'Capricor, Replimune illustrate why FDA must listen to rare disease specialists'

 

Last month’s FDA advisory committee meetings for therapies developed by Capricor Therapeutics and Replimune effectively illustrate the different outcomes for patients when the agency prioritizes specialization in its reviews.

Cardiologists do not operate on brains. Oncologists do not treat Alzheimer’s disease. Yet the FDA has long allowed physicians with little or no experience in rare neurological diseases to decide the fate of novel drug candidates for patients with Duchenne muscular dystrophy, amyotrophic lateral sclerosis (ALS), Huntington’s disease, spinocerebellar ataxia and more. This is a dangerous double standard.

With more than 7,000 rare diseases, it is unreasonable to expect the FDA to possess disease-specific expertise for the 30 million Americans living with them. But in my opinion, as a Johns Hopkins–trained anesthesiologist living with amyotrophic lateral sclerosis (ALS), it is not unreasonable to expect the agency to heed the opinions of physicians whose expertise exceeds that of FDA generalists.

Two recent advisory committees effectively illustrate the disparity.

The panel reviewing Replimune’s immunotherapy RP1 for advanced melanoma showed how specialization changes outcomes. Michael Wong, physician in chief at the Roswell Park Comprehensive Cancer Institute and lead investigator for the Phase 1/2 IGNYTE trial, testified that he and his co-investigators were seeing responses to RP1 they had never seen before.

Adcomm members from MD Anderson and Memorial Sloan Kettering specializing in melanoma corrected agency errors, acknowledged limitations in the clinical outcome assessment, described the unmet need and carried the day. The committee voted 10-3 that the results were reasonably likely to predict clinically meaningful benefit. Even the statisticians deferred. RP1—now Tudriqev—won accelerated approval days later. That is what happens when true disease experts are in the room.

Now, consider the advisory committee meeting for Capricor’s Duchenne muscular dystrophy (DMD) cardiomyopathy cell therapy deramiocel, held a day earlier. DMD paralyzes young boys and kills them as young men. Those in the room without Duchenne expertise emphasized “statistical fragility.” Those who know the disease best focused on the fragility of the boys’ lives.

The advisory committee included two general cardiologists and two pediatric neurologists—none specializing in Duchenne. The trial investigators, by contrast, had spent decades treating the disease. Lead investigator Craig McDonald, chair of the Department of Physical Medicine & Rehabilitation at UC Davis Health who has led natural history studies and designed key Duchenne outcome measures, showed video evidence that deramiocel preserved upper-limb function—one of the most meaningful outcomes for these patients.

In this case, however, the investigators didn’t sway the committee. Rather than focus on this primary endpoint, adcomm members spent significant time debating whether deramiocel effectively treated the cardiomyopathy that these patients can develop—the indication for which Capricor had applied for approval, based on the HOPE-3 trial’s secondary endpoint of left ventricular ejection fraction. Here, disagreements over statistical analyses plans muddied the conclusions, and the committee ultimate voted 9-3 against deramiocel’s approval.

This is a travesty. When statistics are disputed but the clinicians who know the disease best are certain, the tie should go to the experts, who were clear in this case that deramiocel would greatly benefit the Duchenne community. Rather, Capricor seemed headed for a rejection before the company submitted additional data to support a potential approval focused on upper limb function and received a three-month extension to the FDA’s review process.

Unfortunately we’ve seen several other rare disease therapies face similar skepticism from non-experts that have derailed FDA proceedings. University College London professor Ed Wild was the lead investigator on the Phase 1/2 trial of uniQure’s Huntington’s disease gene therapy AMT-130. “My patients in the trial are stable over time in a way I’m not used to seeing in Huntington’s disease,” Wild said in a UCL press release last September.

Despite this, AMT-130 has faced repeated regulatory obstacles. UniQure finally submitted a biologics license application for the therapy this week.

At the 2023 ALS advisory committee meeting for BrainStorm Cell Therapeutics’ NurOwn, The Mayo Clinic’s Anthony Windebank and other ALS investigators described trial participants whose paralysis had been halted and who had even regained function—something they said they had never seen before in more than 40 years of practice. Yet the FDA is requiring BrainStorm to conduct a multi-year Phase 3b trial in a disease where the median survival is 2.5 years. By the time that trial concludes, tens of thousands more people with ALS will have died waiting.

At a February Senate hearing, Harvard neurologist Jeremy Schmahmann described meeting with FDA officials and submitting a letter from 17 ataxia specialists supporting Biohaven’s spinocerebellar ataxia drug troriluzole, which was rejected by the agency last November. One FDA reviewer asked Schmahmann, founding director of Massachusetts General Hospital’s Ataxia Center, “Why should I listen to you?”

Why should the FDA listen to the foremost rare neurological disease experts? Because these are the physicians to whom agency officials would entrust their own family members. Because the law requires that qualified experts conduct clinical trials and then evaluate and conclude whether the drug is safe and effective. And because the cost of failing to approve or delaying approval of a drug that works cost neurons, muscle and lives.

Cancer patients have largely escaped this problem. The Oncology Center of Excellence has brought together leadership and clinical review teams, many who have roots at the National Cancer Institute. That model has driven a majority of accelerated approvals in this space. Rare neurological diseases have no equivalent institutional home. The result is inconsistency and it is a disservice to the patients the FDA serves.

The remedy requires both structural change and immediate action. Congress should create centers of excellence organized by practice groups, as former Center for Drug Evaluation and Research (CDER) head Richard Pazdur has recommended. FDA clinical review teams should include physicians with relevant clinical and research experience. Advisory committees should be populated by clinicians with true sub-specialization in the diseases under review. And the agency should give appropriate weight to the opinions of trial investigators with decades of rare disease expertise, as the statute dictates.

But today’s patients cannot wait for structural reform. The FDA should grant accelerated approval to Capricor’s deramiocel, schedule advisory committees for Biohaven’s troriluzole and uniQure’s AMT-130 and give full consideration to the NurOwn Citizens’ Petition, which now includes eight years of survival data supporting BrainStorm’s and the experts’ views that were communicated in the 2023 adcomm.

Specialization is not a luxury in terminal rare diseases. It is the difference between life and death. FDA practice must align with the principle every patient already demands in the operating room and the clinic: decisions about human life should be made by the specialists who best understand the individual’s disease.

The FDA’s approval of Replimune’s RP1 was a reprieve for people dying of advanced melanoma. People dying of rare neurological diseases deserve the same expertise and the same humanity.

Dr. Shahriar Minokadeh is a Johns Hopkins–trained anesthesiologist and UC San Diego–trained board-certified pain management specialist. Before his ALS diagnosis at 35 years old, he was practicing in Orange County, California, and now resides in San Diego. He is currently a quadriplegic who relies upon a ventilator to breathe. He used his eye-gaze device to write this. He is one of the petitioners in the ALS Citizens’ Petition (FDA-2025-P-2019).

https://www.biospace.com/fda/opinion-capricor-replimune-illustrate-why-fda-must-listen-to-rare-disease-specialists