high potential for improving diagnosis and treatment.”


The use of artificial intelligence is working its way into the clinic to help identify patients who may have a rare disease. In late 2019, Clinerion, a company that uses technology to analyze electronic health records at partner hospitals to improve clinical trial recruitment, entered a partnership with the Swiss data science company Volv Global. The partnership allows Clinerion’s Patient Network Explorer to use Volv’s inTrigue AI algorithms to identify diagnostic signals from electronic health records from Clinerion’s network of hospital partners. The effort is expected to benefit patients who have been on a protracted diagnostic odyssey as well as patients who have been misdiagnosed.


Foundation 29, a non-profit applying artificial intelligence and machine learning to health, developed Dx29, a diagnostic tool intended to make the diagnosis of patients with rare disease faster and more accurate. Dx29 takes symptoms from a patient’s medical history and suggests additional symptoms physicians should look for and for which patients. It considers new symptoms as they arise, as well as genetic data. The system guides physicians through the diagnostic process but leaves the diagnosis up to the physician.


The challenges of diagnosing people with rare diseases have economic consequences. The World Economic Forum says rare diseases consume a disproportionate amount of healthcare resources relative to their prevalence. A recent study showed how diagnostic testing and specialist consultations during the first year of a patient’s diagnostic odyssey cost approximately $2,190. For every additional year that a patient remains undiagnosed, a further $592 is incurred. Annual travel costs and caregiver productivity loss associated with attending diagnosis-related medical appointments are estimated at $1,449 per family.


With the proliferation of various types of biomedical data through electronic health records, genomic sequencing, imaging, and real- word data, along with advances in information technology, the ability to better understand rare diseases and accelerate diagnoses of people with these conditions is before us. But even as the diagnosis of rare disease increasingly becomes a computational issue, one impediment that has hindered researchers and clinicians is lack of access to the data needed.


A white paper from the World Economic Forum in February 2020 argues for the creation of federated data systems to accelerate rare disease diagnosis and the development of treatments. A federated data system is a meta- database made up of other interconnected databases. Each database stores and controls its own data, but they can all be queried at once through a single search. Such an approach can address the problem of data being siloed in hospitals, research institutes, and other entities.


“As we enter a new decade, a person with a rare disease in the U.K., a person with a rare disease in the U.S., a person with a rare disease in Australia, and a person with a rare disease in Canada could confirm a diagnosis of their disease by comparing similar genomic characteristics, but such an exercise is not easily legally feasible due to the complex data-policy landscape,” the authors said. “National, regional and international regulations such as the General Data and Privacy Regulation (GDPR) in Europe and the Health Insurance Portability and Accountability Act (HIPAA) in the U.S. hinder many routes to data sharing that would otherwise unlock the opportunity for people with rare disease—or their clinicians—to share their genomic and clinical data.”

Weighing Newborn Screening Tools

While the use of whole exome and whole genome sequencing can be a fast and cost effective means for diagnosing seriously ill newborns and children, an August 2020 study in the journal Nature Medicine found as a newborn screening tool, it is not better than older, simpler technology. Though it may one day become routine to sequence children at birth as the cost of the technology falls and our ability to interpret genetic data improves, the study suggest older technology works better as a broad screening tool.


Researchers at the University of California, San Francisco; The University of California, Berkeley; and Tata Consultancy Services compared how the use of tandem mass spectrometry compares to whole exome sequencing for newborn screening. Tandem mass spectrometry is what the state of California uses to analyze the blood spots taken at birth from newborns to test for rare metabolic disorders. The study, the first to make a comprehensive assessment of how sequencing compares to conventional screening technology, found whole exome screening fell short of the mark. It failed to identify some infants who had rare conditions while identifying some healthy babies for follow-up testing that wasn’t needed.


“There has been a lot of publicity about universal sequencing for newborns,” said Jennifer Puck, professor of pediatrics at U.C. San Francisco and co-senior author of the study. “But claims that sequencing is the key to health have been made without the support of rigorous studies.”


The researchers used archived residual dried blood spots and data for nearly all cases of inborn errors of metabolism from 4.5 million infants born in California between mid-2005 and 2013. Some of the infants who tested positive by tandem mass spectrometry were found to be unaffected by follow-up testing. They looked for mutations in 78 genes known to be involved in 48 metabolic disorders using whole exome sequencing. Every newborn in California is screened for these conditions at birth. They are rare conditions that affect about 150 of the estimated 500,000 babies born each year in California.


The study found whole exome sequencing was not sensitive or specific enough to serve as a primary screen for newborn screening for these metabolic conditions. However, the researchers said as a secondary test for infants with abnormal screens, the use of whole exome screening could reduce false-positive results, facilitate timely case resolution, and in some cases provide a better diagnosis than that initially obtained.


Puck notes that screening newborns who appear healthy is different from using sequencing as a diagnostic tool for a medical problem that has already been detected. “All of the prior studies of the utility of exome sequencing have started with a patient already in front of a doctor—in other words, a patient with a problem,” Puck said. “You start with a clue in hand, a person with a particular difficulty, and you’re trying to see if there’s an underlying genetic reason for that. When you switch to screening mode, you don’t have any clues. Most newborns look perfectly healthy.”

Expanding Access to Whole Genome Sequencing for Kids Through Medicaid

At the end of 2019, a bipartisan group of U.S. senators introduced legislation they say will help thousands of children with rare diseases get a diagnosis and proper treatment faster through whole genome sequencing.


Children with rare diseases face a “diagnostic odyssey” that typically lasts five to seven years and entails seeing an average of seven different physicians. About 30 percent of these children do not survive beyond the age of five years old.


The Ending the Diagnostic Odyssey Act would allow states to conduct whole genome sequencing services for children on Medicaid with a disease suspected to have a genetic cause. Under the three- year pilot program, the federal medical assistance percentage (FMAP) would be 75 percent. WGS is the most robust genetic test available and the only test that can detect nearly all types of genetic variants. Senators Susan Collins (R-Maine), Doug Jones (D-Alabama), Martha McSally (R-Arizona), and Bob Menendez (D-New Jersey) introduced the bill. Congressman Scott Peters, D-California, entered similar legislation in the House in 2019.


“Whole genome sequencing has changed the lives of those with genetic conditions, like Alström Syndrome, by enabling earlier and more accurate diagnoses, fostering more timely and appropriate medical care, and unlocking a host of social services to combat the educational and psycho-social complications that our children confront,” said Robin Marshall, executive director of the Alström Syndrome International, which is supporting the legislation. “That anyone would be denied access to WGS, particularly children on Medicaid suspected to have genetic conditions like Alström Syndrome, is unfathomable.”


More than 100 patient advocacy organizations are supporting the legislation, including the Genetic Alliance, Parent Project Muscular Dystrophy, Tuberous Sclerosis Alliance, Alström Syndrome International, Epilepsy Foundation, and the Asthma and Allergy Foundation of America.


“For parents of children with an undiagnosed illness, answers cannot come soon enough. The wait to find a cause—never mind a cure—can be excruciating. Parents try to project a calm and reassuring presence for their child while facing a whirlwind of doctor appointments, hospital visits, and unanswered questions,” said Senator Collins. “By giving states an incentive to provide whole genome sequencing for eligible children through Medicaid, our bipartisan legislation will ensure that more children and their families can obtain the right diagnosis and treatment from the start.”


As of the writing of this report, the legislation had not advanced out of committee in the House or Senate in 2020.


Development: Bringing Scale to Individualized Therapies


Rich Horgan was attending Harvard Business School when he started reaching out to leading researchers to learn about his brother Terry’s condition, Duchenne muscular dystrophy, and what could be done to accelerate efforts to find a cure. Horgan was taken with the work of Timothy Yu, a researcher at Boston Children’s Hospital who had developed a customized antisense oligonucleotide therapy for a young girl with a rare neurological condition. Inspired by the work of Yu, Horgan founded the nonprofit organization Cure Rare Disease to develop customized therapies to treat patients with rare, genetic conditions.


It was during a meeting at a medical conference that Horgan spoke to Monkel Lek, a researcher at Yale Medical School who, after hearing Horgan’s frustration, offered to look at Terry’s genetic report. It so happened that Horgan had it with him and surprised Lek by turning it over on the spot. Lek suggested a therapeutic strategy involving the gene editing technology CRISPR that he thought might work for Terry. He explained it had never been done before, but he thought it was worth trying.


Duchenne muscular dystrophy is caused by mutations in the dystrophin gene, which encodes the protein dystrophin, which is involved in maintaining muscle cell integrity. Patients with DMD typically develop muscle weakness in the early years of life and become wheelchair-bound in their early teens. As the disease progresses, patients develop respiratory, orthopedic, and cardiac complications. Few individuals with DMD live beyond their thirties.


Duchenne muscular dystrophy has been the subject of a fair bit of focus and new treatments have emerged, although they target specific subpopulations of patients based on the nature of their underlying genetic mutation. There are at least ten therapies in clinical development, according to the patient advocacy group Parent Project Muscular Dystrophy. While Horgan has seen the emergence of potential therapies to treat some patients with particular genetic mutations, he was frustrated that older boys, and people in their twenties like Terry, were excluded from participation in clinical trials.

Prevalence Matters

Cure Rare Disease is one of a growing number of entities that are pursuing customized therapies for ultra-rare populations or individual patients using a range of technologies including antisense oligonucleotides (ASOs), gene editing, and gene therapy. Proponents of these therapies believe they can deliver customized treatments today at prices that are comparable to commercial gene therapies and that the time and cost of doing so can be reduced through the creation of a tool kit of plug-and-play components that can speed development of these therapies and reduce the regulatory burden.


In 2020, efforts to develop individualized, or so called “n-of-1,” therapies for people with rare conditions advanced rapidly on multiple fronts. The work of Boston Children’s Yu to develop a custom therapy in less than a year and treat Mila Makovec, a 6-year-old girl with a form of the neurodegenerative condition Batten disease, excited the rare disease community because of the potential to do the same for others. A-T Children’s Project has worked with Yu to develop and dose an antisense oligonucleotide to treat a three-year old girl in California with ataxia telangiectasia, a rare neurodegenerative disease. And Yu is working with Makovec’s mother Julia Vitarello to establish a non-profit

to enable the development of individualized therapies for many more patients.


Yu said while the results with Mila have not been perfect, he believes they are promising and provide hope to explore the same path with other patients. But, he said, it will require a lot of collaboration and careful thinking about the right way to pursue these therapies. “The biggest task to be done is to generate more data. Ns-of-1 are a lot of work and at the end of the day you have outcomes in a single patient to study. And as we all know from running clinical trials, results need to be replicated,” he said. So, we have to do a significant amount of work to convince us that this type of path is sustainable, is sufficiently safe. At the same time, we have to acknowledge that at this moment in these super early stages it takes a lot of work.”


In February 2021, as this publication was going to press, Mila died at the age of 10.


Thanks in part to incentives and the high prices rare disease therapies command, drug developers are broadly pursuing therapies to treat rare disease. The range of companies that are working to advance treatments for these conditions are no longer limited to a small subset of emerging biotechs, but today include many of the world’s largest pharmaceutical companies. Nevertheless, many rare disease populations remain too small to attract commercial interest in developing needed therapies. When it comes to attracting drug developers, even in the case of rare diseases, prevalence matters.


A 2019 study in the European Journal of Human Genetics that analyzed the prevalence of 6,172 unique rare diseases identified in the Orphanet database found that 149 rare diseases affect about 80 percent of all people with rare diseases. The most prevalent of these rare diseases affect between 100 to 500 people per million. The next most prevalent rare diseases— those affecting between 10 and 100 people per 1 million include another 241 rare diseases. Together these 390 diseases affect at least 98 percent of all people with a rare condition. The remaining diseases in the database affect less than 10 people per 1 million people, but they account for about 85 percent of all rare diseases.10 That points to some simple but daunting math, which Chris Austin, director of the National Center for Advancing Translational Sciences at the National Institutes of Health, has performed on many occasions. Given the small number of diseases for which there is an approved therapy, and the rate at which new therapies are developed and approved, it will take about 2,000 years until there are available therapies for each rare disease.


That suggests why customized therapeutics may prove to be an essential strategy for developing a therapeutic for most rare diseases. While Yu’s work provides a proof of concept, many obstacles to developing customized therapies remain. These include questions of how regulators should approach these therapies, whether payers should finance them, and how to cost-effectively manufacture them. If the approach is to work for more than a handful of patients, there will be a need to find ways to regularize the process of developing and delivering n-of-1 therapies.

A Regulatory Challenge

Regulators have been quick to recognize the significance of Yu’s work. The publication of a study of his work in the New England Journal of Medicine in October 2019, was accompanied by an editorial written by Janet Woodcock, FDA director of the Center for Drug Evaluation, and Peter Marks, FDA director of the Center for Biologics Evaluation and Research, which addressed the implications of Yu’s work and other ongoing efforts.


“Academic clinician–investigators now have the capacity to rapidly uncover specific mutations and pinpoint the putative mechanisms leading to certain rare disease phenotypes. Various ASOs or other compounds can be produced by third parties, and investigators can evaluate them using in vitro assays or animal models. Similarly, genetic constructs can be developed for cell-based or directly administered gene therapy,” they wrote. “Specialized laboratories can conduct safety testing to support initiation of first-in-human trials, and contract manufac- turers can produce a clinical-grade product. Although this new pathway for drug discovery and development is most advanced for ASOs, other types of treatments, including individ- ualized cell and gene therapies, are following closely behind.”


The editorial, though, focused on questions that the development of these individualized therapies raised rather than any particular action that the agency would need to take in response to their emergence. They included questions of what type of evidence will be needed before dosing a human with an experimental therapy, what assurances of safety will be necessary, how compelling mechanistic data must be, how doses should be determined, how well characterized a product will need to be, how efficacy should be evaluated, and what role the urgency of a patient’s situation should play in the regulatory decision-making process.


Writing in the Journal Gene Therapy in March 2020, Marks, along with his colleague Celia Witten, made a deeper consideration of what a regulatory framework for individualized therapies might look like as they acknowledged that individualized therapies would soon become a regular occurrence. “The features of this framework will need to be developed in a markedly accelerated manner in the coming months, ideally building upon existing statutory authorities, rather than requiring new ones, as it is increasingly clear that the development of such products for the treatment of one to up to a few hundred individuals will soon become routine, rather than an exception,” they wrote. “Given the novelty and potential importance of this new framework to those in need of such treatments, FDA appreciates that a transparent process for its development will be important with input from patients, academics, industry, and other stakeholder groups.”


