Sarepta Retains DMD Gene Therapy Lead As Pfizer Stumbles

Pfizer Inc.’s efforts to launch a gene therapy for Duchenne muscular dystrophy (DMD) have hit a significant setback as its Phase III study of fordadistrogene movaparvovec failed, an outcome that could strengthen the case for Sarepta Therapeutics, Inc.’s gene therapy Elevidys (delandistrogene moxeparvovec-rokl).

The drug maker said 12 June that the Phase III CIFFREO trial did not meet its primary endpoint of improvement in motor function among boys aged four to seven, and it also missed key secondary endpoints, including 10-meter run/walk velocity and time-to-rise from floor velocity.

The results position Sarepta to retain its position as the sole player with an approved gene therapy for DMD and come about a year after the FDA gave accelerated approval to Sarepta’s Elevidys in boys ages four to five (Also see "A Momentous Day For DMD: Sarepta’s Elevidys Is First Gene Therapy Approved" - Scrip, 23 June, 2023.) Sarepta reported sales for Elevidys of $133.9m in the first quarter, a strong result for a gene therapy launch, though questions remain about the efficacy of that product after it failed to show a benefit on the primary endpoint of the confirmatory trial. (Also see "Gene Therapy Q1 Roundup: The Struggle Is Real" - Scrip, 9 May, 2024.)

For Pfizer, the news is disappointing but also underscores the company’s recent pivot away from drugs for rare diseases and towards diseases that impact broader patient populations. Last year, Pfizer sold its preclinical rare disease gene therapy programs to AstraZeneca PLC for $1bn after announcing it was deemphasizing gene therapy and rare diseases.

That said, the company had continued to emphasize its commitment to the DMD program and its other more advanced programs. Pfizer told Scrip it remains committed to its one approved gene therapy and its clinical-stage pipeline. Earlier this year, Pfizer won US Food and Drug Administration approval for the hemophilia B gene therapy Beqvez (fidanacogene elaparvovec-dzkt). It is also partnered with Sangamo Therapeutics, Inc. on a gene therapy for hemophilia A, giroctocogene fitelparvovec, which is in Phase III.

Beqvez competes with uniQure N.V./CSL Limited’s Hemgenix (etranacogene dezaparvovec-drlb), while giroctocogene fitelparvovec would compete with BioMarin Pharmaceutical Inc.’s Roctavian (valoctocogene roxaparvovec-rvox). (Also see "Pfizer Matches Beqvez Price To Hemgenix In Hemophilia B, Plans Warranty Program" - Scrip, 26 April, 2024.) So far, gene therapy launches in those areas have been slow to get off the ground.

Safety And Efficacy Questions

CIFFREO’s failure does not come as a complete surprise, given the announcement of lackluster two-year data from a Phase Ib study of the gene therapy at the American Society of Gene and Cell Therapy congress in May 2023, which showed a mean change from baseline of -2.6 versus -4.9 in the control group according to the North Star Ambulatory Assessment (NSAA), the same measure used in CIFFREO. On the one hand, the results indicated a preservation of function of 2.4 points compared with the control group. However, they had also suggested that the benefits may not be sustained, with fordadistrogene movaparvovec showing a difference of about 3.06 at year one, but 2.37 at year two. (Also see "ASGCT Late Breakers: Pfizer’s Duchenne Results Underwhelm As Next-Gen Approaches Emerge" - Scrip, 17 May, 2023.)

In May, the company also announced a patient death from cardiac arrest in a separate Phase II trial, DAYLIGHT, studying the gene therapy in patients aged two to three. Pfizer also said that CIFFREO is on a dosing pause due to that fatal event.

Given the high unmet need for patients with the progressive and eventually fatal disease and lack of treatment options, Sarepta appears to be in a strong position even though the Phase III EMBARK trial in DMD patients aged four to seven did not meet its primary endpoint, improvement in motor function based on NSAA. Sarepta has an advantage, however, in that the trial did meet secondary endpoints, including time-to-rise and 10-meter walk test. Elevidys also hasn’t experienced the same safety concerns as Pfizer’s gene therapy.

Sarepta is looking to expand the label for the drug to more patients and has submitted the data from EMBARK to FDA. It remains to be seen what FDA will do, but Sarepta, patients and other stakeholders should find out soon; the application has a 21 June action date.

Analysts have expressed confidence that the agency will allow a label expansion given that the gene therapy still showed significant improvements on secondary endpoints. It is also possible FDA could demand Elevidys’s withdrawal or decline to expand its label from patients aged four to five. (Also see "Sarepta Confident Of Full US Approval For Duchenne Gene Therapy By Mid-2024" - Scrip, 9 January, 2024.)

William Blair analyst Tim Lugo questioned the future of Pfizer’s fordadistrogene movaparvovec.

“While we never viewed fordadistrogene movaparvovec as a real competitive threat to Elevidys given the safety concerns it has had throughout its development, we believe this news all but removes it from the competitive landscape as we approach the June 21 PDUFA date for Elevidys’s label expansion and conversion to full approval,” Lugo said in a 13 June note.

Mizuho Securities analyst Uy Ear said in a 12 June note that the consistency of CIFFREO missing key secondary functional endpoints supports the activity that Elevidys showed in EMBARK.

“Overall, we see this news as a positive for Sarepta as Pfizer will unlikely have the necessary clinical data to submit [fordadistrogene movaparvovec] for regulatory approval,” Ear said. “As a result, we believe Elevidys will have no near-term competition, and we see potential upside to our Elevidys sales forecast and consensus estimates.”