NEW YORK – The head of the US Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) in recent months has expressed a desire to shepherd more gene therapies for rare diseases to market through the accelerated approval pathway, bringing cheers from the biotech industry.
The agency will face its first test later this month.
Gene therapies for rare diseases have been a focal point for CBER Director Peter Marks. Earlier this year, Marks established an Office of Therapeutic Products within CBER. He has talked of hiring additional staff with experience with cell and gene therapies to review product applications and respond to sponsors' submissions, as well as kicked off a Rare Disease Endpoint Advancement Pilot Program to work with sponsors on developing evidence on novel endpoints that could facilitate accelerated approval.
On multiple occasions, Marks has said that accelerated approval will be critical to expediting gene therapies to patients, and at the American Society of Gene & Cell Therapy's (ASGCT) annual meeting in Los Angeles last month he said he wants the agency to be flexible when working with companies developing drugs for rare disease populations.
"When you're dealing with very small populations, we're probably willing to use some regulatory flexibility there," Marks said, citing challenges drugmakers face when studying the activity of therapies for rare diseases within randomized, placebo-controlled studies that may otherwise be needed for traditional approval. Accelerated approval, by contrast, allows sponsors to earn the FDA's stamp of approval by demonstrating that a surrogate endpoint is "reasonably likely" to predict clinical benefit for patients, as long as the therapy addresses an unmet medical need for a serious condition when, for example, no other treatments exist.
"That accelerated pathway model is really attractive for gene therapies," said David Barrett, CEO of the American Society of Gene & Cell Therapy, in an interview.
Marks "really seems to understand that we're at a pivotal moment, where the pipeline for new gene therapies is just exploding," added Sharon Hesterlee, chief research officer at the Muscular Dystrophy Association.
Hesterlee said she'd like to see additional guidance from the FDA on drug development for "ultra-rare" diseases, for example, how to manage small clinical studies and what an acceptable surrogate endpoint is for accelerated approvals. With rare diseases, it can be difficult to find enough patients for studies to validate that the surrogate endpoint is a reliable proxy for clinical outcomes, she noted.
"Getting that functional data is just so hard," Hesterlee said, wondering if demonstrating successful delivery of a functional copy of a particular gene or restoring protein expression will be enough, for example.
A balancing act
Marks' proposal to more readily apply the accelerated approval framework to rare disease drugs comes while industry observers are eagerly waiting to see if Sarepta Therapeutics' Duchenne muscular dystrophy gene therapy passes muster under this pathway. The company has sought accelerated approval based on the investigational treatment's impact on a novel surrogate endpoint. The FDA, originally expected to issue a decision by May 29, has pushed back the decision date until June 22.
SRP-9001 (delandistrogene moxeparvovec) is an adeno-associated virus vector (AAV)-based gene therapy designed to address mutations in the DMD gene that result in a lack of the dystrophin protein. The absence of dystrophin, in turn, causes the progressive muscle weakness that is characteristic of the disease. SRP-9001 delivers a transgene that encodes for microdystrophin, a Sarepta-engineered protein that it says can carry out the normal functions of dystrophin.
An FDA advisory committee last month narrowly voted 8-6 in support of accelerated approval, after discussing FDA reviewers' concerns about whether the surrogate endpoint tracked by Sarepta in clinical trials — change in microdystrophin expression — is reasonably likely to predict clinical benefit; FDA reviewers aren't convinced based on the data Sarepta submitted that it will.
A Sarepta spokesperson said a company expert was not available for an interview before press time, and the company previously said it will be in a quiet period until the FDA finishes reviewing its biologics license application.
Sarepta submitted SRP-9001 to the FDA as a treatment for ambulatory DMD patients, but last month, after discussions with the agency, said the gene therapy could potentially garner accelerated approval for DMD patients ages 4 to 5 years old, and there may be opportunities to expand the indication based on data from a confirmatory trial. This could be just the type of flexibility Marks had said the FDA is open to granting drugmakers.
Sarepta has proposed its Phase III EMBARK study, for which it's already finished enrollment, as a confirmatory trial. The company expects to share top-line results in Q4.