In March 2020, the U.S. Food and Drug Administration held a public workshop to address questions of how to facilitate end-to- end development of individualized therapies. “Individualized therapeutic products present unique challenges because they do not fit the traditional paradigm for manufacturing and clinical development,” said Gopa Raychaudhuri, senior scientist in the FDA’s Office of the Director at the Center for Biologics Evaluation and Research, in kicking off the workshop. “This requires that we think outside the box, to establish an evidence-based, clear, and practical pathway for development, regulation, and access for patients to these products, while assuring that the standards for quality, safety, and efficacy are maintained.”


During the workshop, FDA’s Marks noted a few of the problems facing the development of individualized therapies that need to be addressed. This includes the lack of reliable animal models for gene therapy and gene editing, how to document disease in natural history studies so that baseline data can be used as comparators to determine whether a therapy delivers benefit, and addressing manufacturing and the problem that the set-up cost for making a gene therapy for 20 people is roughly the same as it is for 200 people. Furthermore, once a product is developed, what needs to be done to ensure continued access? And then there is the question of what can be done to accelerate the process given that many of the people for whom these therapies are being contemplated have progressive and deadly conditions.


“Typically, when individual investigators develop a gene therapy, they go through all the normal stages of drug development, including submitting an IND, doing the necessary tox studies, doing the manufacturing, which oftentimes they have to learn to do from scratch. And that whole process often takes four to eight years on average,” said Marks. “One could imagine that if one was able to leverage manufacturing processes, use templated INDs, templated protocols—obviously, it would have to be customized somewhat—you could potentially shorten this a fair amount. That shortening of years means a lot. When you talk to parents of children with rare diseases, a few years matter.”

A Plug-and-Play Model

In fact, in the Gene Therapy article Marks outlined a strategy for AAV gene therapies that could address the cost-prohibitive nature of scaling up and manufacturing these therapies for populations too small to be commercially attractive. He suggested a public-private partnership making use of a consortium model could provide end-to-end solutions that address key issues limiting their development and use. Along with his co-author, Marks argued that production by a consortium of a non-proprietary suite of AAV vectors, along with detailed instructions for developing the construct that would address the genetic disorder, could increase the number of products in development addressing unmet medical needs.


Manufacturing challenges, they wrote, could be addressed by having one or a few facilities producing product in a standardized way that could be documented in master files to reduce the regulatory burden, and the development of Investigational New Drug and protocol templates could make it easier for academic researchers, unfamiliar with the regulatory process, to file necessary paperwork to get clearances to treat patients with experimental n-of-1 therapies. He suggested such steps could cut the time to bring a treatment to a patient in half.


The model for individualized AAV gene therapies is in line with work under way at the National Center for Advancing Translational Sciences called Platform Vector Gene Therapy, or PaVe- GT, a collaborative effort involving NCATS, the National Human Genome Research Institute, and the National Institute of Neurological Disorders and Stroke. PaVe-GT is trying to increase the efficiency of moving a gene therapy for a small population into clinical development. The goals of the program are to lower the barriers for new genome editing therapies by testing genome editing reagents and delivery systems and better animal models. The pilot project is focused on the simultaneous development of gene therapies for four rare genetic diseases at once using the same viral vector, the same route of administration, the same serotype, and the same production purification methods. The only difference in the case of each of the therapies is the gene constructs for the different diseases.


PaVe-GT plans to make all of the data publicly available including bio-distribution data, toxicology, and communications with the FDA up to and including the investigational new drug application submission with the expectation that doing so would allow others to use the same documents in a cut and paste manner and bypass much of the time and expense involved in preclinical development for therapies able to use the same AAV vector. Unlike small molecule drugs, genes are unable to enter cells on their own. Instead, they must be carried by a vector to transport them. For each gene therapy program, the vector increases the experimental, regulatory, safety, clinical complexity, and cost of the gene therapy since both the carried gene and the vector are different in every development program. This hinders the expanded application of gene therapy to address many diseases that potentially could be treated through the approach. NIH Director Francis Collins told a House Appropriates Subcommittee in September 2019 that if successful, NCATS will expand this strategy to provide rare diseases researchers with a palette of vectors to treat many, and potentially all, rare genetic diseases.


P.J. Brooks, program director in the Office of Rare Diseases Research at NCATS, told the FDA during the public workshop on individualized therapies that the hope is that once PaVe- GT is making the same vector in the same manufacturing facility and keeping everything the same except for the transgene payload, the FDA review would be streamlined. He said the approach could have significant benefits when it comes to gene editing, noting a separate project at NCATS identified an editing enzyme that could be used to correct nearly 90 percent of known pathogenic genetic mutations. If successful, he said that could lead to the production of a single biologic that could be deployed to treat different rare diseases by simply changing the guide RNAs. Guide RNAs are short strands of RNA known as oligonucleotides that bind to the target sequence for editing.


“This one disease at a time approach that we’re doing now is not going to address these low prevalence diseases of no commercial interest, despite the fact that the biological rationale of treating those diseases is just as good as the common diseases. And that does not seem acceptable,” said Brooks. “That’s a major reason why we need to do something different. We need radically different types of clinical trials and regulatory platforms to bring gene therapy and gene editing therapies to all the patients who might benefit from them.”

Innovators Join the Fray

PaVe-GT is not alone in its efforts. Several other initiatives are underway to enable scalable approaches to developing individualized therapies or therapies that address ultra-rare populations. At the start of 2020, antisense pioneer and Ionis Pharmaceuticals’ founder Stanley Crooke launched a nonprofit to provide experimental RNA-targeted therapies for patients with ultra-rare diseases free of charge. The organization, dubbed n-Lorem Foundation, is backed with funding from Crooke and his wife Rosanne, an Ionis researcher. Ionis and Biogen are providing additional funding as the first corporate donors, in addition to support from individual contributors. Crooke, who is serving as the chairman and CEO of n-Lorem, drove the development of Ionis’ antisense platform.


Antisense oligonucleotides, or ASOs, are small pieces of chemically modified genetic material designed to bind to target RNAs for therapeutic use. They can be developed rapidly, inexpensively, and are highly specific. People hoping to engage n-Lorem in developing an ASO therapy begin by having their physician complete a request for treatment. The information required includes specific details about the disease and the individual’s underlying genomics. The request is reviewed by a treatment committee, which consists of physicians, pediatricians, neurologists, geneticists, and various experts. Among the considerations that are weighed are whether there is adequate information to make an experimental ASO, whether the patient’s problem is addressable with the technology, the severity of the patient’s condition, the urgency of the case, as well as other considerations about the appropriateness of treating the patient. The treatment committee makes a recommendation and the executive team then makes a final decision.


“No single charitable foundation or drug discovery technology can meet the needs of all the patients who suffer from ultra-rare diseases,” said Crooke. “I believe that by bringing together the power of modern genomics and the antisense platform created by Ionis, we can responsibly meet the needs of some of these patients.”


As of the start of October 2020, n-Lorem said it had received about 30 applications for treatment and accepted 10 patients. It also said it has been able to reduce the cost of treatment per patient by more than 30 percent, although it did not provide a total cost.


A separate nonprofit initiative founded by a trio of powerhouses from the biotech world of finance, research, and industry is focused on developing gene therapies for patients with ultra-rare conditions. The Institute for Life Changing Medicines is a nonprofit founded at the start of 2020 by healthcare investor and Deerfield Management partner and managing director Alex Karnal, gene therapy pioneer James Wilson, and pharmaceutical executive turned venture capitalist Tadataka Yamada. While the institute is engaged in advocacy and education, it is also focused on the development of gene therapies. Its goal is to bring these therapies to patients within two years at a cost of between $5 million to $30 million and to change the lives of 1 million people suffering from life threatening and devastating diseases around the world with no barriers to access. Lesch-Nyhan syndrome, AADC deficiency, and Crigler Najjar type 1 are among the diseases the organization is currently working to address. All three conditions are neurological and ultra-rare with just 10 babies born a year in the United States with each condition.

From One to Many

Cure Rare Disease’s pursuit of a therapy for Terry Horgan began with taking a muscle cell biopsy from him in 2018 and analyzing it both on a protein and transcription level. What they found was that Terry was producing low levels of dystrophin. His body was trying to compensate for the lack of dystrophin by upregulating a protein variant. The strategy in Terry’s case is to use gene editing technology to upregulate this alternate form of dystrophin that he produces.


Collaboration has played a critical role in advancing the first wave of individualized therapies, which have involved a combination of patient advocacy organizations, clinical research organizations, academic researchers, and commercial manufacturers. In the case of Cure Rare Disease, its experimental therapy involves what’s known as CRISPR activation. The plan is to use the gene editing tool to turn on alternative forms of the gene to produce the needed dystrophin protein. The effort has relied on a number of partnerships. In addition to the academic researchers who have developed an experimental therapy, a non-profit created to assist organizations like it through the translational research hurdle is helping. In August 2020, Cure Rare Disease formed a strategic partnership with Columbus Children’s Foundation, a nonprofit biotech that advances and accelerates gene therapy programs for ultra- rare genetic diseases for populations too small to attract investment and corporate interests.


Laura Hameed, executive director of Colum- bus Children’s Foundation, said it works with programs that are “clinically promising and not commercially viable.” The foundation sees a critical role for itself to work with people developing gene therapies for ultra-rare diseases by helping with translational work and leveraging its relationships with its co-founders, the contract development and manufacturing organization Viralgen Vector Core and the gene therapy devel- oper AskBio. The partnership came as Cure Rare Disease completed the preclinical testing on the treatment and was preparing to sit down with the FDA about beginning a human clinical trial in which it would dose Terry, now 25. It expects to have the necessary FDA clearance to dose Terry with the gene therapy in early 2021.


Hameed estimates that Columbus Children’s Foundation can provide a 60 percent reduction on the commercial sticker price of what a gene therapy for an ultra-rare condition might command—about a $3 million savings in the case of Cure Rare Disease—but perhaps more critical is the speed at which it can help an experimental therapy advance. “With rare disease programs time equals life,” she said. “Being able to get programs in a queue to be developed without an 18- to 24-month wait is a significant value add that our foundation is able to bring the programs that we work with.”


The clock is running. Terry is no longer able to walk and his upper limb strength is weakening, but his mind remains sharp. “Our goal is not for him to get up and start playing basketball. Of course, we’d welcome that, but we want to keep our expectations tempered in the sense that at the very least, we want to pause the disease,” said Rich Horgan. “If we see some upside in terms of improved motor function in the upper gate, then that’s fantastic.”


As it moves forward, Cure Rare Disease plans to leverage the treatment of Terry as the proof-of- concept for its approach, which it believes has the potential to flip the script for others who are impacted by rare disease. It is moving beyond Duchenne muscular dystrophy into other neuromuscular and neurodegenerative diseases and has a pipeline of at least ten patients with whom it is working to develop individualized therapies. “We will soon,” Horgan said, “see the potential that customized therapeutics can have on some of the most challenging diseases known to humankind.”


A multibillion building boom is underway to create new capacity for both experimental and marketed gene therapies. It comes as some 1,006 gene, gene-modified cell, and cell therapies were in clinical development as of the end of September 2020, according to the trade group the Alliance for Regenerative Medicine.


In November 2020, Ultragenyx Pharmaceutical said it will build a 100,000 square foot facility in Bedford, Massachusetts to enable in-house manufacturing of its pipeline of AAV-based gene thera- pies. It expects to hire 100 to 150 employees there over the next five years and has land that will allow it to double the size of the facility should it need to do so.


Days later, the global contract development and manufacturing organization Vibalogics said it has initiated phase I of its planned $150 million investment in a late- phase clinical and commercial virotherapy manufacturing facility in Wellesley, Massachusetts. The three-year investment plan includes the build out of a 110,000 square foot-facility spending $150 million across redevelopment, equipment and personnel. The facility is expected to create 100 jobs initially, reaching 250 employees in the next four years. The ability for gene therapy developers to get access to needed viral vectors has become a concern throughout the industry as companies face delays because demand is outstripping supply.


“What keeps me up at night is will we be able to manufacture these on a scale that will allow us to bring the benefit of these therapies to patients?” said Peter Marks, director of the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research.


Marks made the comment in response to news in January 2020 that Discovery Labs and Deerfield Management launched the Center for Breakthrough Medicines to address the lack of manufacturing capacity for cell and gene therapies. The $1.1 billion center, Center for Breakthrough Medicines hailed as the largest cell and gene therapy contract development and manufacturing organization, will be housed in 680,000 square- feet of space, part of a 1.6 million life sciences campus in King of Prussia, Pennsylvania.


The Center will provide preclinical through commercial manufacturing of cell and gene therapies and component raw materials. It offers process development, plasmid DNA,
viral vectors, cell banking, cell processing, and support testing capabilities all under one roof. The company expects to hire more than 2,000 team members within the next 30 months.


Days later, Krystal Biotech, which is developing gene therapies for rare diseases, broke ground on a second commercial gene therapy facility in Findlay Township, Pennsylvania, a project expected to cost up to $90 million. It expects to have the 100,000 square foot facility finished and validated in time for the expected launch of B-VEC, its lead experimental gene therapy for the treatment of dystrophic epidermolysis bullosa, a rare and often fatal skin blistering condition.


And just a week before the announcement of the Center for Breakthrough Medicines, Nationwide Children’s Hospital unveiled Andelyn Biosciences, a for-profit company that will manufacture gene therapy products for industry. “The goal of Andelyn Biosciences is to support the advancement of novel gene therapies for rare genetic diseases by building commercial manufacturing capacity, which is needed as more of these treatments are developed over the coming years,” said Dennis Durbin, chief scientific officer

of The Abigail Wexner Research Institute at Nationwide Children’s.


The activity accelerates efforts in 2019 that included Pfizer’s decision in August 2019 to invest $500 million into a gene therapy manufacturing facility in Sanford, North Carolina, an expansion of its initial plan to invest $100 million into the site. A month later, it acquired land and a facility in Durham, North Carolina for $19 million. The building will be retrofitted to double the company’s gene therapy production capabilities.


Novartis, which markets the spinal muscular atrophy gene therapy Zolgensma through its subsidiary Novartis Gene Therapies, is expanding its manufacturing capabilities with a $500 million investment in new gene and cell therapy facilities. The U.K.-based Orchard Therapeutics was building out a 150,000-square-foot gene therapy manufacturing facility in Fremont, California at a cost of up to $90 million. It has subleased the facility as part of a reorganization.


And Harvard and MIT at the end of 2019 announced that they were leading a $50 million public-private effort to establish the non-profit Center for Advanced Biological Innovation and Manufacturing, which is intended to help overcome bottlenecks to getting new treatments into the clinic. It notes scientists may need to wait as long as 18 months to get viral vectors that comply with regulatory standards from contract manufacturers because of existing backlogs.


