Elevidys in DMD: Approved Despite Trial Failed in Primary Efficacy Endpoint

The US Food and Drug Administration has given the green light for the first gene therapy that treats a rare form of muscular dystrophy (Duchenne muscular dystrophy, DMD) to be used in most people who have the disease and a certain genetic mutation. Last year, the drug – Elevidys, from the biotech company Sarepta Therapeutics – was approved (through accelerated approval pathway) to treat only children ages 4 and 5 with Duchenne muscular dystrophy, one of the most severe forms of inherited muscular dystrophies, who have a confirmed mutation in a gene called DMD that is associated with muscle strength. The FDA announced this past Thursday (June 20, 2024) that it had given traditional approval for Elevidys for ambulatory people 4 and older with a confirmed mutation in the DMD gene and accelerated approval for non-ambulatory people 4 and older with this mutation. There’s not enough data on safety to support its use in children under 4, the agency says.

This is another drug approved by the FDA although the pivotal study (so called EMBARK study) failed in the primary efficacy endpoint (the North Star Ambulatory Assessment (NSAA)). While secondary efficacy endpoints (such as Time to Rise From the Floor) were statistically significant in favor of the Elevidys treatment group, the secondary efficacy endpoints were supposed not to be tested if the primary efficacy endpoint was not statistically significant. 

FDA's action of giving Elevidys traditional approval is controversial. According to FDA's review documents, some of FDA internal reviewers (such as statistical reviewer) were against the approval citing there wasn't sufficient evidence, however, the head of FDA CBER division, Dr Peter Marks, overruled the functional group reviewers to approve this gene therapy.  

• Top FDA official overrules staff to approve gene therapy that failed trial
• Duchenne approval exposes FDA rift over Sarepta gene therapy
• Déjà Vu: CBER Director’s Intervention Saves Sarepta’s Elevidys Again
• How controversial was the decision by FDA’s Peter Marks to approve Sarepta’s gene therapy? Check its footnotes

Perhaps, Dr Peter Marks is right. We should not base the approval on the single p-value from the primary efficacy endpoint and we should not be a slave of the p-values. FDA's announcement says "In making this decision, the FDA considered the totality of the evidence, including the potential risks associated with the product, the life-threatening and debilitating nature of the disease and the urgent unmet medical need." In the rare disease setting, selecting a clinical scale as the primary efficacy endpoint can sometimes be a gambling decision. in DMD situation, FDA published a guidance for industry "Duchenne Muscular Dystrophy and Related Dystrophinopathies:  Developing Drugs for Treatment". The guidance did not recommend which endpoint should be used the primary efficacy endpoint. The guidance was indecisive in efficacy endpoints. 

"FDA has no defined set of required or recommended clinical outcome measures for studies in dystrophinopathies.  Although existing outcome measures developed for clinical trials and/or clinical care in dystrophinopathies or related conditions may be appropriate, FDA will also consider proposals for the use of novel outcome measures that are capable of measuring clinically meaningful effects in patients.  FDA encourages sponsors to propose and, if necessary, develop endpoints that can validly and reliably assess patients with a wide spectrum of symptoms and disease stages.  Sponsors should engage FDA early during the selection and/or development of efficacy endpoints.  The sponsor should include an assessment of multiple efficacy endpoints, when feasible, to characterize the breadth of effects on dystrophin-related pathologies, including skeletal, respiratory, and cardiac muscle function, even if the primary endpoint is only one of these measures. "

Even if the drug is effective, the statistical significance for the selected primary efficacy endpoint (NSAA total score in EMBARK study) may not be demonstrated. In the rare disease setting with the urgent unmet medical need, the strict statistical rules may need to be loosened, the sequential testing rule for controlling the overall alpha may need to be skipped, and the totality evidence from the trial needs to be considered in the decision making.

DMD, like the ALS amyotrophic lateral sclerosis, is a challenging disease for clinical trials. Majority of the late phase DMD trials failed. FDA's approval of Elevidys in DMD comes right after two recent failed trials in DMD by Pfizer and NS Pharma. Their clinical programs in DMD were stopped. 