The accelerated approval pathway at times has proven controversial. In 2021, healthcare providers and insurers raised concerns over the FDA granting accelerated approval to the Alzheimer’s disease drug Aduhelm (aducanumab) based on its ability to clear amyloid plaque as a surrogate endpoint, despite unclear clinical benefits.
In response to a question about how the FDA will balance the risks and benefits of approving drugs based on surrogate biomarkers, the agency in an email said, "Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval."
"For effectiveness, the standard is substantial evidence based on adequate and well-controlled clinical investigations," the agency said. "Developing useful biomarkers requires careful scientific work and it takes extensive collaboration and attention to detail to get it right."
Approval isn't the last step
To achieve accelerated approval, drugmakers are required to perform post-market studies that confirm their drugs actually improve patient outcomes. If confirmatory data doesn't prove a clinical benefit, it could potentially result in a drug being taken off the market.
Marks at the ASGCT meeting acknowledged that the agency will "occasionally" have to remove drugs from the market that it greenlighted through the accelerated approval pathway when the benefits suggested by preliminary studies don't bear out in confirmatory trials.
It's challenging for the FDA to withdraw products from the market after they've received accelerated approval, Aaron Seth Kesselheim, a professor at Harvard Medical School and a faculty member within Brigham and Women's Hospital's division of pharmacoepidemiology and pharmacoeconomics, said during a presentation at the ASGCT meeting.
"Accelerated approval is a very useful regulatory pathway when preliminary data look promising," he said. "It's also important to recognize that the FDA has limited ability to ensure the completion of clinical trials done after a drug is approved through accelerated approval," and there's arguably limited motivation from sponsors and the FDA to withdraw treatments, he said.
Historically, sponsors haven't always completed confirmatory trials, which was an issue taken up by the US Department of Health and Human Services' Office of Inspector General in the wake of Aduhelm's approval. Even when drugs fail a confirmatory trial, companies might push back on efforts to remove it from the market.
"Understanding [the FDA's] long-term safety monitoring expectations is something that the field has always struggled with," said Brigid DeCoursey Bondoc, a partner and life sciences attorney at law firm Morrison Foerster, in an interview.
But this is precisely the promise of gene therapies, which are expected to have long-term, durable, and curative benefits. These therapies could, theoretically, be on the market for many years before confirmatory data are available, which Bondoc noted is a common criticism of the accelerated approval pathway. That said, the pathway also enables patients with life-threatening diseases who don't have other options access to the latest advances.
The FDA "will be under a lot of pressure to approve the therapies, but public trust is also on the line," she said. "I don't envy the position that they're in."
In order to ensure the credibility of the accelerated approval program, the FDA has been following up on cancer drugs it previously approved through this pathway. The industrywide review has led several companies to pull their drugs off the market. And, as part of the omnibus spending bill passed by Congress in December, the FDA has the option to require sponsors to begin confirmatory trials before receiving accelerated approval.
Still, accelerated approval alone won't get treatments to patients in need. The ASGCT's Barrett called out challenges that gene therapy developers face when it comes to manufacturing bottlenecks for AAV vector production. Easing such bottlenecks, he said, will require growing the expert workforce skilled at this type of manufacturing.
Facilitating reliable insurance coverage for these therapies, which are sure to be expensive, is another key barrier to patient access, he noted. For example, CSL Behring's hemophilia B gene therapy Hemgenix (etranacogene dezaparvovec) holds the distinction as the world's most expensive drug at a list price of roughly $3.5 million. After assessing the cost-effectiveness of hemophilia gene therapies, the Institute for Clinical and Economic Review, a nonprofit that evaluates the clinical and economic value of medical interventions, recommended last year that payors work with drug manufacturers "to develop and implement outcomes-based agreements to address the uncertainty and the high cost" of these treatments.
Part of the reason these gene therapies are expensive is that they're for rare indications and drugmakers want to recoup the R&D investment they made to develop these advanced, complex treatments. There are a number of diseases that the Muscular Dystrophy Association's Hesterlee described as "ultra-rare" and "potentially highly amenable to gene therapy … but the market is just small."
"That's a big question for both us and the FDA," she said. "What do we do to incentivize gene therapy development around these ultra-rare indications?"