Turning to Patients to Help Drive Rare Disease Drug Development

Doctor and family_Nicole Bean for BioSpace

Pictured: A physician stands with a family against a drug development background/Nicole Bean for BioSpace 

Across industry and academia, many people working to discover new treatments have expertise won through years of formal education and benchwork. But there’s also a faster, harsher path to a very particular scientific expertise: a rare disease diagnosis for oneself or a loved one.

Consider Sam Berns and his family. When Sam was diagnosed with progeria in 1998 at 22 months of age, not only was there no treatment; there was no known cause. Children with progeria show signs of rapid aging by the age of two and had a life expectancy of just 14.5 years when Sam was diagnosed. Today, there are only about 400 people with progeria worldwide.

Leslie Gordon, Sam’s mother, recounts her experiences in a video produced as part of a patient drug development course created by the National Organization for Rare Disorders (NORD), FDA and the Critical Path Institute. With their son’s life on the line, Gordon and Sam’s father, Scott Berns, both doctors, helped launch the Progeria Research Foundation (PRF).

To advance understanding of the disease, PRF started a registry of patients that collected medical information and helped families connect with each other and the organization. The registry enabled PRF and the National Institutes of Health to conduct a natural history study, and it supported research that pinpointed the gene responsible for the condition. PRF then funded the creation of a mouse model and funded and coordinated a clinical trial on a candidate drug, lonafarnib, that had originally been developed as a cancer treatment. In 2020, the FDA approved lonafarnib as the first therapy for progeria. It is now marketed as Zokinvy by Eiger Biopharmaceuticals.

PRF isn’t alone. Many other patient advocacy groups (PAGs) formed by families coping with rare diseases actively support research around the condition. These groups can be a boon to drug companies interested in developing treatments, said Cheryl Herbert, vice president for marketing & communications at NORD.

“The PAGs are the secret sauce. The PAGs are everything,” she told BioSpace. “They’re the patients; they’re the experts on the disease. They know how to get the community to trust the industry, to participate in the clinical trials, to trust to hand over the data.”

As we approach Rare Disease Day (which falls, appropriately, on February 29), BioSpace spoke with Herbert and others involved with PAGs about how these organizations can effectively work with biopharma companies to develop new treatments for their conditions.

Laying the Foundation

As with PRF, it’s common for PAG members to find that basic information about their disease is lacking. To help fill in the gaps, it’s often necessary to organize a natural history study, said NORD Executive Vice President Pam Gavin.

That was the tack taken by the Friedreich’s Ataxia Research Alliance (FARA), founded in 1998 to support patients with the degenerative neuromuscular disorder. “The organization quickly, in establishing the mission and the strategy, made an important decision, which is to focus on advancing research,” said FARA CEO Jennifer Farmer. FARA began raising money and distributing competitive research grants. It also worked with partners on a natural history study and on developing clinical outcome measures, an animal model and a cell line repository.

“We looked at both preclinical and clinical development and said . . . What are the things that we can bring that support all programs . . . that’s meaningful across the space?” Farmer explained. “And that’s how we got to also, from a research perspective, investing and making sure resources and infrastructure were available for industry partners coming into the FA space.”

FARA’s support for basic research led to the discovery of a pathway that’s downregulated in the disease, Farmer said—and it turned out that some drug companies already had candidates in development for other conditions that targeted that pathway. One of them was Reata Pharmaceuticals, which has since been acquired by Biogen.

Teaming Up

FARA contacted Reata to introduce the research around FA and how its drug candidate, omaveloxolone, could be applied. Reata agreed to conduct clinical trials and received the FDA’s go-ahead to use an assessment tool called mFARS, whose development FARA had facilitated. On February 28, 2023, the FDA approved omaveloxolone (brand name Skyclarys) as the first therapy for FA.

Friedreich's ataxia run_FARA

Pictured: FARA CEO Jen Farmer and FARA community members/The Friedreich’s Ataxia Research Alliance

Farmer said Reata is far from the only company FARA has worked with, both in the early discovery phase and during clinical trials. “Pretty much every clinical trial that’s been done in FA, FARA has been able to help companies through that clinical development” with awareness, education, recruitment and an understanding of FA, she said. She added that insights gleaned from FARA’s study of the disease’s natural history can also inform how companies design their trials.

Another group that has had success in helping to bring a new drug to the market is the Desmoid Tumor Research Foundation (DTRF). Desmoid tumors are locally aggressive but non-metastatic growths that, depending on where they occur in the body, can cause pain and affect mobility or organ function. Founded in 2005, DTRF got a call a few years later from a National Cancer Institute (NCI) researcher, Shivaani Kummar, about a potential collaboration.

