ALS disappointment should not close the door on patients

FDA needs to learn from the Relyvrio experience, create consistent science-based policies for reviewing orphan drugs

FDA’s approval of Relyvrio for amyotrophic lateral sclerosis was supposed to be the poster child for regulatory flexibility, an inflection point that would chart a regulatory path for drugs to treat a host of rare neurodegenerative conditions. In the wake of the disappointing results from a Phase III trial, it could turn into something quite different, a cautionary precedent that may reinforce conservative approaches at FDA and further undermine payers’ confidence in the agency’s decisions.

Lawyers say that hard cases make bad law. For the sake of patients, difficult drug development programs should not be allowed to make bad policy.

New regulatory approaches are sorely needed for rare disease drugs. They need to reflect scientific consensus, and to be applied via a well-reasoned and consistent decision-making framework. One-off moves make the drug development process unpredictable for both patients and companies, and are all too likely to backfire.

To prevent Relyvrio from turning into a broader setback for patients and drug developers, FDA, or even better, an independent third party, should conduct an analysis of the experience and make recommendations for improving the way the agency handles similar situations.

Those recommendations are needed because this wasn’t the first and certainly won’t be the last time patients with a terrible, rare disease are clamoring for immediate access to a drug backed by equivocal data with no biomarker in sight.

The worst outcome would be for regulators to close the door on patients by raising the bar for orphan drug developers across the board. A lack of appreciation by some FDA review divisions of the unique challenges presented by small populations suffering from diseases with heterogeneous symptoms coupled with a refusal to accept new tools for generating evidence is already stymieing orphan drug development. The situation is especially acute for ultrarare diseases.

As BioCentury has reported, FDA’s reluctance to even consider a dataset that academic experts in Barth syndrome believe demonstrates efficacy threatens to rob patients with the disease of their best hope.

And the agency’s skepticism about a biomarker for neuronal mucopolysaccharidoses (MPS) has, in the view of scientific opinion leaders, caused children to experience unnecessary and tragic irreversible brain damage. Hopefully, a recent workshop will persuade the agency to adopt a science-based approach to approving neuronal MPS therapies based on heparan sulfate measured in cerebrospinal fluid.

Another bad outcome would be for FDA to send the signal that the only way to get some therapies approved is for patient advocates to convince agency leaders to intervene in the review process. Drug regulation is too important to be left to the whims of individuals, or to be seen as anything but fair and science-based.

There should be clear, consistent standards for approving drugs for rare conditions, not an unspoken and inconsistently applied empathy standard.

An unusual FDA panel, an even more unusual deal

An after-action analysis of the Relyvrio situation should look into the extraordinary steps FDA took to get the drug approved, including the unusual bargain Billy Dunn, the former director of the Office of Neuroscience at FDA’s Center for Drug Evaluation and Research, made with Amylyx Pharmaceuticals Inc. (NASDAQ:AMLX) to justify full approval.

FDA reviewers were deeply skeptical that data from a Phase II trial demonstrated Relyvrio’s efficacy. The agency initially told Amylyx to submit an NDA only after completing a Phase III trial.

In the face of intense criticism from the patient community, FDA relented and accepted an NDA based on the Phase II data. An advisory committee voted 6-4 that the data were insufficient to support approval.

Usually that would have led to a predictable outcome. The company, and patients who were not enrolled in a trial, would have been forced to wait for completion of the Phase III trial.

Dunn, however, scheduled a highly unusual second advisory committee meeting. At that meeting, he described FDA’s imperative to exercise regulatory flexibility for rare, serious diseases, and its legal authority to approve a drug based on a single adequate well-controlled trial plus confirmatory evidence. This was seen by rare disease advocates as a breakthrough.

Dunn then did something even more unusual at the meeting. He asked Amylyx for a verbal commitment to withdraw Relyvrio from the market if it was approved and the Phase III trial failed to demonstrate efficacy.

Following the company’s agreement to this condition, which is not legally binding and was not spelled out in detail, the advisory committee voted 7-2 to recommend approval.

An analysis of the Relyvrio experience should consider whether it was appropriate for Dunn to ask a sponsor to make such a commitment, and whether patients are well served by this kind of unenforceable, vague promise.

Even if Amylyx can be trusted to act on its commitment, it isn’t difficult to imagine other companies wriggling away in a situation in which there is a great deal of money at stake. It also isn’t hard to imagine payers questioning whether they can rely on a full approval when it seems to be contingent.   

Amylyx has reported over $400 million of Relyvrio sales. The negative Phase III trial may diminish demand, but some patients with no other options are likely to want to believe in it.

Maybe the U.S. should have a conditional approval standard, but it doesn’t. It does, however, have an accelerated approval pathway.

An analysis of the Relyvrio situation should evaluate whether an accelerated approval, supported by interim clinical data from the Phase II trial, would have been appropriate. This would have given FDA a clear, legally enforceable basis for withdrawing the drug if the Phase III trial failed to confirm clinical benefit.

The law also allows companies to provide unapproved drugs through expanded access, also called compassionate use. Compassion for patients is certainly what drove FDA to approve Relyvrio.

Given the urgent unmet need, the drug’s benign safety profile, and data that at least suggested benefit, an expanded access program may have been the best option. It would have addressed the desires of ALS patients who were outraged by the prospect of waiting 18 months for completion of the Phase III trial, and it would have allowed Amylyx to collect safety and outcomes data that could have provided useful information.

Under this option, Amylyx would have provided Relyvrio at no cost, and would have paid for administering an expanded access protocol, until the drug was approved. That isn’t an insignificant cost, and companies have the right to decline to bear it.

Congress and the ALS community have recognized the utility of expanded access. The Accelerating Access to Critical Therapies for ALS Act (ACT for ALS), crafted with input from ALS patients and signed into law in December 2021, established an NIH grant program. It pays companies to facilitate expanded access programs that make it possible for ALS patients who are not eligible for a clinical trial to receive unapproved treatments in an expanded access protocol.

Drug developers, especially small biotechs, need to be able to commercialize their products, so expanded access shouldn’t be the default option when FDA has to make a difficult decision. But in some cases, it is the best — or least bad — option.

In the case of Relyvrio, expanded access would have saved the healthcare system hundreds of millions of dollars and allowed ALS patients to access the drug without spending their own money on co-pays and deductibles. It would also have avoided another dent in payer confidence in FDA approvals.

One way to look at the Relyvrio experience is that FDA took a reasonable gamble and lost, and that the risk of such losses is acceptable if similar bets help patients access drugs more quickly.

Another perspective is that the agency short-circuited its procedures and granted full approval when other options, including accelerated approval or expanded access, would have met patient needs without compromising the integrity of the review process.

Patients, FDA and the public would benefit from an investigation that determines which perspective is more accurate.

Signed commentaries do not necessarily reflect the views of BioCentury.