Sarepta Therapeutics' next Duchenne muscular dystrophy (DMD) med seems to be doing the job of spurring dystrophin expression. But do any of the data for SRP-5051 matter given the recent approval of the biotech’s gene therapy for the same condition, Elevidys?
Analysts wanted to know, as the company debuted initial data from the mid-stage MOMENTUM study of SRP-5051, showing mean dystrophin expression of 5.17% and mean exon skipping of 11.11% at 28 weeks.
DMD is caused by a mutation to the dystrophin gene, resulting in limited production of dystrophin protein that's needed to maintain muscle. SRP-5051 is meant to skip exon 51 and allow the production of an internally shortened dystrophin protein.
The dystrophin expression was more than 12 times what Sarepta showed for Exondys 51, a therapy that was controversially approved in 2016 for treating some cases of DMD. The results also represented a more than 24-fold increase in exon skipping compared to the earlier treatment. The results were consistent across ambulatory and non-ambulstory patients, too.
That wasn’t the comparison analysts were interested in, however. The real question was how SRP-5051 stacks up to Elevidys, which was granted an accelerated approval last year for ambulatory patients aged 4-5 years old with a confirmed mutation in the DMD gene. And how will the three meds co-exist on the market?
CEO Doug Ingram told investors on a conference call Monday that his team has “pondered this … for a long time.” He admitted the therapies are “in tension with one another,” which can cause a “cannibalization” of the existing market that Sarepta owns. He expects that would be the case for Exondys 51, which is a phosphorodiamidate morpholino oligomer. SRP-5051, meanwhile, is a next-generation peptide phosphorodiamidate morpholino oligomer.
“We truly believe there are opportunities for both of these modalities to exist and benefit patients,” Ingram said.
As for efficacy, a spokesperson for Sarepta told Fierce Biotech that Elevidys works differently than Exondys 51 and SRP-5051, meaning it does not generate exon-skipping. A comparison is a little harder to make between the new therapy and the gene therapy since they are being tested on different metrics.
On dystrophin expression, Elevidys achieved a 54% change in baseline in 20 patients during a trial called Study 103, which was intended for the commercial process. The earlier Study 102 conducted in early development saw the gene therapy achieve a 39% change in baseline in 29 patients. Sarepta has not yet released expression data from the phase 3 EMBARK trial.
The spokesperson said that DMD gene therapies are generating higher levels of expression than the prior exon-skipping drugs, but SRP-5051 is still showing better results than any previous med in the class. The therapy adds a peptide to the Exondys 51/PMO backbone, which should allow for better dystrophin expression, more exon skipping and less frequent dosing.
Sarepta does not report individual sales of its therapies but attributed $945 million in revenue to the RNA-based PMO products, which also include Vyondys 53 and Amondys 45, in a preliminary report for the full year 2023 issued earlier this month. William Blair sees Elevidys as a potential $1 billion per year opportunity for Sarepta, according to a Monday note.
Standing alone
Sarepta ultimately needs three pieces of information to complete an analysis to guide where SRP-5051 will end up on the market. The first is today’s initial data readout, and according to Ingram, “we think it looks fabulous.”
“We're seeing what would be a significant advancement over what is currently the gold standard for the treatment of children with exon 51 amenable Duchenne,” Ingram said.
Second, Sarepta will need to know what the label will ultimately be for Elevidys. Sarepta has asked the FDA to expand the label to all DMD patients and remove the accelerated banner, which would remove restrictions on the therapy. Elevidys failed a phase 3 trial that was meant to support the full approval in October 2023, but Sarepta pushed on with the request anyway.
While Ingram did not have news to share on the FDA negotiations, he said the decision will determine SRP-5051’s future.
And third, Sarepta needs the FDA’s perspective on SRP-5051 and the path forward. Ingraham expects that information to come in the third quarter of this year.
“And then we're going to do the entire analysis and look at exactly where SRP-5051 fits into the broader paradigm,” he said, adding that more details should be released by the end of the year. “But what we have today is the first piece and in many ways, probably the most important, which is what does this therapy look like in children with Duchenne muscular dystrophy who are exon 51 amenable?”
Another question facing SRP-5051 is whether the FDA will grant an accelerated approval, given Elevidys is already available.
“I really don't on the face of it see a difference there. I think this will stand on its own,” Ingram said.
Executives were also peppered with questions about an electrolyte disturbance seen during the phase 2 study. Nearly all patients experienced hypomagnesaemia, which is caused by low serum levels of magnesium in the blood. The condition is usually asymptomatic, but can cause anorexia, vomiting, nausea and other gastrointestinal symptoms.
Of the 62 patients in the study, 98% experienced a treatment-related adverse event. The trial was split between 32 patients in the low-dose group and 29 in the high-dose cohort. The most common adverse event was hypomagnesaemia, with 94% of the low-dose group reporting the effect and 97% of the high-dose group experiencing it. Hypokalemia, a low level of potassium in the blood, was experienced by 42% of patients across both groups.
Executives said the magnesium adverse event was managed with supplementation and Ingram said the overall benefit-risk profile for SRP-5051 is positive. None of the events were considered serious by the study investigators and no patients discontinued due to treatment-related adverse events, according to Chief Medical Officer Jake Elkins, M.D.
William Blair analysts said the hypomagnesaemia rates were previously identified and has led to a pause in enrollment for the MOMENTUM study. The supplementation was added to the protocol. The firm did, however, flag four serious instances of the adverse event and three serious cases of hypokalemia, contrary to Elkins' remarks.
Even as attention remains on Sarepta's gene therapy offerings, William Blair's team sees potential for SRP-5051 to improve on Exondys 51 and provide an option for patients who are ineligible for gene therapy. Success would also provide validation to the PPMO platform and could see expansion into patients beyond just the exon 51 skipping population.
William Blair sees SRP-5051 replacing Exondys 51 eventually, with further pressure from Elevidys.