The Problem with Clinical Trials in Duchenne—and What We Can Do About It

The recent news that Sarepta Therapeutics is launching a Phase III trial of its leading gene therapy (SRP-9001) for Duchenne muscular dystrophy (DMD) puts the company back in the race with Pfizer (PF-069399926) for this next, potentially breakthrough DMD treatment class. This is welcome news in a field that for years has been marked by promising drugs falling short in pivotal trials.

Earlier this year, results from Sarepta’s first trial of SRP-9001 disappointed investors, experts, and DMD families. The company announced that the trial “met its primary biological endpoint of micro-dystrophin protein expression” in muscle (Sarepta 01/07/21), but did not meet the primary endpoint of improving ambulatory function. (Micro- or mini-dystrophin is a shorter, but still functional, version of the dystrophin protein.)  This result was confusing, as the lack of dystrophin is the fundamental cause of DMD.

DMD is a rare and fatal inherited disorder caused by mutations in the massive gene for dystrophin, a protein crucial to normal muscle cell function. The disease is X-linked, so patients are mostly boys. They suffer initially from skeletal muscle weakness, followed by inability to walk, stand, and feed oneself, and eventually are at risk of death most commonly from cardiac or pulmonary failure. Families describe the patient journey as ‘a thousand deaths’ as losses of function mount.

A wealth of innovation over the past decade has brought more than 20 therapeutic programs into clinical trials for DMD. The DMD market is estimated to reach more than $4 billion in the next few years, with some analysts saying that gene therapies for DMD could be one of the top selling rare disease drugs of all time.

Sadly, most disease-modifying clinical candidates for DMD thus far have been discontinued or have disappointed. While several RNA editing or exon-skipping therapies have secured accelerated approval based on biomarker evidence (dystrophin levels), none has shown clear-cut clinical efficacy in a pivotal trial and most address only a subset of DMD patients because they target specific mutations.

Keys to trial design

Our group—the collaborative Trajectory Analysis Project (cTAP)—has been studying how heterogeneity in DMD progression in boys and young adults undermines trial design and leads to confusing or disappointing results. We have shown that by using rigorous quantitative analysis of natural history, real-world data, and clinical trial data, it is possible to overcome this challenge. 1, 2, 3, 4

The key to DMD trial design is knowing at any point where a given patient is in his own disease trajectory and, based on that knowledge, being able to predict that patient’s progress over the course of the trial.

Against a long backdrop of progress and disappointment, in late 2017 and early 2018 three companies—Solid Biosciences, Sarepta, and Pfizer—initiated clinical trials of gene therapy candidates for DMD patients with any dystrophin mutation. Preclinical and initial human data were encouraging, with early evidence demonstrating that these therapies could induce much higher functional dystrophin levels than that produced by exon-skipping drugs.

In Sarepta’s Phase II study, a single infusion of SRP-9001 produced large 90-day increases in micro-dystrophin. However, that increase did not appear to translate to statistically significant improvements in ambulatory function. Seeking an explanation, Sarepta pointed to problems with patient randomization. The company also found that treated patients retained function better than a matched natural history control in a post-hoc analysis.

But that still left some tough questions for Sarepta and indeed every other drug developer in DMD: Why did this happen? How can a gene therapy induce significant functional dystrophin and still not show corresponding clinical benefit? Is the problem with the trials themselves? And, if so, how can we design better DMD trials?

Through cTAP, we hope that we have a way to answer that critical last question.

In 2015, we established a pan-stakeholder consortium to characterize and account for heterogeneous trajectories of disease progression. cTAP’s goal is to meet the challenge of designing and analyzing clinical trials yielding unequivocal evidence of efficacy benefit for DMD therapeutics.

Together with clinical experts involved in neuromuscular drug development, we studied longitudinal DMD patient trajectories of ambulation and found that they fall into several clusters (see Figure 1). Each patient experiences the same identifiable pattern or phases of progression, but the rate of progression can differ markedly.

