Surrogate Markers vs. Clinical Outcomes: How FDA and EMA Diverged on Sarepta’s Duchenne Therapy

Sarepta Therapeutics, a U.S.-based biotech company, has been a pioneer in developing therapies for Duchenne muscular dystrophy (DMD), a rare and debilitating genetic disorder. DMD primarily affects young boys, causing progressive muscle degeneration. Among Sarepta’s portfolio of exon-skipping therapies, Vyondys 53 (golodirsen) was developed to target patients with mutations in the DMD gene amenable to exon 53 skipping. However, Sarepta’s journey to bring Vyondys 53 to market revealed significant differences in regulatory standards between the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), ultimately shaping the company’s global strategy.

Early FDA Rejection, Then Approval

Sarepta initially encountered regulatory turbulence in the U.S. Despite the FDA granting accelerated approval for its earlier DMD therapy, Exondys 51, the agency took a harder stance with Vyondys 53. In August 2019, the FDA issued a complete response letter (CRL) rejecting Vyondys 53, citing concerns over the risk of infection at the infusion site and doubts about the drug’s effectiveness.

Sarepta’s response was swift. The company submitted additional data to address the FDA’s safety concerns, highlighting the increase in dystrophin production, a protein that DMD patients lack. While dystrophin production is a biomarker for DMD therapies, the FDA had hesitated due to a lack of direct evidence that Vyondys 53 improved clinical outcomes, such as muscle function or quality of life. By December 2019, the FDA reversed its decision and approved Vyondys 53, granting it accelerated approval based on dystrophin production as a surrogate endpoint.

The EMA’s Stricter Stance

While Vyondys 53 received FDA approval, Sarepta faced a much tougher road in Europe. The EMA demanded more robust clinical evidence, particularly around functional outcomes and long-term safety. The European regulator was not convinced that the small increases in dystrophin levels seen in clinical trials translated into meaningful benefits for patients, such as slowing the progression of the disease or improving mobility.

The EMA's concerns echoed those seen in its earlier rejection of Exondys 51, where it required Sarepta to provide more definitive evidence of clinical efficacy rather than relying solely on dystrophin as a biomarker. For Vyondys 53, the EMA requested additional studies to prove that the drug offered real-world functional improvements before it would consider approval. This significantly delayed Sarepta’s entry into the European market.

Approval Delays and Commercial Impact

The regulatory mismatch between the FDA and EMA delayed Vyondys 53’s approval in Europe by two years. While Sarepta was able to market the drug in the U.S. shortly after the FDA’s turnaround, the EMA approval did not come until 2021. This delay meant that while U.S. patients were accessing the treatment, European patients faced a longer wait.

The discrepancy also had a significant commercial impact. Sarepta had to invest heavily in additional clinical trials to meet the EMA’s demands, which drained resources and delayed potential revenue from the European market. Moreover, the FDA’s acceptance of biomarker-based approvals contrasted sharply with the EMA’s insistence on clinical outcomes, adding to the complexity of bringing the drug to global markets.

Lessons Learned: Designing Clinical Trials for Global Markets

Sarepta’s experience with Vyondys 53 highlights the critical importance of understanding the differing regulatory landscapes in the U.S. and Europe. While the FDA granted accelerated approval based on dystrophin production, the EMA demanded stronger proof of clinical efficacy. This misalignment led to delays in getting the drug to European patients, impacting both the company’s commercial strategy and the time-to-market for a critical therapy.

For biotech companies, the key takeaway is clear: clinical trials should be designed from the outset to meet the evidentiary requirements of both regulatory agencies. Relying solely on biomarker data may expedite FDA approval, but the EMA’s more stringent standards require additional functional outcome data. By anticipating these differences early on, companies can reduce approval delays and minimize post-authorization commitments, bringing life-changing therapies to global markets more efficiently.

In the case of Sarepta Therapeutics, understanding these regulatory nuances earlier could have saved time, resources, and, ultimately, helped patients in both the U.S. and Europe access much-needed treatments more quickly.