Baliforsen

horillaz/ Getty Images With its recent data drop for an oligonucleotide candidate, Dyne Therapeutics signals it may become a frontrunner in this disease space alongside Avidity Biosciences, Lupin and AMO Pharma. Last month, Dyne Therapeutics announced positive results in a Phase I/II trial of its candidate DYNE-101. The milestone places Dyne among the companies closest to developing a disease-modifying treatment for myotonic dystrophy type 1. Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy caused by DMPK mutations on chromosome 19. It affects muscles and many organs across multiple systems that depend on muscular activity. Also known as Steinert disease, it is characterized by the inability to relax muscles at will. DM1 affects 140,000 people in the United States alone, and although there are drugs that address its symptoms, there are no currently approved disease-modifying treatments for the condition. There are, however, more than two dozen investigational drugs in development for DM1. Among the companies looking to fill the unmet need is Dyne, whose DYNE-101 is an antisense oligonucleotide fused with a fragment antibody that binds to the transferrin receptor 1 in muscles. In the Phase I/II ACHIEVE trial , key findings included DMPK RNA level reductions, CASI-22 improvements, early and sustained improvement in myotonia as measured by grip myotonia assessment, and multiple other strength and timed assessments. The trial utilized a multiple ascending dose cohort to identify 6.8 mg/kg every 8 weeks as the optimal dose for future studies. Dyne stated in its press release that it plans to initiate a global registrational expansion cohort of the trial to potentially support a submission for FDA Accelerated Approval in the first half of 2026. Meanwhile, Avidity Biosciences is developing AOC 1001, an antibody oligonucleotide conjugate that targets the DMPK gene to treat DM1. Also known as del-desiran, this investigational treatment is currently being studied in the Phase III HARBOR trial and Avidity has announced plans to submit marketing applications in 2026. In March 2024, Avidity announced positive long-term del-desiran data from the Phase II MARINA-OLE trial showing reversal of disease progression in people living with DM1 across multiple endpoints compared to a matched natural history study population over one year. Those endpoints included grip myotonia assessment, muscle strength and activities of daily living. According to Avidity, additional data from the ongoing Phase I/II MARINA trial for AOC 1001, in which patients were split into placebo-controlled single-dose and multiple ascending dose arms, will be released in the first quarter of this year. While clinical-stage investigational oligonucleotide-based therapy candidates are catching up, repurposed drugs such as metformin, tideglusib and mexiletine are also undergoing Phase III trials to treat DM1. Metformin , a biguanide currently approved for type 2 diabetes mellitus, is currently slated for Phase III trials in DM1. In previous Phase II trials, metformin increased the 6-minute walking distance for DM1 patients versus placebo. While it has positive benefits ranging from anticancer effects to cardiovascular protection to neuroprotection, metformin is also associated with adverse effects such as gastrointestinal discomfort and lactic acidosis in high doses. Another approach is AMO Pharma ’s tideglusib (also known as AMO-02), a glycogen synthase kinase 3 beta inhibitor currently in Phase III clinical trials. Despite not reaching its primary endpoint in the Phase II/III REACH-CDM trial due to a strong placebo effect, tideglusib had achieved clinically and statistically significant benefits in various functional and objective assessments as of May 2024. As a result, after meeting with the FDA, AMO Pharma is forging ahead with a Phase III trial of tideglusib. Elsewhere, Lupin is working on repurposing mexiletine, a class I antiarrhythmic drug that is currently in Phase III trials for DM1. In contrast to previous trials that used mexiletine capsules for immediate-release effects, Lupin intends to use mexiletine granules for prolonged-release oral suspension formulations for its Phase III HERCULES and ATLAS trials. Like tideglusib, mexiletine reached Phase III despite less-than-stellar mid-stage results. In its case, Phase II trial data demonstrated no significant change in 6-minute walk distance at 6 months for patients on mexiletine capsules compared to placebo. Also worthy of mention is ARTHex. While clinical data is scant for the company’s ATX-01, it was enrolling patients into its Phase I/IIa ArthemiR trial as of October 2024. The drug is based on microRNA technology. As progress currently stands, antibody-oligonucleotide conjugates appear to be more effective at targeting the genetic source of DM1 and have a more convincing mechanism of action than small molecules and repurposed drugs. However, even though genetic therapies are advancing quickly, the DM1 space is risky. Consider that Ionis Pharmaceuticals stopped working on its antisense compound IONIS-DMPK-2.5Rx in January 2017 after failing to achieve adequate concentration levels in muscles in Phase I/II trials. If all goes well in the late-stage gene therapy space for DM1, expect new treatments to hit the market within the next three to four years at the earliest.