I’ve been reflecting on the disappointing outcomes and the reaction to Sarepta Therapeutics’ recently announced clinical trial results for its Duchenne muscular dystrophy treatments, AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen). The tension is evident: Families want treatments that benefit patients, while critics note the evidence reveals a different story. Duchenne muscular dystrophy is a relentless disease. When a company suggests it has a therapy that could alter its trajectory, hope naturally follows. Hope is meaningful to families. But when the data fail to match those expectations, it forces difficult questions about how we develop and evaluate therapies for rare diseases and what it truly means for a treatment to help.
Duchenne, Sarepta, and the Importance of Hope
Duchenne muscular dystrophy (DMD) is a rare, progressive genetic condition that primarily affects boys. Caused by mutations in the dystrophin gene, DMD leads to severe muscle weakness and degeneration. It typically appears in early childhood and results in loss of ambulation, breathing complications, and eventually cardiac or respiratory failure. Despite decades of research, there is no cure and no treatment that meaningfully changes the overall disease trajectory.
Sarepta as company has roots that date back to the 1980s, but has spent over a decade developing treatments for DMD, becoming both a source of hope and a subject of controversy. Families are eager for breakthroughs. Sarepta has pursued therapies built around “exon skipping”, a genetic technique designed to help cells “skip over” faulty instructions in a gene. Exon skipping is meant to help cells bypass a faulty section of the dystrophin gene, so they can produce a shortened but partially functional version of the protein, similar to what is seen in milder forms of muscular dystrophy. It is not a gene repair strategy, and it does not correct the underlying mutation, but it aims to give muscle cells some of what they are missing. For families facing a disease with so few options, the possibility of even modest benefit is meaningful.
Conditional Approvals
Sarepta’s therapies reached the market through the FDA’s accelerated approval pathway, which allows drugs for serious or life-threatening conditions to be approved on the basis of a surrogate marker or other endpoint that is expected to predict a meaningful benefit. In DMD, the FDA has relied on dystrophin-related biomarkers as surrogate endpoints. This biomarker is considered reasonably likely to predict clinical benefit because dystrophin is essential for muscle integrity, and its absence causes DMD. If a therapy can increase dystrophin levels, it may help stabilize muscle function over time.
Because a surrogate is only a proxy, and is not itself clinically meaningful, companies are required to run confirmatory trials to show that patients actually experience meaningful improvements in strength or mobility. Accelerated approval is meant to balance access with evidence, but it also shifts the uncertainty onto patients and families. Yes the drug is available, but its efficacy is not clear. When the follow-up trials fail to confirm benefit, as we’ve now seen with ESSENCE, it raises difficult but important questions about how much confidence we should place in early signals, and how much risk is acceptable when choices are so limited.
The ESSENCE Trial
The FDA granted accelerated approval to VYONDYS 53 in 2019 and AMONDYS 45 in 2021, on the basis of the drugs’ abilities to increase dystrophin levels in muscle. ESSENCE was the trial developed to meet the FDA’s expectations of showing actual clinical benefit. ESSENCE was a large, randomized, placebo-controlled study that followed boys with DMD for about two years and the primary endpoint was a practical measure of mobility: how quickly a child could climb four steps. This outcome was chosen because it reflects a real and important part of daily life for patients and families living with DMD. Patients were randomized to either weekly injections or placebo for 96 weeks. ESSENCE was meant to answer the central question behind the entire exon-skipping treatment strategy: do dystrophin increases lead to meaningful benefits?
The Results and the Reaction
When Sarepta released the ESSENCE results, the findings were disappointing. The trial failed to meet its primary endpoint: boys receiving AMONDYS 45 or VYONDYS 53 did not improve their ability to climb four steps in a way that reached statistical significance (p = 0.309) compared with placebo. The measured difference was small, showing only a small numerical improvement (0.05 steps/second) in stair-climbing speed. Sarepta attributed much of the underperformance to COVID-19 disruption, noting that excluding patients whose trial participation overlapped with the pandemic yielded a more favorable trend (0.11 steps/second, p ≈ 0.09) – which was still not statistically significant. Analysts were quick to point out these limitations, noting that confirmatory trials are meant to provide clarity—not rely on re-cut data to find a signal. The drugs were well tolerated, however, and serious adverse effects were rare.
What This Means for Patients and the Families
For families living with DMD, these results will be disappointing. But the ESSENCE findings mean that the expected functional benefits of AMONDYS 45 and VYONDYS 53 have not yet been show to be real, despite several years on the market and thousands of doses given. This confirmatory trial highlights the challenge with accelerated approvals based on surrogates. Families want hope, but it may not bear out. A clear understanding, grounded in evidence, is essential, not to diminish that hope, but to sustain it.
Evidence Gaps and Rare Diseases
What has unfolded with ESSENCE is not unique to Sarepta. Companies often rely on surrogate markers, like dystrophin levels, not because they are perfect predictors of benefit, but because they are measurable. But they may not bear out into outcomes that are meaningful. The failure reflects the reality that rare-disease science is difficult, and basing an approval on an unproven surrogate is risky. The challenge is finding ways to push innovation and access forward without lowering the bar so far that ineffective treatments are used for years. Keep in mind that drugs can also cause harmful side effects – although that doesn’t seem to be the case with these drugs. Finally, we need to balance early, promising evidence with a commitment to follow-through with good research and ensure that the drug does what we want it to do.
I’m going to quote from Matthew Herper, writing in Forbes back in 2013 about Sarepta, because this is an evergreen paragraph in drug development:
This same story happens again and again in the drug industry: A new medicine seems to show promise in a terrible disease. Patients and investors become excited, lobbying the Food and Drug Administration to approve it quickly or the company to make the medicine available and bidding up the drug maker’s stock price to dizzying highs. And then, too often, it turns out that the wonderful cure was just a mirage and that the FDA was right in its slow, deliberate pace – that the agency did its job of making sure the treatment actually helped patients before allowing a drug company to charge a very dear price for it.
Where DMD Research Goes From Here
The ESSENCE trial is a setback to DMD, no question. But it points where work is needed. Better biomarkers are essential – ones that reliably predict meaningful functional outcomes rather than serving as hopeful (but faulty) proxies. As gene therapy and other emerging therapies continue to advance, regulators and developers will need to remain cautious about balancing access based on unproven surrogates against the need for real outcomes. The need for treatments for DMD remains as important as ever.