• Pfizer’s Phase III DMD gene therapy trial misses primary endpoint
• NS Pharma's Duchenne therapy Viltepso fails confirmatory trial

Sarepta's Elevidys in DMD (EMBARK trial) and Amylyx's RELYVRIO in ALS (PHOENIX trial) faced similar situations: they received preliminary approval from the FDA but were required to conduct confirmatory studies to demonstrate clinical benefit. However, both trials failed to achieve statistical significance in their primary efficacy endpoints. The key difference lies in the EMBARK study, which showed significant differences in secondary efficacy endpoints, whereas the PHOENIX study failed to demonstrate statistical significance in any endpoints - therefore, the fate for Elevidys (traditional approval is obtained) and Relyvrio (the product was withdrawn from the market) is totally different now.  

"Ensuring Public Trust in an Empowered FDA" - Accelerated Approval

 In the latest issue of New England Journal of Medicine, Drs Ross, Berg, and Ramachandran wrote a paper:

"Ensuring Public Trust in an Empowered FDA". 

The paper discussed the recent trend that FDA is granting drug approval using the accelerated approval pathway - approval based on the biomarker or surrogate end points that are deemed “reasonably likely” to predict clinical benefit. 

The accelerated approval pathway was one of the expedited pathways for drug approval in FDA's guidance "Expedited Programs for Serious Conditions – Drugs and Biologics". The guidance defined the accelerated approval as the following: 

Accelerated approval has been historically used in HIV drug approval and oncology drug approval (mostly successful), however, in recent years, the FDA has increasingly expanded the use of the accelerated approval program beyond HIV and oncology therapies - mainly in the neurology area such as DMD, Alzheimer's disease, and ALS. 

The FDA argued that the FDA should exercise “the greatest flexibility possible” under its statutory authority in considering accelerated approval for drugs for the treatment of serious conditions with unmet medical needs. However, applying "the greatest flexibility possible" can empower the FDA, but it may come with consequences. 

Accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefits, however, the "reasonably likely to predict clinical benefits" can be difficult to prove, and a lot of time is claimed based on conflicting evidence. According to the paper by Drs Fleming and Powers "Biomarkers and Surrogate Endpoints In Clinical Trials", it is extremely difficult to verify a biomarker can be a surrogate endpoint and can reasonably likely predict clinical benefits. 

The authors concluded:

 "An empowered FDA may prioritize using its regulatory authority to enable timely access to innovative products, but to ensure continued trust in the agency, this priority should be balanced against the challenges clinicians, patients, and caregivers face when there is substantial residual uncertainty about product safety and efficacy."

Also noted was that the FDA established a website "Accelerated Approval Program" where drugs approved through accelerated approval pathway were listed and the status of confirmatory trials to prove the clinical benefit was also listed. 'Ongoing' indicates that the confirmatory trial is ongoing; 'verified clinical benefit indicates the clinical benefit has been confirmed; and 'withdrawn' indicates that the clinical benefit has not been confirmed in the confirmatory trials and the drug approved through accelerated approval has been withdrawn. 

Accelerated Approval is a hot topic lately: 

• FDA Issues Draft Guidance Aimed at Improving Oncology Clinical Trials for Accelerated Approval
• Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics
• Top FDA official: Agency needs to start using accelerated approval for gene therapies
• US FDA to take steps to help gene therapies get accelerated approval

The condition for FDA to grant the accelerated approval is that the sponsor is required to do a confirmatory study (either already ongoing or will start right after the accelerated approval) to verify the drug's clinical benefits. A recent article in JAMA titled "Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021" concluded the following:

"Accelerated approval expedites the marketing of medications based on uncertain efficacy evidence, but the process depends on timely follow-up trials.We found that more than half of so-called confirmatory studies were not completed in the agreed-on time. In contrast with a recent Office of the Inspector General Report of incomplete confirmatory trials, our study includes late completed trials and manufacturer-reported delays. Limitations include shorter follow-up for more recent accelerated approvals and inability to identify reasons for trial delays.

Incomplete confirmatory clinical trials harm patients who are prescribed expensive drugs

despite uncertain clinical benefits. However, drug manufacturers face few consequences for delays. The Consolidated Appropriations Act for 20236 included accelerated approval reforms, such as granting the FDA greater authority to ensure confirmatory trials are under way before approval, mandating progress reports every 6 months by manufacturers, and clarifying procedures for withdrawal if follow-up trials do not find clinical benefit. It will be important to monitor whether these changes lead to fewer delays or whether additional authority is needed to assure that confirmatory trials are completed in a timely manner for the benefit of patients."