Sarepta to develop Arrowhead’s muscular dystrophy treatments
ARO-DUX4 and ARO-DM1 are RNAi candidates in Phase 1/2 clinical testing
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Sarepta Therapeutics is acquiring from Arrowhead Pharmaceuticals the exclusive global rights to develop ARO-DUX4 and ARO-DM1, two RNA interference (RNAi) therapeutic candidates in Phase 1/2 clinical testing, each for one type of muscular dystrophy.
ARO-DUX4 is being tested for facioscapulohumeral muscular dystrophy (FSHD) and ARO-DM1 for myotonic dystrophy type 1 (DM1). Both were designed using Arrowhead’s targeted RNAi molecule (TRiM) platform.
“We look forward to embarking on this partnership with Arrowhead, having been impressed with their scientific capabilities in developing a potentially best-in-class approach to siRNA,” Doug Ingram, Sarepta’s president and CEO, said in a company press release.
The deal, which is expected to close in early 2025, also covers two other clinical-stage treatments, one for idiopathic pulmonary fibrosis and another that’s due to enter clinical testing for a neurodegenerative disease called spinocerebellar ataxia 2 by this year’s end. It also covers three still in preclinical testing for Huntington’s disease and other indications.
Under the agreement, Arrowhead will complete the Phase 1/2 clinical trials for all four clinical-stage treatments, after which development will transition to Sarepta. Arrowhead also will finish testing the three preclinical-stage candidates, which Sarepta will take over for human testing. Sarepta also will get to choose up to six more treatment targets for Arrowhead to develop.
In return, Sarepta will pay Arrowhead $500 million up front and invest $325 million in its stock at a 35% premium, and $250 million over five years, plus potential milestone payments and royalties. Sarepta also will spend up to $500 million to buy back company shares.
“Through a strategic deployment of capital, we are able to access Arrowhead’s leading RNAi platform and will work to rapidly advance new treatments for devastating genetic diseases where there is significant unmet need,” said Ingram, who will be appointed to Arrowhead’s board of directors when the deal closes.
Testing ARO-DUX4 and ARO-DM1 in MD
Muscular dystrophy, which results in progressive muscle weakness and loss of function, has long been a focus of Sarepta. The company markets exon-skipping therapies and the gene therapy Elevidys (delandistrogene moxeparvovec-rokl) for Duchenne muscular dystrophy.
“With the launch of Elevidys going exceedingly well, this broad siRNA collaboration with Arrowhead provides a synergistic platform to complement Sarepta’s gene therapy and gene editing engine,” Ingram said. While other candidates remain in Sarepta’s pipeline, the company decided to drop its exon-skipping therapy SRP-5051 (vesleteplirsen). Â
RNAi is a naturally occurring mechanism that cells use to control the production of proteins. Short strands of RNA attach to messenger RNA, a type of molecule that conveys genetic information from DNA, “knocking it down” or blocking it from delivering instructions to produce proteins.
“We see our TRiM platform as a broad and elegant solution for delivery of siRNA to multiple cell types throughout the body,” said Chris Anzalone, PhD, Arrowhead’s president and CEO.
ARO-DUX4 is designed to knock down production of the DUX4 protein in skeletal muscles, which are those under voluntary control. Normally, the DUX4 gene that codes for this protein stays switched off in muscle, but in FSHD, it’s switched on. In preclinical studies, ARO-DUX4 prevented or reversed production of DUX4 in several muscles. Conversely, ARO-DM1 inhibits the production of a protein called DMPK, whose messenger RNA is abnormally long, forming clumps in cells.
The two-part Phase 1/2 clinical trial (NCT06131983) of ARO-DUX4 is testing its safety and tolerability in up to 60 adults with FSHD type 1 who are being recruited at sites in Australia, New Zealand, and Thailand. It’s also testing the candidate’s pharmacokinetics, that is, how it moves into, through, and out of the body, along with its effects on the body, or pharmacodynamics.
In the first part, patients are randomly assigned to a single infusion into the vein, or intravenously, of ARO-DUX4 or a placebo and to four doses in the second part. Those who complete the first part may join the second one and an open-label extension to continue receiving treatment.
Also running in Australia and New Zealand, another Phase 1/2 clinical trial (NCT06138743) is testing the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-DM1 in up to 36 adults with DM1 who will receive a single or multiple doses of the investigational treatment or a placebo.
“Robust and compelling early data from Arrowhead’s differentiated siRNA approach platform suggests potentially best-in-class treatments that will profoundly improve the lives of those with rare, genetic diseases,” said Louise Rodino-Klapac, PhD, Sarepta’s chief scientific officer and head of research and development.
Said Rodino-Klapac: The “targeted ligand approach, combined with Arrowhead’s clinically validated siRNA chemistry, suggests the potential for deep and durable knockdown of proteins that are [produced in higher than normal amounts].”
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