On December 20, 2021, Pfizer announced the unexpected death of a participant in the company’s Phase Ib open-label study (NCT03362502) on PF-06939926 (fordadistrogene movaparvovec), a gene therapy aiming to treat Duchenne muscular dystrophy (DMD). The FDA issued a clinical pause on the trial and Pfizer is in the process of investigating the causes of the death. The patient was part of the non-ambulatory arm of the study. Pfizer also has an active Phase III study (NCT04281485) of the same product, currently being developed globally. PF-06939926 is one of two gene therapies in late-stage development for DMD, with its main rival being Sarepta Therapeutics’s SRP-9001. The uncertainty surrounding PF-06939926’s future following this major safety event could potentially clear the way for Sarepta’s continued dominance in the field.

Despite both therapies having the same mechanism of action, the Pfizer and Sarepta products differ in composition. PF-06939926 delivers a mini-dystrophin encoding gene to patients, enabling them to produce mini-dystrophin, a shorter but still functional version of the protein dystrophin missing in DMD patients’ muscles. Pfizer’s gene therapy has an adeno-associated virus 9 (AAV-9) vector, while Sarepta’s candidate contains an AAVrh74 vector. A group of key opinion leaders (KOLs) interviewed by GlobalData were slightly in favour of Sarepta’s product, as they believed that Pfizer’s vector might more easily induce immune responses among patients, in addition to a group of certain mutation types having been excluded from Pfizer’s trial due to heart-related side effects. However, Pfizer’s AAV-9 vector is able to carry longer genes compared to Sarepta’s AAVrh74, which explains why PF-06939926 and SRP-9001 deliver mini-dystrophin and micro-dystrophin encoding genes, respectively, leading the rest of the KOLs to favour Pfizer’s product. Physicians are waiting for further efficacy and safety data to decide which product they would prefer to administer to their patients.

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Gene therapies are the most anticipated pipeline candidates for the DMD space by patients, influential advocacy groups, and physicians. The latest development on Pfizer’s candidate, along with past efficacy and safety setbacks on both PF-06939926 and SRP-9001, might increase scrutiny by the FDA. This would likely delay its market launch until after 2025. Sarepta is one of the leading players in this space, with three out of five marketed products targeting DMD in the US market. Sarepta is also conducting trials on late-stage gene therapy. Currently, in Phase III (NCT05096221) of development, SRP-9001 (delandistrogene moxeparvovec) could see a potential advantage after PF-06939926’s latest development. Additionally, Sarepta holds three more pipeline drugs in the earlier stages of development, two of which are gene therapies. In contrast to Sarepta, Pfizer lacks further candidates that could penetrate this space and gain market share if its gene therapy fails to receive approval, which indicates the higher stakes for the latter. Even if both gene therapies make it to market, PF-06939926 would likely see a delay because of the recent death during its Phase Ib trial. This would provide SRP-9001 with a first-to-market advantage. Regardless, Pfizer will need to take the time to analyse the situation and gather insight that will allow for the continuation of its Phase Ib trial and modifications to future trials such as the exclusion of specific mutation types. Despite the risks above leading to a potentially lower uptake compared to Sarepta’s product, Pfizer could still capture a considerable market share and see a return on its investment before more gene therapies enter the market.

Cell & Gene Therapy Coverage on Clinical Trials Arena supported by Cytiva.

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