FDA Accelerated Approval (AA) and Duchenne Muscular Dystrophy
Mark Schreiner MD
Original article
Rind DM. The FDA and Gene Therapy for Duchenne Muscular Dystrophy. JAMA. published online 2024 May 1. PMID: 38691382.
Original article
Bendicksen L, Zuckerman DM, Avorn J, Phillips S, Kesselheim AS. The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. Ann Intern Med. 2023;176(9):1251-1256. PMID: 37603868.
Since 1992, the FDA has used accelerated approval to authorize marketing for a drug intended to treat a serious disease/condition that demonstrates a measurable change in a surrogate endpoint.[1] A surrogate endpoint is not a measure of clinical benefit – reduction in mortality, morbidity or improvement of quality of life – it is a biomarker substitute.[2] For example, blood pressure reduction would be a surrogate endpoint for stroke or heart attack prevention. Unfortunately, medical history is littered with proposed biomarkers that utterly failed to predict disease progression.[3] For drugs approved for treatment of cancer under AA, ~26% have been subsequently withdrawn due to lack of benefit.[4]
The FDA has now approved treatments for Duchenne Muscular Dystrophy (DMD) under the accelerated approval pathway.[5] Eteplirsen (Exondys 51), an antisense skipping oligonucleotide (ASO) that overrides sections of the genome responsible for non-functional dystrophin. Eteplirsen was approved despite only being tested in a 12-person clinical trial that used a historical control group. In the pivotal trial, dystrophin levels reached 1%. The expected required level is 10-20%. Predictably, there was no evident clinical benefit. Despite 3 of 13 members of the FDA’s Advisory Committee voting for approval, Janet Woodcock overrode their recommendations and the drug was approved. The FDA approval has led to three more similar drugs being approved.
Now accelerated approval has been granted for an adeno-associated virus gene therapy, delandistrogene moxeparvovec (SRP-9001), for DMD.[6] The gene for dystrophin is the largest human gene so it is not possible to fit the entire gene into a viral capsid. Instead, the gene therapy produces a shortened form of the dystrophin protein, a microdystrophin. The clinical trial, which enrolled 41 boys, failed to demonstrate clinical benefit. Post-hoc analysis of the trial suggested a possible benefit for younger boys (4 – 5 years). SRP-9001 caused serious adverse events in 5 of the 85 subjects. Some of the SAEs were quite worrisome including myocarditis and immune-mediated myositis. A subsequent trial in 125 boys again showed no clinical improvement in measurable outcomes. So far no evidence demonstrating benefit due to increases in microdystrophin has been produced to date.
SRP-9001 is a one-time treatment costing $3.2 million. The ASO drugs need to be administered by infusion weekly and are estimated to cost ~$300,000 a year. Over time, the cost would exceed that of SRP-9001.
Parents of children with DMD are desperate for an effective treatment and FDA flexibility can be warranted and inspires hope. However, approving therapies that fail to prove effective in confirmatory clinical trials threatens the FDA’s standing and integrity. The cost to society will be considerable. Granting full approval on the basis of such flimsy evidence have other side effects; the existence of these drugs and gene therapies may impede clinical trials of innovative, as yet undiscovered therapies all while exposing children to side effects without certainty of benefit.
PS from Myron: from the Washington Post. This is not an isolated event. (https://www.washingtonpost.com/opinions/2024/07/22/fda-gene-therapy-elevidys/ ) another accelerated approval drug delandistrogene moxeparvovec-rokl, brand name Elevidys, for the treatment of patients with Duchenne muscular dystrophy, was found to be ineffective and yet received FDA approval. Why? From the article: “Proponents of the Elevidys approval argue that the FDA’s decision was merited because patients have few alternatives and the new treatment offers families hope. However, as senior FDA reviewers noted, the agency could have kept Elevidys under accelerated approval while its manufacturer pursued further trials in promising subgroups of patients. By granting full approval, the FDA relinquished much of its authority to require additional testing.”
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References
1. Accelerated Approval Program. Accessed at https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program and https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval
2. Aronson JK. Biomarkers and surrogate endpoints. Br J Clin Pharmacol. 2005 May;59(5):491-4.
3. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996 Oct 1;125(7):605-13. PMID: 8815760.
4. Parikh RB, Hubbard RA, Wang E, Royce TJ, Cohen AB, Clark AS, Mamtani R. Exposure to US Cancer Drugs With Lack of Confirmed Benefit After US Food and Drug Administration Accelerated Approval. JAMA Oncol. 2023 Apr 1;9(4):567-569.
5. Bendicksen L, Zuckerman DM, Avorn J, Phillips S, Kesselheim AS. The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. Ann Intern Med. 2023;176(9):1251-1256.
6. Rind DM. The FDA and Gene Therapy for Duchenne Muscular Dystrophy. JAMA. published online 2024 May 1. PMID: 38691382.