Despite hotly debated biomarkers and failed or delayed confirmatory trials, the accelerated approval program has a track record of propelling R&D for some of medicine’s most challenging illnesses.
With notable market withdrawals and failed confirmatory studies, the accelerated approval pathway has come under fire recently, but its naysayers discount one very important byproduct of the program: therapeutic momentum.
Enacted in 1992 in response to the HIV/AIDS epidemic, accelerated approval almost immediately began to have an impact on the disease. In June 1992, Roche’s Hivid became the first product greenlit under the pathway and the third antiretroviral to be approved by the FDA. Hivid, which received full approval in 1996, was followed in quick succession by more than ten new HIV drugs over the next decade—all of which were converted to traditional approval. Following accelerated approval, the drug sponsor is required to conduct a confirmatory trial to keep the product on the market. None of the early HIV therapies that received accelerated approval was withdrawn.
There is a perception that accelerated approval is a regulatory shortcut, but Ultragenyx CEO Emil Kakkis takes issue with this notion. “The biomarker-based approval of HIV drugs was not a compromise,” Kakkis previously told BioSpace. He explained that it would have taken too long to run trials with clinical endpoints like opportunistic infections, hospitalizations or death with three or four combination drugs, “and too many people would have to get sick and die.”
Fast-forward to the 21st century, when cancer therapeutics began to heavily leverage the pathway. While recent market withdrawals such as Takeda’s non-small cell lung cancer drug Exkivity and TG Therapeutics’ leukemia/lymphoma treatment Ukoniq have made headlines, here, too, there are far more wins than failures. Of 133 total cancer accelerated approvals, just 30 have been withdrawn from the market compared to 106 where the drug formulation has proven clinical benefit, according to the FDA’s data.
Accelerated approval drew particular scrutiny in 2021 when the FDA used the pathway to greenlight Biogen and Eisai’s Aduhelm as the first disease-modifying drug for Alzheimer’s disease. One of the regulator’s most controversial decisions so far, going against the near unanimous recommendation of its Peripheral and Central Nervous System Drugs Advisory Committee, it led to the resignation of three committee members.
Then, in another contentious decision, the FDA granted accelerated approval to Sarepta Therapeutics’ Elevidys for Duchenne muscular dystrophy (DMD) in June 2023. FDA advisers had debated whether an increase in microdystrophin was reasonably likely to predict benefit. Skepticism over this approval was further inflamed after Elevidys failed to meet the primary efficacy endpoint in a confirmatory trial four months later.
The common denominator at the heart of these controversial approvals is the surrogate endpoint. Accelerated approval is granted on the basis of a biomarker of the disease that is reasonably likely to predict clinical benefit. In Aduhelm’s case, the surrogate endpoint was the reduction of amyloid beta plaque in the brain—a hotly debated biomarker of Alzheimer’s—while Elevidys’ accelerated approval was supported by levels of the Elevidys micro-dystrophin protein in 4- to 5-year-old patients with DMD.
During the November 2020 advisory committee meeting for Aduhelm, then–FDA neuroscience head Billy Dunn said the agency would not use amyloid as a surrogate for efficacy—a decision that was later reconsidered, leading to the drug’s accelerated approval.
“The problem is, at that time—and actually currently—nobody [has] proved that reduction of amyloid in the brain predicts clinical benefit,” Joel Perlmutter, a professor of neurology at Washington University School of Medicine in St. Louis, recently told BioSpace. Perlmutter was one of the Aduhelm adcomm members who resigned as a result of the drug’s approval.
Unlike Aduhelm, Elevidys secured the (narrow) vote of an FDA advisory committee. However, FDA advisers noted in briefing documents prior to the adcomm that there was no epidemiologic or pathophysiologic evidence of the microdystrophin’s function. “Measurement of levels of Sarepta’s micro-dystrophin in muscle tissue only provides information about expression of the transgene product in cells transduced by [Elevidys], rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease,” according to the document.
This skepticism followed Sarepta’s 2016 encounter with the accelerated approval pathway when its earlier DMD gene therapy Exondys 51 was approved on the basis of an increase of dystrophin in the skeletal muscle of some Exondys 51-treated patients. The approval, which marked the first-ever for a DMD drug, followed an advisory committee voting 7-3 with three abstentions that Exondys 51 had not demonstrated substantial evidence of efficacy.
Experts who spoke to BioSpace agreed that when biomarkers represent the underlying cause of the disease—such as in rare, genetic disorders—they are more reliable than those further downstream of the source in complex illnesses like Alzheimer’s and amyotrophic lateral sclerosis, suggesting that the former diseases might be an ideal use for the accelerated pathway. DMD, for example, is a rare disease caused by a mutation in the gene encoding the dystrophin protein.
A Way Forward
Despite the questions surrounding the validity of certain endpoints, one thing is clear from the history of the program: one approval leads to another and spurs momentum and hope for the treatment of rare and prevalent diseases with high unmet need.
After Aduhelm’s accelerated approval in 2021, two more anti-amyloid drugs quickly followed. Biogen and Eisai’s Leqembi won accelerated approval in January 2023 and was converted to a traditional nod in July 2023, and Eli Lilly’s Kisunla won full approval in July 2024. (The FDA denied Kisunla accelerated approval in January 2023 partly due to an unusual trial design.)
These drugs are not perfect—they come with risks of side effects and their efficacy has been widely questioned—but today, there are two disease-modifying treatments available to patients with Alzheimer’s; just four years ago there were none. I was extremely close to my grandmother growing up, and I had a front-row seat to her suffering in her later years as severe Alzheimer’s took over her mind. I know how desperately even potentially subpar therapeutic options are needed.
In DMD as well, the accelerated approvals for Exondys 51 and Elevidys have provided hope to patients, parents and physicians. Hiram Secrist was the first patient to receive Elevidys outside of a clinical trial. “For our family, it’s a breakthrough in medical care, bringing new hope and a better quality of life,” Secrist’s mother, Kristen, told Muscular Dystrophy News Today.
Once again, science has a ways to go to fully address the unmet need. Jeff Chamberlain, president of the American Society for Gene and Cell Therapy and the McCaw Chair in Muscular Dystrophy at the University of Washington School of Medicine, previously told BioSpace that “some of the patients are showing increased strength, but a lot of them are not.” But for me, the key word here for me is “some.” For those children and their families, some is better than none.
That alone is reason enough to continue to lean into the accelerated approval program when appropriate. It isn’t without its challenges. A better understanding of biomarkers and tighter confirmatory trial timelines are necessary, but throughout its 32-year history, accelerated approval has offered a pathway to light amid certain darkness. Here’s to another 32 years of incremental progress.
