The decision by the US Food and Drug Administration to grant accelerated approval for gene therapy to treat Duchenne muscular dystrophy, and which includes the standard of a surrogate outcome that is “reasonably likely” to predict clinical benefit, has been disputed by an expert, for various reasons.
Dr David Rind writes in JAMA Network that gene therapy for the condition represents a test case for whether the FDA can appropriately apply accelerated approval to a novel gene therapy – and that the agency may well have “stretched the meaning of a surrogate outcome” in this case.
Duchenne muscular dystrophy is a fatal, X-linked neuromuscular disease that results in progressive loss of muscle function. It is caused by alterations in the dystrophin gene (DMD) that reduce dystrophin protein production to less than 3% of the normal level.
Signs of Duchenne muscular dystrophy usually occur in early childhood, with symptoms including muscle weakness, clumsiness, and difficulty going up and down stairs; untreated children usually progress to a loss of ambulation by 10-years-old.
Fatal respiratory or cardiac complications commonly develop in the second or third decade of life.
Duchenne muscular dystrophy has a prevalence of one in 3 500 to 5 000 live male births, or about 400 to 600 live male births per year in the US.
With treatments such as corticosteroids, assisted ventilation, spinal surgery, and management of cardiomyopathy-related heart failure, some patients are now living into their 30s or 40s.
DMD is the largest human gene and has 79 exons. This large size creates issues for gene therapies, but also opportunities, because shortened forms of dystrophin can have some ability to preserve muscle function, although less than the full-length dystrophin protein.
A less severe and clinically variable form of muscular dystrophy, Becker muscular dystrophy, is due to alterations in DMD that result in variable levels of expression (5%-50% of normal) of a shortened form of dystrophin.
The full DMD gene is too large to fit in an adeno-associated virus vector.
In 2023, Sarepta Therapeutics sought accelerated approval for delandistrogene moxeparvovec (SRP-9001), an adeno-associated virus gene therapy for Duchenne muscular dystrophy. SRP-9001 codes for a shortened version of dystrophin (“microdystrophin”) that is distinct from any of the shortened forms of dystrophin found in Becker muscular dystrophy.
FDA evaluators were concerned that although levels of microdystrophin could be measured after gene therapy, there was no evidence linking microdystrophin to clinical benefits. Although significant levels of microdystrophin were produced after treatment, levels of a gene product not known to confer benefit were felt to be problematic as the surrogate outcome.
After FDA leadership strongly encouraged flexibility, the FDA granted SRP-9001 accelerated approval in June 2023 (under the brand name Elevidys) for a subgroup of boys with Duchenne muscular dystrophy.
However, clinical results appeared to influence this approval.
Study 102 was a randomised trial in 41 boys aged four to seven years. At week 48, the change in the primary outcome, North Star Ambulatory Assessment (NSAA) score, was not statistically significantly different for SRP-9001 compared with placebo (change in NSAA score of 1.7 vs 0.9; difference, 0.8 [95% CI, 1.0-2.7]).
Despite the lack of benefit overall, post hoc analyses were conducted looking at younger boys (aged four to five years) and older boys (aged six to seven years). The change in NSAA score for younger boys was greater with treatment than with placebo (4.3 vs 1.9), but statistical testing is not clearly meaningful in this post hoc analysis.
Older boys had numerically worse changes with SRP-9001 than with placebo (−0.2 vs 0.5).
Although accelerated approval by the FDA was purportedly based on the surrogate outcome of microdystrophin production, the FDA only granted this approval for treatment of boys aged four or five-years-old.
This is hard to reconcile with the surrogate measure and appears to reflect the hope that the benefit suggested in study 102 by the post hoc analysis in younger boys represented a true clinical effect, although the outcome in older boys suggested no such benefit.
Although patient and clinician testimonials strongly supported benefits from treatment, FDA staff stressed the importance of randomised comparisons given both placebo effects and the tremendous variability in NSAA scores over time: strength tends to increase over time in young boys, but tends to decrease as Duchenne muscular dystrophy symptoms worsen.
An error in trial dosing also allowed evaluation of dose response.
Compared with patients receiving placebo, those receiving the intended dose had the worst numeric change in NSAA score (−1.5), those receiving a two-thirds dose had the best change (2.6), and those receiving a half dose had an intermediate change (0.7). As such, no dose-response effect was seen with SRP-9001.
SRP-9001 can cause harm. Among 85 patients across three studies, five patients had serious liver injury requiring hospitalisation, though all recovered; and two patients developed myocarditis.
One of these patients required intensive care unit admission, but ultimately symptoms resolved. The other patient developed a chronic cardiomyopathy requiring ongoing treatment with medications.
One additional patient developed a life-threatening immune-mediated myositis that appeared one month after receiving SRP-9001. Symptoms included muscle weakness, dysphagia, dysphonia, and difficulty sitting and walking that only partially resolved after treatment with plasmapheresis and corticosteroids.
At the time of accelerated approval, it was understood that top-line results from the EMBARK trial would soon be available. EMBARK is a phase 3 trial comparing SRP-9001 with placebo and with a primary end point of change in NSAA total score from baseline to 52 weeks in 125 boys aged four to seven years.
In October 2023, Sarepta Therapeutics announced that EMBARK had shown no improvement in NSAA score at 52 weeks with SRP-9001 vs placebo (2.6 vs 1.9; P = .24).6
Top-line results were not presented by age, but focused on secondary end points for timed events (time to rise; time to walk 10m) that were better with SRP-9001 than placebo.
On these timed outcomes, older boys saw greater differences from placebo than younger boys. Sarepta Therapeutics asked for full approval of Elevidys for younger and older boys based on these results.
It seems clear that the evidence for net benefit with SRP-9001 is weak. It also appears that if benefits with SRP-9001 are real, they are not large, although it may be that longer trials could show greater effects.
Although there have been concerns that the NSAA may be relatively insensitive to small benefits, the lack of ability to detect benefits would seem to conflict with the testimony of caregivers and clinicians that treatment with SRP-9001 leads to remarkable functional gains.
Cost is also an issue that cannot be ignored. Sarepta Therapeutics has priced Elevidys at $3.2m. This is an enormous price tag for a therapy that has failed to meet its primary end point in the two randomised trials in which it has been studied and that is clearly not curative.
Curative gene therapies for neuromuscular disorders affecting young children can be extremely valuable and worth very high prices.
The Institute for Clinical and Economic Review (ICER) felt that Zolgensma, a gene therapy for spinal muscular atrophy, could be worth up to $2.1m and that OTL-200, a gene therapy for metachromatic leukodystrophy, could be worth up to $3.9m.
Although the FDA has made it clear that some therapies granted accelerated approval are ultimately expected not to show net benefits, the FDA has stretched the meaning of a “surrogate outcome” when it comes to SRP-9001.
Flexibility around accelerated approval can benefit patients. However, the integrity of accelerated approval will be called into question if the FDA grants subsequent full approval to therapies that have failed confirmatory trials.
David Rind, MD – Institute for Clinical and Economic Review, Harvard Medical School
JAMA Network article – The FDA and Gene Therapy for Duchenne Muscular Dystrophy (Open access)
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