Pepgen aims to overtake Sarepta

Data are early, but the small group already claims that it could have the best-in-class exon skipper for Duchenne.

Sarepta has built a $9.5bn business off the back of exon skippers for Duchenne muscular dystrophy with questionable efficacy. The company is trying to up its game with its next-generation project, but a new challenger reckons it can go one better with an enhanced exon skipper of its own.

That group, Pepgen, today reported phase 1 healthy volunteer data with PGN-EDO51 that it says support its case. The small player, one of 2022’s few IPOs, still has much to prove, but if it can meet its goals for phase 2 Sarepta could be looking over its shoulder.

True, the DMD landscape might soon be changed by gene therapies, but these have hardly had a smooth ride, with their development path marked by safety scares and mixed clinical data. Nevertheless, Sarepta plans to file for accelerated approval of its gene therapy project, SRP-9001, this autumn.

Pepgen’s chief executive, James McArthur, believes that gene therapy will not mean the end of exon skippers. The two might one day be used in combination “to take it to the point where this is transformative for patients, where we begin to stop disease progression and, who knows, perhaps even see some return of functionality”, he tells Evaluate Vantage.

Exon skipping

For now, Pepgen’s main concern is how PGN-EDO51 compares against Sarepta’s next-gen exon skipper, SRP-5051.

Both PGN-EDO51 and SRP-5051 are designed to boost cell penetration and uptake – and therefore efficacy – compared with the first-generation exon skippers, which were naked oligonucleotides.

Pepgen’s phase 1 study in 32 healthy subjects found mean exon 51 skipping levels of 1.4% and 2.0% 28 days after a single 10mg/kg and 15mg/kg dose of PGN-EDO51 respectively, the two highest doses tested in the trial.

SRP-5051 produced median exon skipping levels of just under 0.2% with a single 20mg/kg dose in its healthy volunteer trial, though the usual caveats about cross-trial comparison apply here.

In the Momentum study, testing multiple doses in DMD patients, SRP-5051 went on to show mean exon skipping levels of 2.57% and 10.79% at 20mg/kg and 30mg/kg respectively – higher than that seen with the first-gen exon skipper Exondys 51 (Jury still out on Sarepta’s next generation, May 4, 2021).

If PGN-EDO51 continues to exceed SRP-5051 at the same kind of level, “we could imagine that we might be able to see something in the neighbourhood of 21% exon skipping” in a multidose trial in DMD patients, Mr McArthur says.

Investors will be most interested in another surrogate marker at that stage: dystrophin expression. Here, Pepgen hopes to see levels of over 10%.

The company plans to start a phase 2a study in DMD patients in the first half of next year, with results expected in 2024 – representing the big test for PGN-EDO51.


Efficacy is not the only consideration here. The Momentum trial of SRP-5051 was put on clinical hold following cases of hypomagnesemia, a hold that was lifted earlier this month with expanded patient monitoring.

Mr McArthur maintains that low magnesium will not be a problem with PGN-EDO51, though two cases of hypomagnesemia were seen with the 15mg/kg dose. Both were mild to moderate and did not require any intervention.

However, one subject receiving 15mg/kg experienced kidney biomarker changes and needed intravenous hydration. Kidney toxicity is a known worry with next-gen exon skippers. Mr McArthur says the “meaningful movement in kidney biomarkers” started at this high dose – and that 5mg/kg and 10mg/kg are the likely doses for phase 2.

These safety issues will need to be closely monitored as the project is pushed forward, though investors were encouraged by the update, with Pepgen stock opening up 15% at $6. The stock floated at $12 per share in May, however, so the company needs to keep the good news coming. 

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