“Improving manufacturing methods and capacity will be immensely important as the gene therapy sector continues to grow,” said Michael Lehmicke, director
of science and industry affairs for the Alliance for Regenerative Medicine. “With the number of regenerative medicine clinical trials and approved products expected
to grow exponentially over the next few years, it’s imperative that the sector continue to invest in scalable manufacturing opportunities.”

First Human Patients Dosed with in Vivo CRISPR Genome Editing Medicine

Allergan and Editas Medicine made history in 2020 when investigators at Oregon Health & Science University Casey Eye Institute treated the first patient in a clinical study with an experimental gene editing therapy for a rare genetic form of blindness.


The BRILLIANCE clinical trial is a phase 1/2 study to evaluate AGN-151587, an experimental therapy for the treatment of patients diagnosed with LCA10. It is the world’s first human study of an in vivo CRISPR genome editing medicine. The trial will assess the safety, tolerability, and efficacy of AGN-151587 in approximately 18 patients with LCA10.

Leber congenital amaurosis, or LCA, is a group of inherited retinal degenerative disorders caused by mutations in at least 18 different genes. Symptoms of LCA appear within the first years of life, resulting in significant vision loss and potentially blindness. The most common form of the disease, LCA10, is caused by mutations in the CEP290 gene and is the cause of disease in approximately 20 to 30 percent of all LCA patients.


AGN-151587, is a CRISPR-based experimental medicine under development for the treatment of Leber congenital amaurosis 10. It is administered via a subretinal injection to deliver the gene editing machinery directly to photoreceptor cells.


“This dosing is a truly historic event–for science, for medicine, and most importantly for people living with this eye disease,” said Cynthia Collins, president and CEO, Editas Medicine. “The first patient dosed in the BRILLIANCE clinical trial marks a significant milestone toward delivering on the promise and potential of CRISPR medicines to durably treat devastating diseases such as LCA10.”


Drugs: A Year of Many Firsts as Drug Approvals Rise


“What we see across the board is that the agency has gotten very conservative in the last several months. They’ve had progressive leadership in the past. Oftentimes when the progressive leadership disappears, they retreat to conservative. And when stressed, they become conservative.”


The U.S. Food and Administration’s Center for Drug Evaluation and Research approved 53 new molecular entities in 2020, up from 48 approvals in 2019 despite disruptions from the pandemic. Nevertheless, the number of drug approvals fell short of the record 59 new molecular entities approved by the agency in 2018. A total of 31 (58 percent) of these drugs were approved to treat rare diseases. That compared to 21 (44 percent) of the novel drugs approved for rare indications by the CDER in 2019. A total of 12 of the novel orphan drugs the agency approved were first-in-class therapies.


One ongoing trend in rare disease drug development is the advent of multiple therapies that take different approaches to treating the same rare disease. The FDA in August approved Genentech’s Evrysdi, the first oral, at-home treatment for the progressive and deadly neuromuscular disease spinal muscular atrophy for adults and children two months of age or older. The approval of Evrysdi followed the approval in 2016 of Biogen’s antisense therapy Spinraza and the 2019 approval of Novartis’ gene therapy Zolgensma.


Spinal muscular atrophy (SMA) is a genetic disease caused by a mutation of the survival motor neuron 1 (SMN1) gene, which leads to a deficiency of the SMN protein. This protein is found throughout the body and is essential to the function of nerves that control muscles and movement. Depending on the type of SMA, an individual’s physical strength and their ability to walk, eat or breathe can be significantly diminished or lost. Evrysdi works by altering the production of protein from the SMN2 gene to produce a stable form of the SMN protein.


“Given the majority of people with SMA in the U.S. remain untreated, we believe Evrysdi, with its favorable clinical profile and oral administration, may offer meaningful benefits for many living with this rare neurological disease,” said Levi Garraway, chief medical officer and head of global product development for Genentech.

Evrysdi was the first of two rare disease drug approvals Genentech won in 2020. A week after the FDA approved the Evrysdi, it approved Enspryng, a subcutaneous injection for the treatment of the rare autoimmune disease neuromyelitis optica spectrum disorder (NMOSD). It was one of two therapies the FDA approved for NMOSD in 2020, and the third therapy for the condition. The FDA in June approved Viela Bio’s Uplizna, an intravenous treatment for NMOSD and in 2019, expanded the approved uses of Alexion’s Soliris to include NMOSD. The agency approved Enspryng and Uplinza for NMOSD patients who produce a specific antibody under- lying their disease.


In patients with NMOSD, the immune system attacks healthy cells and proteins in the body, most often those in the optic nerves and spinal cord. Individuals with NMOSD suffer attacks of eye pain and vision loss. About half of patients with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks. NMOSD can be associated with antibodies that bind to a protein called aquaporin-4 (AQP4). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system. The condition is thought to affect 4,000 to 8,000 Americans.


The FDA approved two therapies for rare endocrine disorders in 2020. Horizon Therapeutics won approval for Tepezza, a monoclonal anti- body that is the first approved therapeutic for the treatment of thyroid eye disease. Thyroid eye disease (TED) is a progressive and vision- threatening rare autoimmune disease that is associated with eye bulging, double vision, blurred vision, pain, inflammation, and facial disfigurement. TED is caused by autoantibodies activating an IGF-1R-mediated signaling complex on cells within the retro-orbital space, leading to a cascade of negative effects, which may cause long-term, irreversible damage, including blind- ness in some cases.


Historically, patients have had to live with TED until the inflammation subsides, after which they are often left with permanent and vision-impairing consequences. Tepezza is a fully human monoclonal antibody and a targeted inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) that is administered to patients once every three weeks for a total of eight infusions.


“Tepezza is a much-needed breakthrough for a community of people who have historically had to struggle in pain as their symptoms progress— risking permanent damage to their eyes and making it extremely difficult to go about their daily lives,” said Jeff Todd, president and CEO, Prevent Blindness. “This approval is meaningful to our organization because we are committed to helping patients with vision impairment and those who are at significant risk.”


The FDA also approved Novartis’ Isturisa for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have under- gone the surgery but still have the disease. It is the first FDA-approved drug to directly address cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis.


Cushing’s disease is a rare endocrine condition caused by a pituitary tumor that results in the adrenal glands making too much of the cortisol hormone adrenocorticotropin. Cushing’s disease can cause significant health issues, such as high blood pressure, obesity, type 2 diabetes, blood clots in the legs and lungs, bone loss and fractures, a weakened immune system, and depression. Patients may have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, purple stretch marks, and weak muscles.


In the area of neuromuscular diseases, the FDA in August 2020 granted accelerated approval to NS Pharma’s Viltepso for patients with the rare and progressive condition Duchenne muscular dystrophy. The therapy is approved for patients who have a mutation of the DMD gene that is amenable to exon 53 skipping. Viltepso is the second antisense oligonucleotide approved for this specific mutation. The approval came eight months after the FDA granted Sarepta Pharmaceuticals’ Vyondys 53 accelerated approval in December 2019.


Duchenne muscular dystrophy (DMD) is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.


Viltepso was evaluated in two clinical studies with a total of 32 patients who had genetically confirmed DMD. The agency said NS Pharma’s data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. However, a clinical benefit of the drug had not been established. In making its decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.


As part of the accelerated approval process, the FDA is requiring the company to conduct a clinical trial to confirm the drug’s clinical benefit. The ongoing study is designed to assess whether Viltepso improves the time to stand for DMD patients with this confirmed mutation. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.


The FDA also approved the first treatment for progeria, an ultra-rare condition that causes pre- mature aging. The FDA in November approved Eiger Pharmaceuticals’ Zokinvy capsules to reduce the risk of death due to progeria and progeroid laminopathies. Progeria, also known as Hutchinson-Gilford progeria syndrome (HGPS), and progeria laminopathies (PL) are ultra-rare, multisystemic, premature aging diseases that accelerate mortality in young patients due to accumulation of cellular progerin in HGPS or an abnormal lamin A protein in PL.


Untreated children with progeria often die of heart disease at an average age of 14.5 years. It is estimated that there are 400 children worldwide with progeria and 200 children with PL. Of these patients, approximately 180 children and young adults have been identified, including 20 in the United States and 23 in Europe. Until now, the only treatment options included supportive care and therapies directed towards the complications arising from the disease.


Zokinvy has shown survival benefit in children with progeria. In patients with progeria, Zokinvy reduced the incidence of mortality by 60 percent and increased average survival time by 2.5 years. The most commonly reported adverse reactions were gastrointestinal (vomiting, diarrhea, nausea), and most were mild or moderate in severity. Many progeria patients have received continuous Zokinvy therapy for more than 10 years. The approval of the drug resulted from a partnership between the Progeria Research Foundation and Eiger BioPharmaceuticals.


Three other drugs approved in 2020 address rare genetic metabolic conditions. This includes Alnylam Pharmaceuticals’ Oxlumo for primary hyperoxaluria type 1 (PH1), an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to life threatening end-stage renal disease and other systemic complications. Oxlumo (lumasiran) is an RNAi therapeutic targeting messenger RNA that encodes an enzyme upstream of the disease- causing defect in PH1. By degrading the HAO1 mRNA and reducing the synthesis of the enzyme glycolate oxidase, lumasiran stops the production of oxalate—the toxic metabolite that directly contributes to the clinical manifestations of PH1. The FDA granted Alnylam a Rare Pediatric Disease Priority Review Voucher with the approval.


Ultragenyx won FDA approval for Dojolvi to treat long-chain fatty acid oxidation disorders (LC-FAOD), a group of genetic disorders characterized by metabolic deficiencies in which the body is unable to convert long-chain fatty acids into energy. The inability to produce energy from fat can lead to severe depletion of glucose in the body and serious complications, which can lead to hospitalizations or early death. Dojolvi is a highly purified, synthetic, 7-carbon fatty acid triglyceride specifically designed to 

provide medium-chain, odd-carbon fatty acids as an energy source and metabolite replace- ment for people with LC-FAOD. The approval garnered Ultragenyx a Rare Pediatric Disease Priority Review Voucher.


And the agency also approved BioCryst’s Orladeyo to prevent attacks from hereditary angioedema in patients 12 years and older. Orladeyo is the first orally administered non- steroidal option for preventing HAE attacks, which can cause debilitating, painful, and life- threatening swelling to various parts of the body.


Four (13 percent) of the orphan drug approvals in 2020 were for treatments for tropical diseases. This included Regeneron’s Inmazeb and Ridgeback Biotherapeutics Ebanga, both for Ebola virus. It also included Amivas’ Artesunate to treat severe malaria, and Bayer Healthcare’s Lampit to treat Chagas disease in certain pediatric patients younger than 18 years of age.

More than Half of Orphan Approvals for Cancer Drugs

More than half (55 percent) of the new orphan drug approvals in 2020 were for cancer indications. This included approvals for two different drugs to treat gastrointestinal stromal tumor (GIST), a rare cancer affecting the digestive tract or nearby areas within the abdomen. GIST is the most common sarcoma of the gastrointes- tinal tract, with approximately 4,000 to 6,000 new GIST cases each year in the United States and a similar incidence rate in Europe and other countries. Most cases of GIST are driven by a spectrum of mutations. Current therapies are unable to inhibit the full spectrum of primary and secondary mutations, which drives resistance and disease progression. Five-year survival ranges from an estimated 48 percent to 90 percent, depending on the stage of the disease at diagnosis.


The FDA in January 2020 approved Blueprint Medicines’ Ayvakit, the first precision therapy approved to treat a genomically defined population of patients with metastatic GIST that harbors specific mutations (PDGFRA exon 18 mutation, including PDGFRA D842V). Ayvakit is a kinase inhibitor that works by blocking a cell signal enzyme that plays a role in tumor growth.


“For the first time, we can offer these patients a highly effective treatment that targets the underlying genetic cause of their disease,” said Michael Heinrich, professor of medicine at Oregon Health & Science University and an investigator on the Ayvakit trial. “Building on our growing understanding of the molecular basis of GIST, this milestone ushers in a new era of precision medicine in this disease.” He said the approval represents “a call to action” for doctors to perform mutational testing in all patients with GIST before treating with a kinase inhibitor.


The agency also granted accelerated approval to Deciphera Pharmaceuticals’ Qinlock (ripretinib) tablets in May 2020 as the first new drug specifically approved as a fourth- line treatment for advanced GIST in adults who have received prior treatment with three or more kinase inhibitor therapies. Qinlock is a kinase inhibitor that targets the broad spectrum of KIT and PDGFRα mutations known to drive the growth of GIST.


Several of the FDA approvals in rare cancers represented the first therapies approved specifically for their indications. The agency approved AstraZeneca and Merck’s Koselugo, the first therapy for the treatment of pediatric patients 2 years and older with neurofibromatosis type 1 (NF1), a debilitating, progressive and often disfiguring rare disease that typically begins early in life. It is a genetic disorder that causes tumors to grow on nerves. Koselugo is approved specifically for patients who have symptomatic, inoperable plexiform neurofibromas (PN), which are tumors involving the nerve sheaths (coating around nerve fibers) and can grow anywhere in the body, including the face, extremities, areas around the spine and deep in the body where they may affect organs. Koselugo is a kinase inhibitor that blocks a key enzyme involved in tumor growth.


People with NF1 may experience a number of complications, such as learning difficulties, visual impairment, twisting and curvature of the spine, high blood pressure, and epilepsy. NF1 also increases a person’s risk of developing other cancers, including malignant brain tumors, malignant peripheral nerve sheath tumor, and leukemia. Symptoms begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.


Y-mAbs Therapeutics in November 2020 won approval for Danyelza, in combination with granulocyte-macrophage colony-stimulating factor, for the treatment of pediatric patients 1 year of age and older and adult patients. Danyelza is a humanized, monoclonal antibody that targets the ganglioside GD2, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. Danyelza was approved for use in patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. Neuroblastoma is a solid tumor of childhood that arises in the nervous system, outside of the brain. The clinical behavior of neuroblastoma is highly variable, with some tumors being easily treatable, but the majority being very aggressive. The FDA granted Y-mAbs a Rare Pediatric Disease Priority Review voucher with the approval.


Incyte’s Pemazyre, a kinase inhibitor for the treatment of cholangiocarcinoma, won accelerated approval for adults with previously treated, unresectable locally advanced, or other rearrangement disease as detected by an FDA- approved test. It is the first targeted therapy for cholangiocarcinoma, a rare cancer that forms in bile ducts that carry the digestive fluid from the liver to the gallbladder and small intestine.


Most patients with the condition are diagnosed with advanced disease that is no longer treatable with surgery. Until now, their only option was a combination of chemotherapy drugs. FGFR2 fusions have been found in the tumors of approximately 9 percent to 14 percent of patients with cholangiocarcinoma.

Pemazyre is a tablet that works by blocking FGFR2 in tumor cells to prevent them from growing and spreading. It is the first and only FDA-approved treatment for patients with cholangiocarcinoma that is locally advanced who have tumors that have a fusion or other rearrangement of the FGFR2 gene.