Figure 1. Heterogeneity of individual DMD patient trajectories of distanced walked in 6 minutes (6MWD) by age
A: Progressive decline in ambulatory function in DMD boys compared to normal boys. Highlighted is the mean trajectory for DMD patients (red)1 and the mean distance normal boys walk (blue).2 B: Clinical trials using age-based inclusion/exclusion criteria are likely to enroll patients with different trajectories of progression. Color-coding shows categories of patient trajectories identified by longitudinal cluster analysis of time from baseline 6MWD values.1

As a result, it is not surprising that patient sensitivity to a drug will differ in a clinical trial. For example, patients whose trajectory over the duration of a trial is relatively stable or those with too little muscle left to rescue risk ‘drowning out’ demonstrable drug effect seen in patients with more modifiable trajectories.

The “brute force” approach to overcoming the impact of heterogeneity in longitudinal progression would be to conduct randomized placebo-controlled trials that are much larger or of long duration. But neither of these approaches is practical in many rare diseases where patient numbers are small and use of placebo control can raise ethical concerns.

Historically, age coupled with steroid use and baseline function on the chosen outcome measure have been used to establish criteria for inclusion/exclusion, enrichment and stratification of DMD trials. But how predictive are these baseline factors for any patient? And are there other baseline measures that could improve prediction?

Figure 2. Impact of prognostic factors on DMD trial design
Relationship between the total number of patients needed for a typical DMD clinical trial (80% power to detect a 30m difference in 6MWD between placebo and drug treated arms of equal size) is dependent on how much of the variability in a trial is unexplained.Prognostic factors can explain a significant portion of patient heterogeneity in 48-week change in 6MWD in DMD. This reduction in unexplained variation can be used to reduce trial size (as shown) to enrich a trial with patients whose predicted trajectory is most likely to be modified by a drug or to pre-specify subgroups of patients with similar trajectories providing greater power to detect and confirm drug’s effect.3

These questions are critical. Our team at cTAP has attempted to answer them using a large body of clinical data. By letting the data speak for itself and quantifying the prognostic strength of all widely measured baseline characteristics, we have doubled prognostic power, halving variance due to patient heterogeneity (Figure 2). 

We believe that predicting trajectories is the key to improved trials in DMD; the better we understand prognostic factors, the more profound the impact. Gene therapy trials need to compare treated patients to natural history/real-world data external controls. Pre-specified prognostic factors will be crucial to demonstrating to regulators that the cohort is well matched.4 These advances will save time and money and accelerate the development of treatments for the patients and families who are anxiously waiting for them.

With Pfizer’s Phase III CIFFREO trial recruiting patients in the EU since January 2021 and the launch of Sarepta’s Phase III EMBARK trial, we should soon have new and valuable data about how dystrophin replacement works in DMD patients. We are particularly encouraged that Sarepta has announced that the design of this new trial stratifies participants by age and also  by predicted functional trajectory—i.e., where each boy is in his own progression of the disease. (Sarepta, 10/11/21).

This is a major step forward for trials in DMD and, as a result, for patients in the U.S. and around the world who suffer from this devastating disease.


Susan J. Ward ([email protected]) is Co-founder and Executive Director of cTAP (The collaborative Trajectory Analysis Project).

James Signorovitch ([email protected]) is Co-founder of cTAP and Managing Partner at Analysis Group.



1. Mercuri, E., et al. Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy. Neuromuscular Disorders, Vol. 26, Issue 9, Sept. 1, 2016.

2. Goemans, N. et al. Six-minute walk test: Reference values and prediction Eequation in healthy boys aged 5 to 12 years. PLoS ONE 8(12): e84120, 2013. doi:10.1371/journal.pone.0084120

3. Goemans, N. et al. Individualized prediction of changes in 6-minute walk distance for patients with Duchenne muscular dystrophy. PLOS. PLoS ONE 11(10): e0164684. Oct. 13, 2016. doi:10.1371/journal.pone.0164684

4. Goemans, N. et al. Suitability of external controls for drug evaluation in Duchenne muscular dystrophy. Neurology. Vol. 95, Issue 10, Sept. 8, 2020.

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