The full results from Pfizer’s pivotal study of its Duchenne muscular dystrophy gene therapy show patients saw no significant functional benefit one year after receiving the therapy despite the expression of mini-dystrophin.
In the Phase 3 study known as CIFFREO, 64 participants received Pfizer’s experimental therapy called fordadistrogene movaparvovec, while 28 received placebo.
Over one year, it appeared as if the two groups were beginning to diverge based on a motor function measure called the North Star Ambulatory Assessment (NSAA). But at the one-year mark, the lines from the groups converged, meaning that the gene therapy failed to improve motor function for patients with Duchenne.
The change from baseline at one year measured by the NSAA was 1.46 in the group that received Pfizer’s gene therapy and 1.37 in the placebo group, resulting in a p-value of 0.91. (A p-value close to 1 means there was virtually no difference between the two groups.)
“At week 52, there was a complete absence of efficacy,” said Francesco Muntoni, chair of pediatric neurology at Great Ormond Street Hospital in London, when presenting the results on Saturday at the World Muscle Society’s annual meeting in Prague. Muntoni was not an investigator for the study, but was on its steering committee.
Pfizer’s experimental Duchenne gene therapy was second in development behind Sarepta Therapeutics’ Elevidys — which first gained approval in 2023 and then won a much broader label in June, though with controversy on both occasions. That same month, Pfizer announced that its pivotal study failed, later saying in July that it was discontinuing work on its gene therapy and laying off staff involved with the program.
There was also no significant difference in motor function improvement between the gene therapy and placebo when looking at different age subgroups, according to Saturday’s presentation. In June, Pfizer had reported that there was no significant difference between the groups on key secondary measures like 10-meter run/walk velocity and rise-from-floor velocity.
People with Duchenne often have elevated levels of creatine kinase, and results from the study showed that those who received the gene therapy had lower creatine kinase concentrations compared to placebo. “We can argue how significant that is,” Muntoni said during the presentation.
Micro-dystrophin
Interestingly, the study showed that the gene therapy did express mini-dystrophin in muscle at one year, and Pfizer pointed to the “robust transduction” of the gene in its slides.
People with Duchenne muscular dystrophy make little to no functional dystrophin, which is a key protein that protects the muscles. As a result, their muscles weaken over time. Dystrophin is also coded by the largest human gene, meaning that it’s too big to fit in the viral vectors used to deliver gene therapies. Gene therapy makers have developed treatments that express various truncated forms of the protein — which they call mini- or micro-dystrophin — that they hope can restore some dystrophin function and slow muscle degeneration.
“When the data were announced, I was hoping almost that there was no dystrophin expression or very little dystrophin because it would have been much easier to say, ‘Well, it’s 0.5% micro-dystrophin expression,'” Muntoni said. “The level of micro-dystrophin expression are appreciable here.”
Pfizer’s results complicate the picture painted by gene therapy makers, which often point to micro-dystrophin expression levels to suggest their Duchenne therapies show promise. Notably in Sarepta’s case, the FDA granted Elevidys its initial approval based on micro-dystrophin expression. And in March, Regenxbio touted micro-dystrophin expression levels from its own experimental gene therapy.
However in Pfizer’s case, micro-dystrophin expression didn’t translate to clinical benefit. “What is the optimal way to restore dystrophin? And which dystrophin?” Muntoni said.