And the FDA also approved Epizyme’s Tazverik for the treatment of adults and pediatric patients ages 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. It is the first therapy approved to treat epithelioid sarcoma, a rare sub-type of soft tissue sarcoma that often occurs in young adults and accounts for less than one percent of all soft tissue sarcomas.


Most cases of epithelioid sarcoma begin in the soft tissue under the skin of an extremity  though it can start in other areas of the body. Surgical removal is considered the main treatment when the cancer is localized to one area of the body. However, there is a high likelihood for local and regional spread of the disease even with treatment and approximately 50 percent of patients have metastatic disease at the time of diagnosis with median overall survival of less than one year.


Tazverik is a methyltransferase inhibitor that blocks activity of EZH2, which may help keep the cancer cells from growing. Even though one-third of study patients experienced serious adverse effects and the overall response rate was modest, an FDA advisory committee unanimously agreed at a meeting in December 2019 that the drug’s benefit outweighed its risks. The approval, though, is contingent upon verification of clinical benefit in a confirmatory trial to assess the combination of Tazverik plus doxorubicin compared with doxorubicin plus placebo as a front-line treatment for epithelioid sarcoma.


“For people with epithelioid sarcoma, an aggressive life threatening cancer that affects young adults, having new treatment options can offer much needed hope,” said Denise Reinke, president and CEO of the Sarcoma Alliance for Research through Collaboration and co-founder of the Sarcoma Coalition.


The FDA in April 2020 approved Seattle Genetics’ Tukysa to treat metastatic HER2-positive breast cancer in combination with chemotherapy. Tukysa is a tyrosine kinase inhibitor of HER2, a protein that contributes to cancer cell growth. The approval of Tukysa was the first under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncol- ogy products among international partners.


In the area of rare blood cancers, the FDA approved three new drugs in 2020. GlaxoSmith- Kline’s antibody drug conjugate Blenrep won FDA approval for patients with multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.


Multiple myeloma, which is rare, is the second most common blood cancer in the United States and is generally considered treatable, but not curable. In the United States more than 32,000 people are estimated to be diagnosed with multiple myeloma this year and nearly 13,000 people will die from the disease. Blenrep is an antibody drug conjugate that links a humanized anti-B cell maturation antigen (BCMA) monoclonal antibody to the cytotoxic agent auristatin F. Blenrep is the first anti-BCMA therapy approved anywhere in the world. The normal function of BCMA is to promote plasma cell survival. BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.


The FDA also approved Astex Pharmaceuticals’ Inqovi tablets for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. It is the first and only orally administered hypomethylating agent for the treatment of adults with intermediate and high-risk myelodysplastic syndromes including chronic myelomonocytic leukemia. Hypomethylating agents affect expressions of genes that have been silenced.


Myelodysplastic syndromes (MDS) are a group of cancers in which blood cells do not develop and function properly. The condition can cause infections and bleeding, affecting one or more of the three lineages. Incidence of MDS in the United States is estimated to be 10,000 cases per year, with an estimated prevalence of 60,000 to 170,000 patients. MDS may evolve into acute myeloid leukemia in one-third of patients, and the prognosis is poor. Chronic myelomonocytic leukemia (CMML) is a malignancy that starts in the blood forming cells in the bone marrow and moves into the blood. The incidence of CMML in the United States is approximately 1,100 new cases per year, and CMML may transform into AML in 15 percent to 30 percent of patients.


The hypomethylating agents decitabine and azacitidine are effective treatments that are FDA- approved for intermediate and high-risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections, which must be done at a health care facility. Inqovi (decitabine and cedazuridine) is taken as one tablet by mouth once daily for five consecutive days of each 28-day cycle. The approval of Inqovi allows patients to treat themselves at home. The agency also approved MophoSys and Incyte’s Monjuvi in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large- B-cell lymphoma for patients who are not eligible for autologous stem cell transplant. Monjuvi, a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody, was approved under accelerated approval.


Finally, in the area of rare cancers, the FDA approved four drugs for lung cancer. This included Blueprint Medicines’ Gavreto for the treatment of adult patients with a rare form of non-small cell lung cancer (NSCLC). It was the second rare disease approval in 2020 for the company along with its GIST therapy Ayvakit. Patients eligible to use Gavreto must first take a test that shows they have the metastatic RET-fusion positive form of the disease. The approval was based on data from the phase 1/2 ARROW clinical trial, which showed efficacy for Gavreto in patients with RET fusion-positive NSCLC with or without prior therapy. RET-fusion positive patients make up 1 to 2 percent of patients with NSCLC.


Gavreto is a once-daily oral RET-targeted therapy. It is designed to selectively inhibit RET alterations that drive many cancer types, including the approximately 1 to 2 percent of patients with NSCLC. Currently, RET is one of seven NSCLC biomarkers that can be targeted with an FDA- approved therapy.


The agency additionally approved Loxo Oncology’s Retevemo to treat non-small cell lung cancer as well as certain thyroid cancers with RET mutations. The FDA also approved Novartis’ Tabrecta for patients with non-small cell lung cancer that has spread to other parts of the body. Tabrecta is approved to treat MET exon 14 skipping mutations and was approved with a companion diagnostic. It is the first approved drug to treat non-small cell lung cancer with these types of mutations.


And the agency granted accelerated approval to Pharma Mar for Zepzelca, a treatment for adult patients with metastatic small cell lung cancer with disease progression after platinum-based chemotherapy. Zepzelca triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in eventual cell death.

Clinical Trials and Tribulations

Several companies that had thought they were on the way to an FDA approval of their rare disease therapeutics in 2020 found the agency derailed their plans as it refused to approve their medicines without additional data. The highest profile example of that came in August 2020, when the FDA dealt a blow to BioMarin’s closely watched experimental gene therapy Roctavian, in development for the most severe form of hemophilia A, telling the company it would not approve the therapy without further data demonstrating its durability.


People with hemophilia A lack sufficient functioning factor VIII protein to help their blood clot and are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. Those with the most severe form of hemophilia A make up approximately half of the hemophilia A population, and often experience painful, spontaneous bleeds into their muscles or joints. The standard of care for these individuals is a prophylactic regimen of replacement factor VIII infusions administered intravenously up to two to three times per week or 100 to 150 infusions per year. Despite these regimens, many people continue to experience breakthrough bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.


Roctavian is designed to restore adequate levels of factor VIII for normal clotting. It is being developed as a one-time treatment for adults with severe hemophilia A and could eliminate the need for ongoing factor VIII treatments. In late May, BioMarin reported results from an open-label phase 1/2 study of the gene therapy noting that all study participants remain off prophylactic therapy after a single dose. But the data also showed that factor VIII activity levels declined in the most recent year’s observations, even as BioMarin said they remained in a range to prevent spontaneous bleeding events.


In rejecting BioMarin’s application, the agency recommended the company provide it with two years of data from the company’s ongoing phase 3 study to provide substantial evidence of a durable effect using annualized bleeding rate as the primary endpoint. The decision surprised the company, which said it was the first time the agency raised the issue during development or review. The phase 3 study was fully enrolled in November 2019, and the last patient will complete two years of follow up in November 2021.


Henry Fuchs, president of worldwide research and development for BioMarin, told analysts on a conference call in November that he believed the agency has grown more cautious under new leadership. “What we see across the board is that the agency has gotten very conservative in the last several months,” said Fuchs. “They’ve had progressive leadership in the past. Oftentimes when the progressive leadership disappears, they retreat to conservative. And when stressed, they become conservative.”


BioMarin was not alone in suffering a rejection from the FDA. The agency notified Mallinckrodt in September that it would not approve the company’s therapy for adults with hepatorenal syndrome type 1, a life-threatening condition for people with advanced liver disease that causes kidney failure. The decision was surprising because it came despite an advisory committee’s recommendation for approval of its terlipressin to treat adults with HRS-1 based, in part, on results from a phase 3 trial. If left untreated, patients with HRS-1 have a median survival time of approximately two weeks and greater than 80 percent mortality within three months.


Terlipressin is a potent vasopressin analogue selective for V1 receptors being investigated for the treatment of HRS-1 in the U.S. and Canada. Terlipressin is approved for use outside the United States and Canada, but the FDA said based on the available data, the agency could not approve terlipressin in its current form and required more information to support a positive risk-benefit profile for terlipressin for patients with HRS-1.


Mesoblast was also stung by a complete response letter from the agency declining to approve the company’s experimental therapy remestemcel-L for the treatment of pediatric steroid-refractory acute graft versus host disease despite an advisory panel’s 9-1 vote in favor of approval. The FDA told Mesoblast it would not approve the therapy without at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for steroid-refractory acute graft versus host disease. The FDA also wanted additional demonstration of the relationship of potency measurements to the product’s biologic activity. Assays measuring the potency of remestemcel-L will continue to be refined to provide further scientific rationale for its use in severe inflammatory diseases with high mortality risk, such as steroid-refractory acute graft versus host disease.


Remestemcel-L, the company’s lead experimental therapy, consists of culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. Remestemcel-L is thought to have immunomodulatory proper- ties to counteract the cytokine storms that are implicated in various inflammatory conditions by down-regulating the production of pro- inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflam- matory cells to involved tissues.

Missed Endpoints

Several companies ended development of experimental rare disease therapies following clinical trial failures. Ocugen in June said it would not continue development of its experimental therapy OCU300 for ocular graft versus host disease based on results of a pre-planned interim sample size analysis conducted by an independent data monitoring committee, which indicated the trial was unlikely to meet its co-primary endpoints upon completion. Graft versus host disease is a rare disorder that can occur when the immune system is deficient or suppressed, and is a reaction to donor immune cells against host tissues after receiving a bone marrow transplant or a non-irradiated blood transfusion. The company said it would shift its resources to focus on its modifier gene therapy programs for patients suffering from blindness diseases.


Santhera Pharmaceuticals discontinued development of its experimental drug Puldysa in patients with the neuromuscular condition Duchenne muscular dystrophy after an interim analysis of its phase 3 study concluded that the study was unlikely to meet its primary end- point. Santhera had been developing Puldysa for DMD patients in respiratory decline who receive concomitant glucocorticoid treatment. The company withdrew its European market- ing authorization application and ended the global development program for Puldysa.


Puldysa was not the only DMD therapy to end in a late-stage failure. Catabasis Pharmaceuticals stopped development of its experimental drug edasalonextent when it failed to meet its primary and secondary endpoints in the phase 3 PolarisDMD study in patients with DMD. Edasalonexent is an experimental small molecule that was being developed as a treatment for DMD, regardless of the underlying mutation driving the disease. The drug inhibits NF-kB, a protein that is activated in DMD and drives inflammation and fibrosis, muscle degeneration, and suppresses muscle regeneration.


Other companies terminated development of their therapeutic programs after they failed  to meet study endpoints. Newron Pharmaceuticals’ terminated of the development of its experimental drug sarizotan for the rare neurodevelopmental condition Rett syndrome after top-line results from its phase 2/3 study evaluating sarizotan showed it failed to meet the primary or secondary efficacy endpoints. ChemoCentryx ended development of its experimental therapy CCX140 for the treatment of focal segmental glomerulosclerosis, a condition that causes scar tissue to form on parts of the kidney that filter the blood, after it failed in a phase 2 study.


And Millendo Therapeutics ended development of its experimental treatment livoletide in patients with Prader-Willi syndrome after topline results from a pivotal trial showed no significant improvement in key symptoms compared to placebo, the primary endpoint of the study. Prader-Willi syndrome is a complex neurodevelopmental genetic disorder characterized by an insatiable hunger.

Seeking a Way Forward

Two other companies that suffered clinical disappointments for experimental Prader-Willi therapies continued to seek a path forward for their therapies despite missing their primary study endpoints.


Soleno Therapeutics in June reported that its experimental therapy diazoxide choline- controlled release tablets for Prader-Willi syndrome failed to meet the primary endpoint in a phase 3 study. However, the company said significant changes were observed in two of three key secondary endpoints from baseline to week 13 in subjects receiving the drug as compared to placebo. This includes improvement in Clinical Global Impression of Improvement score as assessed by the investigator and in reduction of measured body fat mass. Caregivers also reported improvements in certain behaviors based on responses to a questionnaire.


Another Prader-Willi drug, Levo Therapeutics’ LV-101, also failed to meet its primary end- point of controlling appetite in a late-stage study. LV-101 is an intranasal formulation of carbetocin, an analog of oxytocin and a selective oxytocin-receptor agonist. A deficiency of the neuroendocrine hormone oxytocin is believed to be contributory to the hyperphagia of Prader-Willi syndrome.


Zynerba is also seeking a way forward for its CBD gel Zygel, which was in a pivotal study for the rare genetic developmental disability fragile X. Top line results from the 14-week pivotal study failed to achieve statistical significance versus placebo in its primary endpoint of improvement in the Social Avoidance subscale of the Aberrant Behavior Checklist. It also failed to demonstrate statistical significance versus placebo in the three key secondary endpoints.


But a pre-planned ad hoc analysis of the most severely impacted patients in the trial, as defined by patients having at least 90 percent methylation of the impacted FMR1 gene, demonstrated that patients receiving Zygel achieved statistical significance in the primary endpoint of improvement at 12 weeks of treatment in the Social Avoidance subscale of the ABC-CFXS compared to placebo. This group comprised 80 percent of the patients enrolled in the CONNECT-FX study. Zynerba believes that full methylation occurs in approximately 60 percent of the overall FXS patient population. Based on this analysis, Zynerba said it would meet with the FDA regarding a regulatory path forward for Zygel.

A New Administration

With the Biden administration taking power in Washington and a new head of the FDA expected, whether the FDA becomes more or less aggressive about rare disease drug approvals remains an open question. Though the COVID-19 pandemic may have affected the ability of trial sponsors to conduct clinical studies, the FDA has said it did not impede its ability to review applications for new drug approvals. In June, FDA Commissioner Stephen Hahn wrote on the agency’s blog that the FDA maintained the same pace of meeting its goals on review of applications for medical products during the pandemic that it has in recent years. It expected to meet the prescription drug user fee act goals for at least 90 percent of brand, generic, and biosimilar applications.


The bigger question will be whether the delays in clinical trials caused by the pandemic translate into a slower pace of new drug applications in 2021 and beyond. A related question is whether measures taken by the new administration and the emergence of vaccines and therapies to address COVID-19 will arrest the pandemic and allow a full-throttled pace of clinical trials to resume. In fact, despite the rosy comments from Hahn, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, offered a more sober assessment in October during the Alliance for Regenerative Medicine’s Meeting on the Mesa. He acknowledged the adverse impacts of COVID-19 on all aspects of development of cell and gene therapies.


