Should FDA Grant Accelerated Approval to Duchenne Muscular Dystrophy Gene Therapy?

— Waiting for the results of the SRP-9001 confirmatory trial may be a better move

A photo of a little boy in a wheelchair.
Reshma Ramachandran, MD, MPP, MHS, is a family physician and health services researcher. Holly Fernandez Lynch, JD, MBe, is a bioethics and law expert.

On May 12, independent experts narrowly recommended that the FDA grant accelerated approval to Sarepta's new gene therapy, SRP-9001 (delandistrogene moxeparvovec), for the treatment of Duchenne muscular dystrophy (DMD). These experts were called to vote after FDA's scientific reviewers raised concerns about the data Sarepta submitted to support the drug's safety and effectiveness.

While those concerns failed to sway the majority of the advisory committee, we believe the FDA's reviewers were right. The standard for accelerated approval does not appear to have been met here -- to the contrary, the drug's risks may outweigh its benefits. DMD patients need better treatment options, but they also need FDA to uphold strong evidentiary standards so they can be confident in approved drugs.


FDA's accelerated approval pathway offers a compromise for drugs that meet certain criteria. Drugs can be granted early market access before confirming patient benefit if they demonstrate an effect on surrogate endpoints deemed "reasonably likely" to predict more meaningful clinical outcomes in how patients feel, function, or survive. In return, FDA typically requires manufacturers to complete additional studies after approval to confirm the predicted clinical benefit.

As a devastating, rare disease affecting approximately 1 out of 3,500 boys globally, DMD is exactly the sort of disease envisaged by early approval pathways. DMD is caused by a mutation in the dystrophin gene, leading to progressive weakening of skeletal muscles and subsequently, the inability to walk, breathing difficulties, and heart complications that lead to an early death. Life expectancy has improved such that patients may live up to their 40s, but DMD has no cure.

Prior Accelerated Approvals for DMD

In 2016, Sarepta's first DMD drug, eteplirsen (Exondys 51), was granted accelerated approval against the recommendation of another advisory committee and FDA's own scientific staff – probably the most controversial accelerated approval until aducanumab (Aduhelm) for Alzheimer's disease. A single, small clinical trial showed that eteplirsen led to a small increase in the protein dystrophin, which became the surrogate endpoint supporting the drug's accelerated approval. However, this same study showed no improvement in clinical progression measured by a functional 6-minute walk test. Increased dystrophin still has not been validated as a measure of clinical benefit. Nevertheless, FDA has awarded three more approvals for similar DMD drugs using this same surrogate endpoint. Confirmation of clinical benefit for all four treatments remains pending, with none of the required confirmatory trials yet completed. Meanwhile, DMD patients continue to be prescribed these drugs in hopes that more conclusive evidence will emerge showing meaningful, functional improvement.

Shakier Ground

In contrast to these earlier drugs, SRP-9001 is intended to work through the production of a new, genetically-engineered protein called micro-dystrophin. While the drug successfully increases levels of this protein, it is another unvalidated surrogate endpoint: we don't know that micro-dystrophin will actually improve function in boys with DMD or what levels of micro-dystrophin would be needed to do so. Importantly, as noted by FDA reviewers and several advisory committee members, we don't know that more micro-dystrophin is even "reasonably likely to predict" improved function, the standard for accelerated approval. The only randomized, double-blinded, placebo-controlled study of SRP-9001 failed to show any correlation between the expression of micro-dystrophin in patients who received the drug and functional outcome. Although analyses of data from other studies show a possible association between micro-dystrophin and function, most participants were enrolled in open-label studies, raising questions around the validity of the results due to expectation bias (i.e., improved performance in patients aware that they received the treatment, and vice versa). While accelerated approvals are expected to entail some uncertainty, there seems to be more here than should be acceptable.

Safety Concerns

Besides questionable efficacy, SRP-9001 also poses potentially significant safety risks. Some trial participants who received SRP-9001 were reported to have serious adverse effects, including acute liver injury, immune-mediated myositis, and myocarditis. The viral vector through which the gene therapy is delivered has also been associated with liver complications, small blood clots, mutations leading to cancer, and death. As the treatment would be administered to young children, such significant safety risks should not be ignored, especially as these harms may manifest well after being treated and may not emerge during the clinical trial period. Even for a serious disease like DMD, the risks of SRP-9001 may outweigh benefits. Moreover, substantial risks call for greater certainty about benefit; that certainty is precisely what's in question here.

Worrisome Tradeoffs

There are also other important tradeoffs to consider in the specific context of accelerated approval for gene therapies. Once a patient is given SRP-9001, they would likely not be able to enroll in clinical trials for other similar vector-based gene therapies or be able to receive a future FDA-approved vector-based gene therapy, precluding the possibility of receiving a better treatment should one become available. Although patients supportive of accelerated approval often indicate a willingness to accept some uncertainty in hopes of earlier access to promising drugs, gene therapies may involve a unique loss of chance. This suggests that FDA should be especially rigorous in evaluating accelerated approval's "reasonably likely" standard in the context of these treatments.

Another concern, although technically outside FDA's purview, is that gene therapies are among the most expensive treatments, with drug manufacturers setting prices from a few hundred thousand to a few million dollars. Sarepta has already set high prices for its non-gene therapy DMD treatments -- as much as $300,000 per year -- so it's likely that SRP-9001 will be even more expensive. Payers are demonstrating increasing resistance to paying for drugs granted accelerated approval, especially when prices are high and the evidence supporting benefit is thin. In addition, resources spent on unproven drugs can shift funds away from other necessary interventions such as physical, occupational, and speech therapy.

Finally, although some have argued that granting accelerated approval will promote further clinical development to the benefit of patients, prematurely awarding accelerated approval can problematically lower the threshold for the entire field, resulting in more -- but not better -- treatments. Approving SRP-9001 would signal to other companies that FDA is willing to accept micro-dystrophin despite shaky foundations. If these surrogates fail to pan out, the DMD field will have lost valuable time pursuing alternate approaches.

Tread Carefully

The desire to move as quickly as possible toward promising treatments for patients living with serious and life-threatening diseases is understandable. But it is important to calibrate regulatory approaches to the time likely to be saved. Sarepta's ongoing confirmatory trial of SRP-9001 is expected to have results within a few months. Waiting for those findings, rather than granting accelerated approval now, will not only provide FDA, patients, clinicians, and payers with more insight as to the clinical effectiveness of SRP-9001, it may also prevent children with DMD and their loved ones from shutting the door on better options down the road.

Reshma Ramachandran, MD, MPP, MHS, is an assistant professor at Yale School of Medicine, co-director the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT), and chair of the Doctors for America FDA Task Force. Holly Fernandez Lynch, JD, MBe, is an assistant professor of medical ethics and law at the University of Pennsylvania.