Pfizer adds to gene therapy woes

But another safety scare for the big pharma’s Duchenne muscular dystrophy project could be good news for Sarepta.

Pfizer’s Duchenne muscular dystrophy gene therapy candidate fordadistrogene movaparvovec previously weathered reports of complement activation in an early-stage study. Now the project’s phase 3 trial has been hit by new side effects of muscle weakness and myocarditis. On the plus side for Pfizer the trial is continuing, although the group is excluding certain patients.

One rival that could benefit from Pfizer's difficulties is Sarepta, which despite its own setbacks is about to start a pivotal trial of its DMD gene therapy SRP-9001. But another gene therapy scare cannot be good for patient confidence overall, and Sarepta’s stock crept up a mere 1% yesterday.

Pfizer is leading the pack of DMD gene therapy hopefuls, with its pivotal Ciffreo trial set for an interim readout in the third quarter of next year. However, it has not been plain sailing: the study is only enrolling patients in Europe and Asia and is yet to start in the US, with the FDA requesting potency assay measures.

Drug related

Now Pfizer has reported three cases of severe muscle weakness in Ciffreo, two of which involved myocarditis, or inflammation of heart tissue.

Evercore ISI’s Umer Raffat noted that muscle weakness was a hallmark of DMD, while myocarditis was “not uncommon” in these patients; however, the adverse events have been attributed to fordadistrogene movaparvovec, previously known as PF-06939926. The project aims to deliver a shortened version of the human dystrophin gene, which is mutated in DMD.

The trial’s data monitoring committee has concluded that the risk of these problems could be higher in patients who have certain mutations in the dystrophin gene.

Pfizer is therefore excluding patients with any mutations affecting exons 9 to 13, as well as those with a deletion affecting both exon 29 and 30. Overall, these account for around 15% of patients with DMD – not a number to be sniffed at in a disease that only affects around 13,000 people in the US.   

It is not clear why these mutations could confer an increased risk of these adverse events. Mr Raffat hypothesised that gene transfer into dystrophic muscles could trigger an immune response “as some patients will not have been exposed to some (or many) epitopes of dystrophin”.

He added that these issues were not seen in an 18-patient phase 1 study; the problem there was complement activation, but Pfizer has addressed this with prophylactic steroids in phase 3.

Sarepta start

The latest setback might not mean the end for fordadistrogene movaparvovec, but it might make patients wary of enrolling into Ciffreo, particularly if other options are available.

Step forward Sarepta, which plans to start the phase 3 Embark trial of SRP-9001 this month. That project previously flunked a phase 2 study, a setback from which Sarepta’s stock has yet to recover (Gene therapy trial fails to rectify Sarepta’s sorry record, January 8, 2021).

The other main DMD gene therapy contender is Solid Biosciences, whose SGT-001, like fordadistrogene movaparvovec, uses an AAV9 vector, and which has also been linked with complement activation.

In March interim data from the phase 1/2 Ignite DMD study of SGT-001 disappointed. At the time, processes put in place to prevent adverse events looked to have paid off, but since then a patient has experienced a serious inflammatory response. Solid, citing a strengthened risk-mitigation plan, hopes to dose the next subject in Ignite DMD in the next quarter.

A look at the late-stage DMD pipeline shows several more conventional therapies in development. Given the mounting concerns about the safety of gene therapy in general, perhaps these projects will end up being the real beneficiaries of Pfizer’s latest stumble.

DMD: marketed products and late-stage projects
Project/product Company Description 2026e indication sales ($m) Note
Exondys 51 Sarepta Exon 51 skipping antisense 431 Covers ~13% of DMD population
Viltepso Nippon Shinyaku Exon 53 skipping antisense 415* Covers ~8% of DMD population
Vyondys 53 Sarepta Exon 53 skipping antisense 212 Covers ~8% of DMD population
Amondys 45 Sarepta Exon 45 skipping antisense 216 Covers ~8% of DMD population
Phase 3
SRP-9001  Sarepta/Roche Micro-dystrophin gene therapy (AAVrh74 vector) 1,026 Ph2 study 102 disappointed; ph3 Embark to start Sep 2021
Fordadistrogene movaparvovec (PF-06939926) Pfizer Mini-dystrophin gene therapy (AAV9 vector) 425 Ciffreo protocol changed to exclude certain mutations
Pamrevlumab Fibrogen Anti-CTGF MAb 39 Topline data from Lelantos-1 delayed until H1 2023 (from H2 2022)
Givinostat  Italfarmaco HDAC inhibitor - Ph3 data due Q2 2022
TAS-205 Taiho (Otsuka) Haematopoietic prostaglandin D synthase inhibitor - Reach-DMD, Japan only, completes May 2027
*Excludes undisclosed partner sales; Source: Evaluate Pharma &

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