Marks said the pandemic has forced him to spend far less of his time on cell and gene therapies as demands have required him to spend about 80 percent of his time on COVID- related activities. His division is not only responsible for cell and gene therapies, but vaccines too.


“We were stretched thin before the pandemic, and with the flood of work that came in, it really had an impact,” he said, according to a report in Endpoints News. “Sometimes folks don’t like to admit this, but we all know we’ve had delayed meetings, we’ve had to delay review of some applications because of giving priority to the pandemic.”


Healthcare is expected to be a high priority for the Biden administration. And policy debates on healthcare are likely to focus on how to expand healthcare, strengthen the Affordable Care Act, add a public option to it, and address drug pricing. The Biden campaign’s statements on health policy have included the repeal of the exception to allow drug companies to avoid having to negotiate drug prices with Medicare. The campaign also called for limiting launch prices for specialty drugs that face no competition, and called for the Secretary of Health and Human Services to establish an independent review board to assess their value. The board would recommend a price based on the average price of the drug in other countries. If the drug is first entering the U.S. market, a reasonable price would be determined by members of the independent board and the rate Medicare and the public option will pay.


Other aspects of the Biden plan call for allowing consumers to import drugs from other countries if the U.S. Department of Health and Human Services has certified that the drugs are safe, taking steps to limit price increases on approved drugs, and eliminating a tax break drug companies enjoy on their ad spending. The question will be how these policies take shape and whether they will cause investors and drug developers to turn away from developing innovative therapies for rare diseases, or if they will find the smaller patient populations provide protection from any changes to the pricing landscape.

Legislation Extends Rare Pediatric Disease Voucher Program for Four Years

As the Rare Pediatric Disease Priority Review Voucher program was set to end September 30, 2020, companies began to scramble to file for the coveted designation before it expired. Congress provided a short-term extension to the program before passing legislation that will extend the program for four years.


The extension came in a $1.4 trillion appropriations bill that passed on December 21, 2020. The voucher program will now continue through the end of fiscal 2026 for therapies granted Rare Pediatric Disease designations by September 30, 2024.


One reason why the designation is prized is because if a therapy with the Rare Pediatric Disease designation wins approval, the sponsor can be awarded a priority review voucher. The vouchers can be used to reduce the time of an FDA new drug approval review to six months from ten months. The vouchers are transferable and can be sold. That makes them potentially lucrative.


Under the 21st Century Cures Act, the General Accounting Office was instructed to make a review of the FDA’s Priority Review Voucher program. In January, the GAO reported that there had been a few studies that examined the PRV programs, but those that did found they had little or no effect on drug development.


The GAO, however, said all seven drug sponsors that it spoke with stated that vouchers were a factor in drug development decisions. Six sponsors said they were one of several factors, while one sponsor said they were pivotal in its decision to develop a drug. The GAO also noted that some academic researchers and stakeholders expressed concerns about the vouchers as incentives for drug development, including the potential for the expected revenue from the sale of a PRV to decline as more are awarded and available for sale. Congress created the Rare Pediatric Disease Voucher program in 2012.


It followed a similar program intended to incentivize companies to develop therapies for tropical diseases. An additional voucher program was later created to encourage the development of medical countermeasures.


Companies that have earned a voucher have been able to sell them at a wide range of prices from a high of $350 million to a low of $67.5 million. Though there is no obligation to report the price of a sale, many companies do so, particularly if they are publicly held.


The vouchers are also a source of revenue for the FDA as it collects user fees for priority reviews. From 2011 through 2018, the GAO reported the agency collected $44 million in priority review voucher user fees.


While there may be debate about how powerful an incentive the vouchers provide for encouraging the development of therapies for rare pediatric diseases, they have been an undeniable source of non-dilutive funding for rare disease drug developers. The 11 voucher sales by rare pediatric disease developers for which the GAO recorded known voucher sale prices between February 2014 and May of 2019 generated nearly $1.6 billion for the companies.

Legislation Expected to Boost Development of Precision Medicines for Rare Pediatric Cancers

In August 2020, the Research to Accelerate Cures and Equity (RACE) for Children Act took effect, requiring developers of molecularly targeted cancer therapies to evaluate their therapies for children’s cancer if the molecular target is relevant to pediatric cancers. Though cancer is the leading cause of disease-related death in children in the United States, pediatric cancers are considered rare diseases.


While precision medicine is transforming the treatment of cancer, its benefits have largely come in medicines for adults. Pediatric cancers have not benefited from these advances in part because cancers have been described by where they occur in the body rather than the underlying molecular mechanisms driving the disease. There are nearly 900 drugs in the adult cancer pipeline, however only a handful are in development for children, according to Kids v Cancer, a patient advocacy organization.


“This innovation gap is due to the incentives companies have to focus on adult treatments,” the organization said, “and, as a result, the difficulties researchers have accessing promising new drugs for children.”


The legislation, which updates the Pediatric Research Equity Act, requires drug developers who seek an approval for a new precision cancer therapy create a pediatric study plan before they can seek marketing approval.


“Put simply, it is now standard practice for drug companies to develop their drugs for children with cancer. As a result, pediatric oncologists will have more precision medicine clinical trial options to offer young cancer patients and their families,” PRA Health Sciences wrote on the contract research organization’s blog. “These types of trials are expected to put more pediatric oncology drugs in the pipeline, ultimately offering improved therapeutic outcomes and decreased long-term side effects.”


Finance: A Stellar Year for Rare Disease Financings


The COVID-19 pandemic didn’t hurt rare disease drug developers’ ability to raise capital in 2020. In fact, investors in the biopharmaceutical sector broadly, and the rare diseases sector in particular, had an infectious enthusiasm for funding these companies. With major market indices setting record highs despite a brief and sudden pandemic bear market, rare disease companies took advantage of the buoyant atmosphere to fill their coffers. Rare disease therapeutics developers raised $23.2 billion in 2020 through the public and private sale of debt and equity, up from $12.0 billion in 2019, a 92.6 percent increase. Rare disease companies accounted for nearly 22 percent of the total $107.7 billion raised by biopharmaceutical therapeutics companies broadly last year, up from 11 percent in 2019, according to data from DealForma and Global Genes.


One distinct difference in the year-to-year numbers was the absence of large financings to pay for blockbuster acquisitions. In 2018, Takeda raised $30.8 billion in a debt offering to fund its acquisition of Shire and in 2019, AbbVie raised $30 billion through debt to fund its acquisition of Allergan and Bristol-Myers Squibb raised $19 billion through debt to fund its acquisition of Celgene. As a result, total investment in biotherapeutics broadly and rare disease companies fell short of the record levels reached in 2018, but set records for IPOs and venture funding.


To calculate financial data for this report, Global Genes used the DealForma database in addition to its own proprietary data gathering. We considered only therapeutics developers for tracking purposes and did not include diagnostic, device, or other life sciences companies. We sought to get an accurate representation of financial activity in the rare disease sector. While it is not difficult to find data by indication (such as cancer, neurology, cardiovascular), companies are not categorized as rare disease companies.


Because many companies pursue both orphan and non-orphan indications, we did not want to distort these figures by categorizing a transaction or financing as rare disease just because a drug in a company’s pipeline had an orphan designation. The difference between a rare disease company and a traditional biopharmaceutical company can be particularly blurred in the area of cancer as the targeting of narrow indications can cause a large number of drugs to be considered orphan therapies. In the end, our editor and financial editor made judgment calls through multiple discussions to determine whether a transaction or financing should be most accurately categorized as general biopharmaceutical or rare disease on a transaction by transaction, product by product, and company by company basis. We have sought to be consistent in our analysis but recognize that others doing this same exercise might include or exclude companies differently.

A Banner Year for Venture Funding

Venture investors turned up their spending on rare disease companies in 2020 as drug developers targeting orphan indications raised $7.2 billion in venture capital in 96 transactions with disclosed values. That was more than three times the $2.2 billion raised in 2019 through 34 transactions with disclosed values. Average deal values in 2020 rose to $74.7 million up from $66.1 million the previous year. That’s more than that $54.1 million average for biopharmaceutical venture financings overall in 2020. A total of 45 financings were series A rounds, up from just 10 deals in 2019. These rounds accounted for $2.2 billion (31 percent) of the total rare disease venture funding, up from $562.4 million (25 percent) of the total rare disease venture funding in 2019.


Cell and gene therapy companies dominated the list of biggest venture deals in 2020 accounting for seven of the year’s ten largest funding rounds. Sana Biotechnology, which is developing engineered cells as medicines, topped the list with an eye-popping $700 million in venture funding. The company, founded by former Juno Therapeutics CEO Hans Bishop, is developing therapies for serious diseases such as cancer, central nervous system diseases, heart disease, and various genetic disorders. It has not revealed specific indications it is pursuing.


Of the 96 rare disease venture financings in 2020, 22 carried values of $100 million or more. Only two financings raised $10 million or less. Investors were unafraid to pursue early-stage companies. A total of 25 deals were for plat- form/discovery stage companies and 28 were for preclinical/IND stage companies. Of the financings for companies in clinical development, 13 companies had a lead asset in phase 1 studies, 14 had a lead asset in phase 2 studies, and five had a lead asset in phase 3 clinical trials.


Companies developing therapies for neurologic indications were the largest group of companies to raise venture funding as 28 companies raised nearly $1.7 billion. For example, Praxis Precision Medicines raised $210 in venture funding—launching in May with more than $100 million in funding and a phase 2 pipeline of experimental therapies for genetic epilepsies, movement disorders, and psychiatric disorders, then following at the end of July with a $110 million round. It completed $218.5 million IPO in October. Annexon, which is developing complement inhibitors for neurologic and immune disorders, raised $100 million in a series D round at the beginning of July, then completed an IPO at the end of the month adding another $251 million to its coffers.

A Go-Go IPO Market

One thing that may have helped drive venture financings was the liquidity the IPO market provided investors as 2020 proved to be a record setting year for rare disease initial public offerings. Rare disease therapeutics developers raised $4.5 billion in 2020 in 25 offerings. That eclipsed the $1.5 billion that 11 rare disease companies raised through IPOs in 2019. The IPO class of 2020 raised an average of $180 million per offering, up from $137.9 million a year ago and greater than the $171.1 million raised on average by biotech IPOs overall.


The market quickly rewarded investors for their confidence in these companies as these issues enjoyed an average 35.8 percent first day return, roughly the same as the 35.1 percent for biotech IPOs overall. Rare disease IPOs ended the year up 81.7 percent from their offering price but were bested by the 93.5 percent change in price for biotech IPO shares overall at year-end. One other sign of the enthusiasm for these issues was that in 2020, they involved no insider buy-ins. That compared to buy-ins of 36.4 percent in 2019 and 71.4 percent in 2018.


Forma Therapeutics, a clinical-stage biopharmaceutical focused on the development of therapies for rare hematologic diseases and cancer, completed the largest rare disease IPO of the year at $319.3 million. The company’s lead experimental therapy is olustasidenib, a selective inhibitor of mutations in the enzyme isocitrate dehyodrogenase 1 in development for acute myeloid leuke- mia. It is also being studied in certain forms of brain cancer and may have use in other solid tumors. The company is also developing an experimental ther- apy for the rare hematological condition sickle cell disease.


At the time Forma went public, the company’s lead program was in phase 1 clinical development, a sign that public investors were not afraid to buy shares

in early-stage companies. Perhaps more telling is that six of the ten largest rare disease IPOs involved companies that had a lead program that had not yet reached human clinical trials. Overall, 24 of the 25 rare disease IPOs were for companies with a lead program that was phase 2 or earlier. Eight of the companies had lead programs that were preclinical. Only one company, Harmony Biosciences, had a marketed product. Harmony developed pitolisant for narcolepsy and is working to broaden its indications to include Prader-Willi syndrome.


Gene therapy companies dominated the IPO haul with Beam Therapeutics, Passage Bio, Generation Bio, Akouos, Freeline Therapeutics, Taysha Gene Therapies, and 4D Molecular Therapeutics raising a combined $1.5 billion. Together, they accounted for nearly a third of the overall rare disease IPO investment in 2020. The most advanced programs for each of these companies were either in preclinical or phase 1 development.

Secondary and Debt Offerings Rise

Rare disease companies already trading publicly also took advantage of the welcoming capital markets. Overall, public rare disease companies (excluding IPOs) raised a total of $9.7 billion in equity financings, up from $6.1 billion in 2019. Equity fundings by rare disease companies in 2020 represented nearly a quarter of the total $41.2 billion raised by therapeutics companies across the biotech sector.


Rare drug developers raised $1.8 billion in debt in 2020, down from the $2.2 billion raised in debt offerings in 2019. Three of the offerings in 2020—a $600 million convertible debt from BioMarin Pharmaceutical, a $400 million debt offering from Amicus Therapeutics, and a $425 million convertible offering from BridgeBio accounted for 77 percent of the total.


Rare disease companies developing therapies for endocrine/metabolic disorders, neurologic, and hematologic diseases accounted for $5 billion or 43 percent of the total equity and debt raised by these companies in 2020. Companies developing gene therapies or gene editing raised a total of $4.5 billion in public equity and debt, 39 percent of the total raised.

Rare Partnering Slows, But Deal Values Grow

With capital markets a welcoming source of cash, rare disease partnering activity fell 5.9 percent to $4.5 billion at signing from $4.8 billion at signing in 2019. The number of rare disease therapeutics partnering deals with disclosed values fell to 48 in 2020 from 65, but deal values grew richer. The median upfront cash and R&D funding in partnering rose to $40 million in 2020. That compared to median upfront cash and R&D funding value of $30 million in 2019. Partnering activity for all biotherapeutics deals rose 19.7 percent to $18 billion from $15.1 billion the previous year.


Total potential deal value for rare disease partnerships rose to $35.2 billion, a 10.1 percent increase from the $32 billion in partnering deals in 2019. That was a smaller increase than the 37.3 percent in potential deal value for all therapeutics partnering deals in 2020, up from $111.3 billion in 2019. The total number of rare disease partnerships fell to 135 from 192 the previous year. Of the 48 deals with disclosed upfront payments, ten included the sale of equity. That compared to 65 deals with disclosed values the previous year in which 8 included the sale of equity.


Despite the drop in partnering activity, the average upfront payments (including R&D funding) rose to a median of $40 million, a 33 percent increase over the $30 million median upfront payment in 2019, and more than twice the $19 million companies secured through partnerships in 2018. The average total potential deal value grew to $734.9 million, up from $492.4 million in 2019 and continued the upward trend from $308.6 million in 2018.