Kummar had seen a poster at a conference with the results of a Phase I trial run by Pfizer that tested a candidate called nirogacestat in solid tumors. The trial included some patients with desmoid tumors, and Kummar noted that the results had been promising. She was interested in organizing a Phase II trial of the drug at NCI in desmoid tumors specifically but needed DTRF’s help to recruit enough patients with this rare disease.

“We have a database of thousands of patients and caregivers,” said DTRF co-founder Jeanne Whiting. “We reached out to them, and where [the trial organizers] thought it would take two years or more to fill the trial, we filled it in a matter of less than six months.”

Although nirogacestat continued to show promise in the Phase II trial, Pfizer made a business decision before the trial was finished to end its production and development. DTRF lobbied the company to change course. Marlene Portnoy, DTRF’s other co-founder, remembered calling a contact at Pfizer every week for months. “We didn’t let go; we kept moving,” she said. While they couldn’t get Pfizer to restart nirogacestat’s development, Portnoy and Whiting heard that there was support within the company for pushing the candidate forward. Whiting recalled meeting a Pfizer scientist at a cocktail party who told her, “‘I’ve spent my 25-year career at Pfizer throwing compounds together and trying different combinations. . . . This is the only one that has ever worked. We have to get this to patients.’”

In 2017, Pfizer formed a spinoff company, SpringWorks Therapeutics, to which it licensed nirogacestat. Whiting was invited to speak to the entire staff of the new company. “I’ll never forget the feeling of walking into that room at SpringWorks where I was going to give my talk,” she said. “It was only 30 [employees] but . . . to have that many people dedicated to studying our disease—I mean, it was just the beginning of a huge success in so many different ways for us.”

Soon after its founding, SpringWorks began a Phase III trial of nirogacestat in desmoid tumors, and again DTRF helped connect interested members with the trial. With positive Phase III trial results in hand, SpringWorks won FDA approval for nirogacestat (Ogsiveo) in November 2023. “It was, in all, 12 years or more of a journey for us,” Whiting said. “But that is really record time, actually, especially given the fact that [desmoid tumors are] a rare disease.”

DTRF will “continue to be very valuable partners for us and important for the patient community,” Kim Diamond, vice president of communications and investor relations at SpringWorks, told BioSpace.

DTRF Co-founders_Bob Carey

Pictured: DTRF co-founders Jeanne Whiting (L) and Marlene Portnoy (R) in 2023/ Bob Carey

Keys to Successful Collaboration

Even under the best of circumstances, many drug candidates won’t make it over the finish line. But experts who spoke with BioSpace noted some steps that both companies and PAGs can take to boost the chances of a successful collaboration. At the outset, said NORD’s Gavin, “I think it’s really helpful for companies to assess the readiness of the PAGs to engage in a way that allows them to rigorously move forward.”

Namely, the PAG should be a 501(c)(3) with a board of governance, she said. It’s also helpful if the group has a scientific and medical advisory committee. “If some of these building blocks are missing, it puts more onus on the company and potentially more risk to them,” she explained.

NORD’s Herbert added that companies should invest in PAGs they decide to work with, given that the organizations are typically volunteer-run and have limited resources. “That doesn’t always just mean money,” she said. “That can be a dedicated person that can help with things, just as simple as educational materials, a dedicated person to work on the website.”

Good communication is also vital, Diamond said. “It’s a two-way street in terms of listening to the patient groups—they know their patient community better than anyone else,” she said. Concurrently, SpringWorks made staff available to answer questions from the organization and notified DTRF right away when it publicly released information relevant to the group, such as when the clinical trial was fully enrolled and when results were released.

In FARA’s collaboration with Reata, “having respect and trust was absolutely essential,” Farmer said.

Even once there’s an approved treatment for a given rare disease, a PAG’s research-related work isn’t done, PRF’s Gordon noted in her video presentation. Zokinvy, for example, expands patients’ average life expectancy by several years, and the organization has continued to push for the development of additional options. “Never think that you’re finished,” she advised, “because there’s always more you can study, examine, and more you can discover.”

Collaborations with patient groups are “beneficial for any treatment, but they are essential for rare disease,” Gavin said, given the need to connect with a relatively small number of patients and with academics who’ve studied the condition. And the stakes are high, she noted. “In many cases, these companies have one chance at bat. Just like the patients.”

Shawna Williams is a freelance writer and editor based in New York City. She can be reached at shawna.williams@biospace.com or on LinkedIn.

Clarification (Feb. 27): The article has been updated to list all the partners involved in creating the online course in which Leslie Gordon spoke.

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