Sarepta Therapeutics has shared initial clinical data on two siRNA candidates, delivering an early look at the wisdom of its decision to bet big on Arrowhead Pharmaceuticals’ pipeline.
Massachusetts-based Sarepta paid Arrowhead $500 million upfront in 2024 for rights to seven programs. The programs’ importance to Sarepta has grown. Guggenheim Securities analysts said in a note to investors this month that Sarepta “in essence is an early clinical-stage company” because of the threats facing its core business. Viewed from that position, the siRNA programs are critical to Sarepta’s future.
Sarepta provided a glimpse of that future Wednesday, reporting phase 1/2 results for SRP-1001 in facioscapulohumeral muscular dystrophy type 1 (FSHD1) and for SRP-1003 in myotonic dystrophy type 1 (DM1). The readout covered patients who received a single dose of the peptide-linked siRNA candidates.
On a call with investors to discuss the data, Sarepta CEO Doug Ingram said the data show the technology underpinning the candidates “drives multiples greater construct into the muscle than other approaches, with dose-dependent increases in plasma and muscle concentration and no saturation of siRNA uptake.” Sarepta said most adverse events were mild to moderate and were not dose dependent.
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At Day 42, SRP-1001 achieved 28.4 nM muscle concentration without dose-limiting toxicities that would limit further dose escalation. Sarepta compared the result to the median 4.5 nM muscle concentration on the pivotal trial dose of Avidity Biosciences’ FSHD1 candidate. James Richardson, M.D., Sarepta’s chief medical officer, told investors SRP-1001’s suppression of the target gene is “potentially unprecedented.”
Discussing SRP-1003, Richardson said Sarepta has seen a 50% placebo-adjusted reduction in DMPK, the gene at the root of DM1. The figure exceeds Sarepta’s preclinical predictions. Given the small number of participants and variability in placebo, Richardson focused on muscle concentration data on SRP-1003.
At the lowest dose of SRP-1003, Richardson said the muscle concentration was “manyfold” higher than seen at comparable doses of rival siRNA and antisense oligonucleotide (ASO) assets. Avidity and Dyne Therapeutics have more advanced programs, but Sarepta is betting it can improve on their candidates. Avidity is running phase 3 DM1 and FSHD trials of an antibody-linked siRNA candidate.
Without naming Avidity, Ian Estepan, chief operating officer at Sarepta, said at a TD Cowen event this month that the antibody-linked siRNA approach has failed to show a dose response. Avidity’s phase 1/2 DM1 trial reported declines in DMPK mRNA levels in muscle-biopsy samples of 46% in the 1-mg group, 44% in the 2-mg group and 37% in the 4-mg group, compared to a 0.9% increase on placebo.
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Dyne is preparing to start a phase 3 study of its ASO drug candidate in DM1 and has a FSHD prospect in preclinical development. Again without naming names, Estepan said the ASO approach gives a very good dose-response curve from a muscle concentration perspective, but the dependence on RNAs being available for knockdown means siRNA could be more potent.
Sarepta shares rose 14% to $20 in premarket trading.