Takeda was among the most active drug companies on the partnering front, entering seven rare disease therapeutics collaborations in 2020. These included an agreement with Carmine Therapeutics worth up to $900 million to dis- cover, develop, and commercialize non-viral gene therapies for two rare disease targets using the company’s platform technology based on red blood cell extracellular vesicles. As part of the agreement, Takeda committed a $5 million convertible loan to support development of Carmine’s platform technology.


Takeda also entered into an agreement with Evox Therapeutics covering up to five novel protein replacement and mRNA therapies for rare diseases including Evox’s preclinical program in the rare lysosomal storage disorder Neimann-Pick type C disease. Takeda paid $44 million upfront and committed to milestones of up to $838 million.


Sarepta Therapeutics was also active on the partnering front, completing five deals in 2020. The largest of these involved an exclusive global license to develop and promote Hansa Biopharma’s imlifidase as a pre-treatment for gene therapy in Duchenne and limb-gridle muscular dystrophy patients who have pre-existing anti- bodies to adeno-associated viruses, which are used as vectors for gene therapies. Sarepta paid Hansa $10 million up front and will pay up to an additional $397.5 million in milestones in addition to tiered royalties in the mid-teens on incremental gene therapy sales that arise from treating antibody positive patients enabled through imilfidase pre-treatment.


Other companies that were involved in substantial partnering activity include Moderna, which entered into separate agreements with Vertex focused on genetic therapies for cystic fibrosis, and with Chiesi Farmaceutical focused on mRNA therapies for rare diseases. The three-year collaboration with Vertex provided Moderna with $75 million upfront and up to $38 million in milestones plus tiered royalties on any products that result from the collaboration. The Chiesi agreement, which provided a $25 million up front and more than $400 million in milestones and double-digit royalties on sales, is focused on pulmonary arterial hypertension, a rare and progressive disorder characterized by high blood pressure in the arteries of the lungs with concomitant heart failure.

AstraZeneca Buys a Rare Disease Giant

Rare disease M&A deal value at signing rose to $58.9 billion in 2020, up from $18.9 billion in 2019 thanks largely to AstraZeneca’s $39 billion acquisition of Alexion, a company focused on rare immune-mediated diseases. Alexion shareholders will receive $60 in cash and 2.1 AstraZeneca American Depository Shares for each Alexion share, which values Alexion at $175 per share, a 43 percent premium on its closing price ahead of the announcement of the deal. The acquisition provides AstraZeneca with a strong footing in rare dis- eases and enhances its position in immunology.


Alexion is a pioneer in developing therapies that inhibit the complement system, part of the immune system. The complement cascade is pivotal to the innate immune sys- tem. It plays a crucial role in many inflammatory and autoimmune diseases across multiple therapeutics areas, including hematology, nephrology, neurology, metabolic disorders, cardiology, ophthalmology and acute care. Activist share- holders had been pushing Alexion to explore a sale because of what they had termed “persistent underperformance.”


Alexion markets therapies that treat immune- mediated rare diseases caused by uncontrolled activation of the complement system, including Soliris, a first-in-class C5 monoclonal antibody for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. The company also markets Ultomiris, a second-generation C5 monoclonal antibody with a more convenient dosing regimen. Alexion has a pipeline of 11 molecules across more than 20 clinical-development programs in a spectrum of indications, in rare diseases and beyond.


Johnson & Johnson’s acquisition of Momenta Pharmaceuticals, a developer of therapies for rare immune-mediated diseases for $6.5 billion was the second largest acquisition in the rare disease space in 2020. The deal will allow J&J’s Janssen Pharmaceutical to broaden its leadership in immune-mediated diseases and drive further growth through expansion into autoantibody-driven disease. The deal gives the company full global rights to the late-stage experimental therapy nipocalimab, a potential best-in-class drug in a new class of therapies. Nipocalimab is in development for warm autoimmune hemolytic anemia, myasthenia gravis, and hemolytic diseases of the fetus.


Bayer’s acquisition of the gene therapy developer Asklepios Biopharmaceuticals for $2 billion upfront and up to an additional $2 billion in milestone payments continued a move among the largest pharmaceutical companies to stake a claim in the emerging area of gene therapy. Asklepios, known as AskBio, has a pipeline of experimental preclinical and clinical stage candidates that includes treatments for rare neuromuscular, central nervous system, cardiovascular, and metabolic diseases. Lead programs include treatments for Pompe disease, Parkinson’s disease, and congestive heart failure. The company also has several active collaborations, including ones with Pfizer in Duchenne muscular dystrophy and with Takeda Pharmaceutical in hemophilia. The company provides Bayer with coveted gene therapy manufacturing capabilities, a robust pipeline of clinical programs, and a broad estate of more than 500 patents.


The deal follows M&A activity of several large biopharma companies in recent years to move into gene therapy. This includes the 2019 acquisitions by Roche of Spark Therapeutics for $4.3 billion, Astellas Pharma of Audentes Therapeutics for $3 billion, Biogen of Nightstar Therapeutics for $800 million; and the 2018 acquisitions by Sanofi of Bioverativ for $11.6 billion, and Novartis of AveXis for $8.7 billion.

The Year Ahead

The year in biotech financings usually gets a jump start with the annual J.P. Morgan Healthcare Conference in San Francisco, along with a number of shadow conferences that run concurrently. But the COVID-19 pandemic cast its shadow over capital markets at the start of 2021. Rather than bringing together thousands of biotech executives and investors in San Francisco for a week, the investment conferences that set the tone for the year were conducted virtually.


Though the wear of the pandemic on the economy could dampen investors’ appetites, the rare disease and therapeutics sectors more broadly have some insulation from the impact of the pandemic relative to sectors like retail, real estate, and tourism, all of which are more directly impacted.


The bigger concern for the industry will be questions about the future of the Affordable Care Act, the landmark healthcare legislation passed during the Obama administration, how the U.S. Supreme Court will rule in the challenge to the law before it, and what the new Biden administration will do to address healthcare reform. With those policy discus- sions there will be renewed focus on drug pricing and that could cause drug developers to become less attractive to investors and lead to questions about the economic viability of emerging therapeutics with high price tags.


Treatment: A Pandemic Thrusts Telehealth into the Spotlight


For Shafali Jeste, one outcome of the COVID-19 pandemic may be a long-term change to the way medical services are delivered. Jeste, a physician- researcher, has been doing her best to adjust to continuing her work during an infectious disease pandemic. While she did what she could to keep her long- term research projects going, she also needed to meet the needs of patients with complex medical conditions who faced disruptions to their access to services. Like many practitioners, the solution for Jeste has been to make a shift in her clinical practice to telehealth.


Instead of seeing patients in her office, the behavioral neurologist who specializes in autism and related neurodevelopmental disorders, calls patients from her home. Like many physicians, she admits to having long-held resistance to telehealth, something that was not part of her medical school training. But, she said, she has come to embrace it.


“I think of it like ripping off the Band-Aid. In large healthcare systems, we have all been trained in telehealth because we need to be moving towards making our work more scalable across the board,” said Jeste, director of the Care and Research in Neurogenetics, or CARING, Clinic at UCLA. “It does not replace in-person human contact at all, but it can be helpful, especially in rare diseases where these families are all over the country and there are very few specialty sites for them to be seen by someone who has expertise in whatever their condition is.”


The families of her patients, she said, have had concerns about the threat the virus may represent for their children. These patients have comorbidities, such as seizure disorders. Parents have also expressed concern about the closing of schools, which brought with it the loss of access to critical services and fears that their children would regress and pay a price for the loss of structure in their daily lives that the school day provided. For Jeste, the key was to get her patients through the immediate crisis of the pandemic, manage expectations, and help parents address any challenges around severe issues, such as self-injurious behavior and aggression.


Using telehealth opened Jeste’s eyes to its potential. She believes the experience will accelerate its adoption throughout health systems after the pandemic ends. “It’s taught me I could do a lot more telehealth,” she said. “Patients appreciate it, especially in L.A. where you have to navigate traffic and parking. It’s such a pain in the neck, especially when you have a child with a developmental disability and challenges. It’s stressful.”

A Global Disruption to Care

The COVID-19 pandemic created a seismic disruption to the treatment of patients with rare conditions. Several rare disease and health organizations surveyed the rare disease community to document the effects of the pandemic on patients and their access to needed medications and care.


“People affected by a rare disease, and families and caregivers, initially asked how to avoid the virus. Then they became concerned about access to medicines and maintaining medical care during the pandemic, and the status of clinical trials,” said Tiina Urv, program director of the National Institutes of Health’s Rare Diseases Clinical Research Network, which launched a research survey of 5,000 members of the rare diseases community to determine how the pandemic was impacting patients, their families, and caregivers. “They were concerned about meeting the medical challenges that they face every day. We were hearing enough anecdotally that we wanted to get a clearer picture of the problem.” As of this writing, the RDCRN had not released the results from its study.


But what Urv was hearing anecdotally was being documented in other surveys of rare disease patients that found the pandemic was having far-reaching effects on patients and their families. A National Organization for Rare Disorders study conducted in April 2020 that surveyed 772 rare disease patients and caregivers across the United States reported 95 percent of respondents said the pandemic had impacted their long-term health and well-being. Almost all of the respondents (98 percent) expressed worry about the virus and nearly three quarters (74 percent) said they had a medical appointment canceled because of the pandemic.


In Europe, the European Organisation for Rare Diseases, EURODIS, released preliminary results from a multi-country survey that explored how the pandemic was affecting people living with a rare disease. The survey, also conducted in April 2020, included responses from more than 5,000 rare disease patients and their family members from all European Union countries, as well as unspecified other countries from April 18 to April 28. Respondents represented nearly 1,000 different rare diseases.


Six in 10 respondents who said they had experienced an interruption in care because of the pandemic said it was detrimental to their health or the health of the person for whom they care. Three in 10 of those said the interruptions “could definitely” or “probably” be life threatening. As hospitals curtailed services to focus on responding to the pandemic and minimizing the risk of infecting people, the survey found that six in 10 rare disease patients said they did not have access to medical therapies at home or at the hospital anymore, such as infusions, chemotherapy, and hormonal treatment. More than half of rare disease patients who needed surgery or a transplant saw their interventions canceled or postponed.


Routine testing and visits have been impacted as well. More than six in 10 rare disease patients lost access to diagnostic tests, such as blood or cardiac tests, and medical imaging that are often a crucial part of their daily care. Nearly seven in 10 had appointments canceled with general practitioners or specialists who provide care for the rare disease. And eight in 10 saw their appointments for rehabilitation therapies postponed or canceled.


About half of those surveyed said that they have made use of some form of telemedicine since the start of the pandemic. Almost nine in 10 of those who have experienced this type of consultation said they were happy with the experience and said that it has been very or fairly helpful. “It is clear the COVID-19 pandemic has a collateral impact on the health and quality of life of the 30 million people living with a rare disease in Europe, and indeed around the world,” said Sandra Courbier, social research director at EURORDIS, which has long collected data on the experience of rare disease patients’ difficulties in accessing care. “By creating new barriers, the current pandemic is worsening this already difficult situation. We are seeing cases where this triggers a strong feeling of anxiety among families.”


The patient organization Rare Disease Ireland called on the Irish government to ensure that in the effort to address the COVID-19 pandemic, rare disease patients weren’t left behind. “Since COVID-19 arrived in Ireland, we have witnessed huge restrictions on hospitals for everything except COVID-19 and emergency care,” said Vicky McGrath, CEO of Rare Diseases Ireland. “The fact that rare disease care is routinely provided by hospital- based consultants within the hospital setting, has had particularly negative consequences for the care of rare disease patients during this pandemic.”


In conducting its own survey on the impacts of the pandemic on rare disease patients in Ireland, the organization found similar problems with canceled appointments and difficulty accessing medicines and medical supplies. But it also found patients expressing anxiety over the pandemic and its effect on access to care. Three quarters (73 percent) of the 176 patients and caregivers who responded to its survey in the spring of 2020 indicated that they were concerned about their own or their loved one’s rare disease. They also expressed concern about how their health was deteriorating without access to the usual healthcare they receive, and fear about how an already complex disease may be negatively impacted if they became infected with COVID-19.


“It’s a black hole with no light,” wrote one respondent. “Condition has deteriorated—once a skill isn’t used consistently, it’s forgotten, and can’t be retaught,” wrote another respondent. “I am scared,” wrote a third. “If they have too many persons in intensive care would they make the decision not to treat me due to me having several comorbidities? As my condition is so rare, most staff in hospitals do not know how to treat me.” Some two-thirds (62 percent) of the survey participants reported that they believe that COVID-19 was having a negative impact on their mental health.


Rare Diseases Ireland’s McGrath said many rare disease community members feel as if they have been left to fend for themselves and they are struggling to best manage. She said the government needs to consider the full range of people’s medical needs during this pandemic, including those with rare diseases. “Many people with rare conditions spend years pursuing a diagnosis in the hope of therapeutic relief, so it is particularly frustrating when we hear of empty hospital beds and under-utilized resources,” she said. “In our collective efforts to combat one disease, COVID-19, it is important that other diseases are not left behind.”

Telehealth Enters the Spotlight

The use of telehealth has soared in the wake of the pandemic. By May 2020, 46 percent of U.S. consumers were using telehealth compared to just 11 percent in 2019, according to the consulting service McKinsey & Company. It reported that providers moved quickly to scale their telehealth offerings and were seeing 50 to 175 times the number of patients through telehealth visits than prior to the pandemic. Though many healthcare providers were using telehealth prior to the pandemic, they were doing so in a limited way.


Before COVID-19, approximately 13,000 Americans enrolled in the traditional Medicare program received telehealth services in an average week. In the last week of April, nearly 1.7 million Americans enrolled in traditional Medicare received telehealth services. In total, more than 9 million Americans in traditional Medicare received a telehealth service between mid-March and mid-June, according to Senator Lamar Alexander, R-Tennessee, during remarks he made at the end of July when he introduced legislation to expand the use of telehealth.


At Children’s Mercy Health in Kansas City, Missouri, telehealth has long been promoted in its epilepsy clinic, but with the pandemic, the hospital moved quickly to apply it in other areas. Patients and their families responded well to being able to access care in this way. “It can be efficient, and in some areas, for example, in behavioral medicine, psychiatric disorders, in adolescent kids, they’re more comfortable in front of a computer than in front of a human being,” said Tom Curran, executive director and

chief scientific officer of the Children’s Mercy Research Institute. “There are many lessons that came from COVID-19 that we want to retain for the future. Flexible working strategies and a greater embrace of telehealth are two of the most important ones.”


Jeffrey Gelblum, a senior attending physician with First Choice Neurology in Florida, the largest neurology group in the United States, has long used telehealth to see patients, but prior to the pandemic, he said its use was largely driven by the need to accommodate patients who were traveling, or couldn’t get away from work, or take the time to drive to the office and find parking. Since the pandemic, though, it’s grown to about 50 percent of the patient visits compared to about 10 percent before the pandemic.


Gelblum, who follows a number of patients with the rare disease hereditary amyloid neuropathy, said making an office visit can often become a significant logistical challenge for people with the rare disease. People with the condition suffer weakness and numbness in their hands and legs, and they may encounter difficulties driving or walking. They may also rely on help from caregivers who work during the day. “Televisits, in terms of rare diseases, are transformational,” he said. “There’s really no barrier in terms of works. The laboratories can go to the patients. Mobile diagnostics are available. It’s allowed us to keep in touch with patients in disparate geographies, but also to enable access to people who have difficulty getting to the office.”


Telehealth has gained recognition in the rare disease community as an important mechanism for delivering care. In September 2020, Global Genes (the publisher of NEXT 2021) and the Child Neurology Foundation released a report out- lining a set of guiding principles for rare disease care and access that the groups said are universally relevant to all patients with rare diseases. The report grows out of the groups’ Rare Access to Critical Therapies collaboration begun in 2018. In it, the groups discuss non-conventional channels for healthcare delivery, such as telehealth, as a way to ensure equitable delivery of care for people with rare diseases and the potential for reducing the burden of providing care to them. “Telehealth is an under-leveraged tool to address the challenges of wide geographic dis- persion, travel burden, and access to specialty care experts for rare disease patients,” the report said. “Telehealth may also provide economic efficiencies compared to traditional in-person care when leveraged alongside conventional approaches appropriately.”


The groups noted that while many states man- date that Medicaid and private insurers provide  coverage for telehealth to the same extent as coverage for in-person and local care, the reality is that payer and access trends in telehealth vary widely with no two states defining, reimbursing, or regulating telehealth in the same way.


That’s an issue of some consequence. U.S. telehealth players, which generated annual revenue of $3 billion, could see telehealth capture up to $250 billion in current healthcare spending, according to McKinsey & Company. But the consulting firm said that despite the rapid uptake, there is nothing inevitable about a shift to telehealth. Providers remain concerned about security, workflow integration, and the effectiveness of telehealth visits. And perhaps the bigger obstacle is the long-term question about how payers will treat reimbursement for televisits.

The Payer’s Call

In fact, reimbursement, rather than technology, has been the long-standing barrier to telehealth. Payers have long been unwilling to reimburse most types of telehealth visits. Nevertheless, many payers were quick to change their policies in the face of the pandemic, if only on a temporary basis. The Coronavirus Aid, Relief, and Economic Securities (CARES) Act expanded the use of telehealth and provided waivers and flexibility to Medicaid. That legislation was subsequently extended through the end of 2021. Several bills have been introduced to extend or make permanent changes to the range of telehealth services for which Medicaid will pay.


Senator Alexander, chairman of the Senate Committee on Health, Education, Labor & Pensions, introduced legislation at the end of July 2020 that would make permanent certain changes to telehealth. He said the bill, dubbed the Telehealth Modernization Act, would help to “ensure that patients do not lose the benefits that they have gained from using telehealth during the COVID-19 pandemic.”


The legislation would make permanent in-home visits and rural telehealth access, but it would also give the Secretary of Health and Human Services au- thority to make permanent other changes implemented during the pandemic. It would ensure that patients can access telehealth anywhere by permanently removing Medicare’s so-called “geo- graphic and originating site” restrictions, which required both that the patient live in a rural area and use telehealth at a doctor’s office or clinic. Congress temporarily ended these restrictions in March 2020, allowing millions of Americans to talk with their doctor virtually during the pandemic. Making this change permanent, he said, will ensure Medicare beneficiaries do not lose that ability when the pandemic ends.


The legislation would also give the Secretary of Health and Human Services new authority to help patients continue to access telehealth from physical therapists, speech language pathologists, and other health care providers. And it would allow the secretary to permanently expand the types of healthcare providers who can offer telehealth services beyond just doctors, nurse practitioners, and physician assistants.


Though patients seem ready to embrace telehealth, questions remain about payers’ commitment to paying for these services and at what level they are willing to do so. They would like to see evidence of the value of these services, and that in turn threatens to slow the rate at which providers are willing to invest in the needed infrastructure to support an expansion of telehealth offerings.


Girish Navani, CEO of the health technology company eClinicalWorks, is quick to point to the economic benefits that telehealth pro- vides, noting that the travel cost and time off from work a patient must commit to see a physician generates immediate savings. While that may provide financial benefits to patients, it does not represent a benefit to payers, who have long resisted providing reimbursement for telehealth visits broadly and only imple- mented temporary measures in the face of the pandemic.


“If there is not reimbursement, it will become a difficult thing to be used in terms of care delivery, because you’re now asking for somebody to spend time that they’re never going to get reimbursed for,” said Navani. “That’s clearly been a hurdle in the past. The COVID pandemic relaxed it. And so we saw a significant steep increase because reimbursement was not the barrier to entry or usage for telehealth.”

Free Monitoring Devices to Rare Disease Patients

The Rare Genomics Institute in March 2020 launched the RareWear program, a global philanthropic initiative to connect rare disease patients with medical device technology providers to better monitor and manage rare disease conditions.


Three medical device technology providers—Bodimetrics, Biotricity, and Strados Labs—are participating in the initial phase of the program. Rare disease patients will have the opportunity to apply for and receive free device technologies that do such things as monitor vital signs, track activity and sleep, monitor seizures, and provide pain management among other things.


“Traditionally, the application of medical device, monitoring, and wearable technology to manage rare diseases has been an underserved space, and this initiative to bring patients and technology providers together fills a much needed gap,” said Jimmy Lin, founder of Rare Genomics, which works to fill the healthcare gap for patients with undiagnosed rare conditions. “The partnerships with current medical device providers will allow patients with cardiac, respiratory, neuromuscular, and other conditions, as well as their families and clinicians, to monitor metrics relevant to their disease area and benefit from the real-time information these devices provide.”


Rare Genomics said it is working to expand the scope of the program both in terms of technology partners and its outreach to patients through collaborations like the one it has for the program with Inspire, a patient social network with more than 700,000 rare disease patients.

Rare Disease Patients More Likely to Suffer Depression and Anxiety

People with a rare disease are more likely to suffer depression and anxiety than people with more common diseases, even if symptoms are similar, researchers at Oregon State University report in a study published in the journal Health Psychology.


Just being rare invites in a whole other set of challenges that we think most people with any sort of rare disorder experience,” Oregon State University researcher Kathleen Bogart of the School of Psychological Science in the College of Liberal Arts said, pointing to such things as stigma, psychological distress, and struggle getting a diagnosis and treatment.


The study, which surveyed 1,218 adults across the United States who have a rare disease, grouped participants in clusters based on age of onset, disease progression, visibility and symptom severity. The survey asked participants how their disease affects their daily life, including physical pain and fatigue as well as depression and anxiety.


Results showed that regardless of the specific disease, people in the “early onset with very severe symptoms” and “severe symptoms” clusters showed the highest rates of psychological distress, though almost all clusters studied reported clinically significant anxiety and depression. The “stable” cluster fared much better, results showed, likely because the more predictable nature of the disease process resulted in less uncertainty and distress.


While funding for diseases tends to focus on looking for treatments and cures, the cost of developing basic psychological tools could be far lower, Bogart said. There is currently no specific psychological intervention to support people with rare diseases, such as cognitive behavioral therapy or standards for screening patients for depression and anxiety.


Other measures could involve the rare disease community and organizations. They could help a patient with a rare disease meet with other rare disease patients close to home, instead of the patient having to travel three states to find a support group for people with their specific disease.


“When there are 7,000 disorders, it’s unreasonable to expect that you could cure them all within patients’ lifetimes. Only 5 percent of those diseases have treatments or cures,” Bogart said. “So, we need to think about practical ways that we can improve people’s quality of life in the meantime, and fortunately, we don’t have to think about it disease by disease when we think about psychological distress.”

Finding Others with the Same Condition

Shortly after Claire Barrow was diagnosed in 2019 with hypophosphatasia, a rare, genetic disorder that causes abnormal development of bones and teeth and leaves them prone to fracture and deformity, she tried to learn about how it would affect her.


Claire, who is 13, was diagnosed a month after her mother was diagnosed with the condition. She was having a hard time coming to terms with what having the disease meant for her future. When Claire tried to learn about the condition, she found that neither her mother nor information available online could give her the answers she sought about what being a teenager with hypophosphatasia was like. That’s when her mother gave her some tough love.


“My husband and I told her, and what I was really telling myself,” said Heather, “is that, ‘We found out about this and it’s not what anybody would want to have, but you need to stop dwelling on being diagnosed with it and find something positive.’”


Claire and her brother Hill liked to watch Shark Tank, the reality TV show where entrepreneurs pitch investors, and last summer they decided to pitch their parents on an idea Claire had. They told their parents that they should create an app to help rare disease patients with the same conditions connect with each other.


The family was still trying to deal with finding doctors and developing a treatment plan, but the kids persisted. As Heather and her husband Bennett talked, they decided it would not only be good for Claire, but also for the whole family, and could help others experiencing the same challenges they were.


“We talked about it and thought this would be a great outlet for her and for us to bring something positive from this, not just for people with hypophosphatasia, but help other families not have to go through years and years of getting turned away by doctors, and trying to find answers,” said Heather, “by connecting patients who know about their disease with each other so they could share information about what they are doing that works and the doctor that they are seeing.”


The RareGuru app is free. It is available in the United States, Canada, Australia, New Zealand, Ireland, and the United Kingdom. It is designed for people age 13 and older. Patients and caregivers can use the RareGuru app to connect with other users that have the same conditions, are experiencing the same symptoms, or using similar treatments. Users can create individual or group messages with connections to share personal stories and health data to support one another and obtain new knowledge on shared diagnoses.


Because the app can connect users not only based on disease, but also on symptoms, it is intended to be useful to people who have not yet received a diagnosis, as well as people who may face common issues.


Claire, who said she has dealt with anxiety and found it helpful to talk to friends, pushed her parents to include mental health symptoms in the app as well.

If a RareGuru user is matched to another user, they will see their name, age, status (patient/caregiver/ both), shared diagnosis, shared symptoms, location, and when they were last active on the app. Users are free to share as much or as little information as they like in their profiles.


By October 2020, the app had more than 2,500 users and was growing steadily. It also planned to launch a news feed on the app for users to receive customized information based on their diagnosis, symptoms, or users they choose to follow. As for Claire, she has since launched her own interview series Rare with Claire on the company’s website and Facebook.

Co-Pays for Kids’ Rare Disease Drugs Soar

The proportion of inflation-adjusted total healthcare spending on orphan drugs for privately insured children grew by 65 percent between 2013 and 2018 as it rose to 6.6 percent from 4 percent, largely due to price growth of these medicines, according to a study in Health Affairs.


The study, authored by Kao-Ping Chua, assistant professor in the department of pediatrics at the University of Michigan Medical School in Ann Arbor, and Rena Conti, associate professor in the department of markets, public policy and law at the Questrom School of Business at Boston University, found that mean annual out-of-pocket spending for orphan drugs was higher for children than adults.


Though insurance companies pay much of the cost of orphan drugs that treat rare childhood diseases, families’ share of the cost has risen rapidly. The researchers found that mean out-of- pocket spending on orphan drugs for kids rose to $866 in 2018, up from $486 in 2013. The out-of-pocket costs for these families were higher than those faced by adults who take orphan drugs.


About 1 in 8 families paid more than $2,000 out-of-pocket on orphan drugs in 2018, twice the percentage of those who spent that much in 2013. The sharp increase was largely due to the approval of new drugs and the overall price growth of these drugs, the authors said. Small-molecule drugs drove much of the increase in orphan drug spending, with a 162 percent rise in five years, compared with a 16 percent rise for biologic drugs.


Ten orphan drugs accounted for 52.9 percent of pediatric orphan drug spending in 2018. During each year of the study period, orphan drugs approved to treat short stature represented at least two of the five top- selling biologics. The researchers note that other research has shown that many children who don’t have a rare condition receive these two drugs through off-label prescribing aimed at boosting their height.


In 2018, the SMA drug Spinraza and the cystic fibrosis drugs Kalydeco and Orkambi accounted for the three highest spending totals among small-molecule orphan drugs.

“Findings demonstrate that pediatric orphan drug spending is increasingly burdening payers and families and suggest that payers should better protect families against the prices of orphan drugs by improving benefit designs,” the authors wrote.


Endworld: Beyond the Pandemic


At the start of 2020, the 11th International Conference on Rare Diseases and Orphan Drugs published a “call for global action for rare diseases in Africa” in Nature Genetics. The conference included the launch of the Africa-Rare initiative, an alliance of advocacy organizations working for the recognition and treatment of rare diseases in Africa. The commentary, developed in collaboration with the International Rare Diseases Consortium, synthesized the deliberation outcomes and offered a summary of the efforts required to address the global effects of rare diseases on public health.


“To address global rare-disease burden, jurisdictional initiatives must be coordinated with international research, development, and collaboration across health systems to ensure that the benefits of these activities accrue to patients and families globally,” they wrote.


In China, where the government released its first list of rare diseases in 2018 consisting of 121 conditions, it followed in 2019 with a reduction of the value-added tax to 3 percent from 16 percent on 21 drugs and four active pharmaceutical ingredients for rare diseases. Separately, it also launched an information system to register all patients treated for a rare disease since 2015 in the hopes of improving their diagnosis and treatment. In a country where the availability and affordability of therapies to treat rare diseases remains a problem, these changes are laying the groundwork for the emergence of rare disease drug companies in China.


For instance, Citrine Medicine, a company founded by a group of Western venture capital firms, completed an $80 million financing round with Chinese venture capital firms to support its efforts to bring rare disease therapies to the Chinese market. It already announced a licensing deal with the French drug developer Bioprojet SCR that provides Citrine with exclusive rights to the narcolepsy drug pitolisant in China.


“Recent regulatory reforms and policy changes in China are paving the way for an expedited drug approval pathway for rare disease drugs, and Citrine is poised to leverage this positive environment to deliver much-needed therapies to the people who need them,” said Chong Xu, principal at F-Prime Capital and a Citrine board member.


In India, after the government failed to implement a rare disease policy approved in May 2017, India’s Ministry of Health and Family Welfare in January 2020 issued a draft national policy for rare diseases. The policy outlined a set of immediate measures including the creation of a rare disease patient registry, the formation of a definition of rare disease suitable to India, the development of materials to raise awareness of rare diseases among the public and healthcare providers, and the creation of a central and state level fund to provide partial payment for rare disease treatments. Longer-term measures call for the establishment of systems for data collection and reporting; improvements in research, diagnostics, and development of treatments for rare diseases; the pursuit of measures to encourage drug development; and a measure to control prices of drugs for rare diseases to ensure affordability and health system sustainability. Patient advocates, though, said the policy falls short of what is needed to assure rare disease patients access to rare disease therapies that exist today.


In Latin America, a 2020 study of six countries found that while rare disease regulatory frameworks and legal protections are relatively new, decision makers lack reliable information and have only recently become aware of the  challenges posed by rare diseases. While in Canada, where the Speech of the Thrones lays out the government’s goals at the opening of a new session of parliament, Governor General of Canada Julie Payette kicked off the new session on September 23, 2020. Among the initiatives outlined in the speech was a call for a rare disease strategy to help Canadians save money on high-cost drugs. The call comes less than a year after the government committed $760 million (CAD $1 billion) to a national Rare Disease Drug Strategy to be put in place in 2022. The Canadian Organization for Rare Disorders has initiated an effort to build a consensus on what a national Rare Disease Drug Strategy should look like.


While none of these efforts represent a solution to the issue rare disease patients and their families face in obtaining a diagnosis, therapies, or care for rare diseases, it does represent a growing trend around the world to create rare disease frameworks and policies that could help address what is largely an unmet need for as many as 400 million people worldwide.


While global efforts to recognize, diagnose, and treat rare diseases have increased, the development of policies have been slow, and implementation remains a challenge in places where policies have been formulated. Two notable trends have been the emergence of rare disease consortia to expand advocacy efforts in various parts of the world and speak with a coherent voice, and the effort to create mechanisms to recognize and pay for rare disease therapies. In fact, a December 2020 study in Value in Health that examined orphan drug polices in 194 countries and six areas found that of the 200 countries or areas examined, 92 had orphan drug policies.


There is no worldwide agreement on what con- stitutes a rare disease, how many rare diseases there are, and how many people are afflicted by them. Nevertheless, if there is a theme that speaks to the challenges faced by people with rare diseases and the researchers, healthcare providers, and diagnostic and drug developers, it can be summed up in the word “access.” Researchers need access to data. Drug develop- ers need access to capital and patients. Patients need access to diagnoses, treatments and care.


As the new year in biotechnology kicked off with the annual J.P. Morgan Healthcare Conference going virtual, it was a reminder of the persistence of the COVID-19 pandemic and its broad ranging effects on efforts to advance the treatment of rare diseases. There is reason for optimism in the year ahead. Below is a list of major trends to watch for in 2021 in rare disease.


Moving Beyond the Pandemic


As 2020 drew to a close at least two vaccines that appeared to be highly effective at protecting people against the COVID-19 virus were being delivered to patients. There are logistical challenges in manufacturing and distributing the vaccines, but there’s reason to believe the pandemic could be brought under control by the third quarter of 2021, if not sooner. The pace of progress should increase as rare disease organizations, researchers, drug developers, and others are able to pursue their work unimpeded by the need for social distancing and travel restrictions, and can once again meet in person rather than convening on Zoom.


It is still hard to tell how deep the delays and damage from the pandemic will prove on the rare disease sector. One area that will likely come into focus as the pandemic ebbs is the extent to which rare disease organizations have suffered a financial toll from the virus. While there are likely to be some positive changes in the way organizations work as a result of the pandemic, some that were overly reliant on annual events to fund their operations will likely look to broaden and diversify their fundraising sources.


Reaching Patients Where They Live


While the pandemic did not create telehealth or invent remote clinical trials, it has accelerated the trend among providers and clinical trials sponsors to make use of video conferencing technology, to use remote monitoring tools, and to use in-home testing services or remote labs to gather biosamples. While ubiquitous broadband, smartphones, and camera- enabled devices had already armed patients with the tools they would need for a world of digital health, payers, providers, and regulators had moved cautiously until the pandemic necessitated swift action.


Payers have warmed to telemedicine and demonstrated a willingness to reimburse providers for services delivered this way. The U.S. Food and Drug Administration also demonstrated a flexibility to allow for remote clinical trials and this can be particularly useful in the world of rare diseases where patients may be geographically dispersed and have difficulty traveling because of medical conditions.


In the year ahead, look for legislation and regulations to expand the use of telehealth and remote clinical trials, as well as the growing availability of technology to better enable the ability to perform care and studies remotely. While the embrace of these technologies served an immediate need, they have also proven to provide savings of time, money, and increased convenience to patients. In the rare disease world, where patients often have to travel great distances to meet with specialists, the greater use of telehealth promises to improve care.


Getting Real


The growing use of telehealth and remote monitoring devices is also expanding the ability to capture real-world data that can be harnessed to help address the challenges of understanding rare diseases, revealing how a condition progresses over time, and identifying appropriate endpoints for therapeutic studies. It can also allow drug developers to gain greater insight into what a meaningful benefit to a patient might be.


With the signing of the 21st Century Cures Act at the end of 2016, Congress gave the FDA a mandate to consider how it could incorporate real-world evidence into the regulatory review process to accelerate the development of life-saving medicines so that people who needed them could get them faster. Real-world evidence comes in many forms. In today’s connected world, it can come from a diverse range of sources as information technology has enabled the collection and analysis of unstructured data. Real-world data includes electronic health records, medical claims and billing data, data from patient registries, as well as patient-generated data from the use of mobile devices. As the ability to harness real- world data becomes easier through advances in information technology, it promises to help address a data gap in rare disease therapeutic development that can slow or limit patient access to transformative therapies.


Learning to Share


Like other forms of data, real-world data will have the greater impact the more widely it is made available. There is a growing movement to break data free from silos and foster data sharing to improve the diagnosis of rare disease and accelerate the development of new therapies. In addition to the establishment of RARE-X, a non-profit that is building a federated platform for the sharing of patient-owned data, other efforts are seeking to remove barriers to data sharing. The World Economic Forum has called for a global approach to diagnosing and treating rare diseases. It has laid out a framework for sharing genomic data and is seeking to demonstrate its vision of a federated approach through an international pilot program it hopes will serve as a proof of concept. And in Europe, an effort, led by the Berlin Institute of Health involving 20 university hospitals and partner institutions across Germany, announced a rare disease collaboration known as CORD-MI, a project that seeks to improve patient care and research in the field of rare diseases.


The efforts reflect a recognition that because there are limited patients with any particular rare disease, it is critical to pool and share data. Such efforts will also enable researchers to look across diseases to find common links in seemingly disparate conditions. These efforts will require significant investment, technology, and cooperation among different stakeholders, but 2021 will be an important time for these projects to show that they can tackle obstacles, overcome cultural

barriers, and convince data holders of the value of cooperation.


Speaking Bespoke


The year ahead will also be an important one for advancing the feasibility of individualized therapies and therapies for ultra-rare populations. There are several efforts underway to deliver treatments to individual patients. While this has already been achieved, the feasibility of these approaches remains unproven across multiple patients.


As efforts become more numerous one challenge will be for regulators to develop an efficient and predictable path for these therapies. Developers will also need to find ways to scale and industrialize the process if it is to reach a broad number of patients in need. And patient advocates will need to engage payers and demonstrate that the approach can deliver meaningful benefits to patients and value to justify their support.


Reforming Healthcare


A week after the national election, the U.S. Supreme Court heard a challenge to the Patient Protection and Affordable Care Act, the signature healthcare reform legislation passed by the Obama Administration. At question is the constitutionality of the portion of the law known as the individual mandate, which requires virtually everyone to have insurance or face a penalty for not complying, and whether the rest of the legislation could stand without it. The individual mandate survived an earlier Supreme Court challenge as it was ruled within the taxing authority of Congress.


What set the stage for the current challenge was the package of tax cuts Congress passed in 2017 in legislation known as the Tax Cuts and Jobs Act. Among other things, the legislation established that the penalty for individuals failing to comply with ACA’s individual mandate would be nothing. In 2018, the state of Texas and 19 other states, along with two individuals, argued that setting the penalty for failing to comply with the individual mandate to nothing meant it could no longer be considered a tax and therefore made the mandate unconstitutional. But they didn’t stop there. The plaintiffs argued the mandate is essential to the Affordable Care Act and if it is struck down, the entire law becomes invalid. A group of 20 patient organizations, including the National Organization for Rare Disorders, the Muscular Dystrophy Association, and the Hemophilia Federation of America, filed an amicus brief with the court asking the court to keep the ACA in place.


“The costs of treating such serious conditions are often staggering and beyond the financial means of most individuals and families. The central question is not whether individual Americans will incur health care expenses but how those expenses will be financed, and the extent to which patients will forgo treatment if they cannot afford it,” the patient organizations said in the amicus brief. “Without the health insurance facilitated by the ACA, access to vital health care services and the quality of health outcomes diminishes, making it more difficult to manage the myriad chronic diseases and conditions that Amici help Americans fight and treat every day. Few Americans have the means to pay for adequate treatment of these diseases without insurance coverage—for most Americans, insurance is a not a luxury, but a prerequisite to obtaining life-saving and life-sustaining treatment.”


The court is expected to rule in the first half of 2021, but the questioning from the justices indicate that even if a majority finds a reason to toss out the individual mandate, they do not see it essential for the rest of the law to remain in place. With the new administration, the question will likely shift to efforts to expand the law and put into place a government-run health insurance plan that people could choose to buy into as an alternative to private insurance. Though Vice President Kamala Harris will give Democrats a tie-breaking vote in the Senate, the 50-50 split in the chamber will limit how ambitious the Biden administration will be able to be on healthcare reform and will likely require it to build consensus across the aisle.


Advancing a Rare Disease Agenda


As the new Congress takes office, the seventh incarnation of the Prescription Drug User Fee Act (PDUFA) is already taking shape. The law, which will need to be passed in 2022 and take effect in 2023, was first passed in 1992 and must be reauthorized every five years. The law was created to ensure applications for drug approvals are reviewed in a timely fashion and led to industry paying user fees to ensure predictable timelines for drug reviews. The PDUFA legislation, though, has served an important role in bringing about changes to the drug review process.


One issue rare disease advocates are expected to push for in PDUFA VII is the creation of a Rare Disease Center of Excellence at FDA similar to what the agency did when it created the Oncology Center of Excellence. The center would provide a ready source of expertise to weigh in on issues ranging from clinical trial design to drug reviews, and work across the different centers and offices of the agency. The other issue likely to get attention from rare disease advocates is to strengthen efforts that began with the 21st Century Cures Act to put into place additional means of ensuring patient-centered drug development by incorporating patient input throughout the drug development process and getting regulators to take into account the patient perspective on the daily burden of disease and what meaningful benefits from treatments look like.


In 2020, the FCS Foundation and the Haystack Project succeeded in getting the Helping Experts Accelerate Rare Treatments Act, or HEART Act, introduced. Among other things, the act would require the FDA to include members of its rare disease program staff in reviews of therapies for rare diseases, would require the FDA to include rare disease experts on advisory committee panels for rare disease drugs, and consult members of the rare disease patient community when creating or reviewing risk evaluation and mitigation strategies for rare disease therapies. The legislation was introduced in July 2020 and referred to the House Committee on Energy and Commerce without further action. PDUFA VII will be an opportunity for advocates to push for the HEART Act as well.


Firing All Cylinders of the Drug Development Engine


While the emergence of vaccines provides hope of the pandemic receding, once it is extinguished the question will remain about how long its impact will last on drug development. As regulators and drug developers focus on their existing pipelines, a clearer picture should emerge on whether the pace of new drug approvals will suffer any ill effects.


At the same time, a new administration in Washington, D.C. will bring with it a new chairman at the U.S. Food and Drug Administration. Newly elected President Joe Biden has been an advocate for greater clinical trials transparency, as well as greater cost transparency. As someone who lost a son to cancer and played a leading role in the Obama Administration’s Cancer Moonshot, Biden has been a strong advocate for government funded R&D and this should be a plus for the rare disease community. One key appointment to watch is Biden’s pick to head the FDA and to what extent leadership embraces emerging technologies, works to increase the patient voice in drug development, reduces barriers to the approval of therapies for rare diseases, and addresses the unique circumstances of trials in these conditions, or brings a more conservative approach to regulating therapeutics.


Thinking Globally


Rare diseases know no borders. Often rare disease patient populations are too small within a given country to collect adequate data needed by researchers to understand a condition and bring together participants for a clinical trial. In parts of the world where advocacy efforts have lagged, more developed organizations can help educate patient populations and help advocates in other countries learn from their experience to raise awareness about rare diseases.


There is an awakening of rare disease advocates beyond the wealthiest and most developed nations. Already there are organizations working on a large international scale to advance issues of import to rare disease patients, but small organizations, particularly for ultra-rare conditions, have an opportunity to amplify their voices and build critical mass more quickly by thinking globally. While the pandemic has increased the comfort level for online conferencing, organizations will still need to consider new ways to build connections, making materials available in multiple languages and engaging researchers and physicians outside of their home country. As advocates raise their visibility in places like China, India, and Nigeria, there is an opportunity to reach millions of people with rare diseases to help each other in both big and small ways.


Testing Commitment


The death of George Floyd at the hands of Minneapolis police officers in May 2020 ignited a social movement beyond the United States in calls for racial equality and justice. As with many other industries, biopharmaceutical executives issued statements about their commitment to diversity and inclusion and their social media channels featured similar proclamations. Within rare disease advocacy, organizations began to consider diversity, equity, and inclusion policies, and to consider their importance.


Among the most visible efforts in rare disease came from The Black Women’s Health Imperative, a nonprofit organization dedicated to advancing health equity and social justice. It established the Rare Disease Diversity Coalition to focus on reducing racial disparities in the rare disease community against what’s been called the “twin pandemics of pervasive racism and the COVID-19 outbreak that has hit people of color hardest. In November, it launched its RISE for Rare campaign to build awareness around the health disparities communities of color face in the context of rare diseases.


While the challenges of finding a diagnosis and treatment for a rare disease are well documented, racial disparities can intensify the ability to access care, lead to underrepresentation in research, and impede participation in clinical trials. It contributes to the challenges of getting a timely diagnosis and adequate treatment, and delays in doing so can result in more serious health consequences for people of color.


The issues are layered and complex. Social determinants of health, such as income and environment, can play a role in worsening health outcomes for minorities. At the same time, there is distrust within the African American community toward biomedical researchers and doctors due to a history of events ranging from the Tuskegee study (in which African American men who were infected with syphilis were followed by doctors, but denied treatment) to the case of Henrietta Lacks, whose cancer cell line has been central to research, but was used without her consent or knowledge and without compensation.


If the COVID-19 pandemic has taught us anything, it is that we all pay a price for inequities in healthcare. The same is true in the rare disease space, where expanding patient communities are critical to developing an understanding of a condition and driving action to combat it. In the case of genetic-based diseases, where understanding genetic variation is essential, rare diseases advocates would be wise to recognize it is in their own self-interest to foster inclusivity.

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