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Patient Dosing Commenced for Phase 1/2 ArthemiR Trial of ATX-01 in Myotonic Dystrophy Type 1
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Key Takeaways
- ATX-01 targets miR-23b to treat DM1 by increasing MBNL production and reducing toxic DMPK mRNA.
- The phase 1/2 trial will enroll 56 participants to evaluate safety, tolerability, and efficacy of ATX-01.
ArthemiR, a placebo-controlled study, primarily evaluates the safety of ATX-01 in myotonic dystrophy type 1, with other assessments that include target engagement and measures associated with muscle function.
Frédéric Legros, PhD
According to a recent announcement, the first patient has been dosed in ARTHEx’s phase 1/2 trial assessing its investigational agent ATX-01, an antimiR oligonucleotide designed to target microRNA 23b (miR-23b), as a new treatment for myotonic dystrophy type 1 (DM1). The double-blind, placebo-controlled, single- and multiple-ascending dose study will aim to enroll 56 participants with the disease to assess the efficacy and safety of the therapeutic.1
DM1, a disease with no approved treatments, is caused by sequestration of muscle blind like (MBNL) proteins by toxic dystrophia myotonica protein kinase (DMPK) mRNA in the nucleus, and by translational repression of MBNL production caused by miR23b overexpression, both of which lead to a net decrease of MBNL available to exert its usual regulatory functions. ATX-01 is unique in that it has a dual mechanism of action, working to increase MBNL production while also destabilizing the toxic DMPK foci leading to a reduction of DMPK mRNA and release of sequestered MBNL.
The phase 1/2 trial mainly aims to test the safety and tolerability of the drug, but also its effect on target engagement at the muscle level through biomarkers, including MBNL levels and RNA splicing index. In addition, investigators will also measure the maximum observed plasma concentration of ATX-01, area under the plasma concentration-time curve of ATX-01, video hand opening time, change in ankle dorsiflexion strength by quantitative myometry, and change in Activities of Daily Living questionnaire item scores.
"Since the founding of ARTHEx, we have been working tirelessly to achieve our goal of creating a new therapeutic option for persons living with DM1 and their families. We are proud to have reached a major milestone in our company's journey with the dosing of the first participant in our ArthemiR™ trial," Frédéric Legros, chairman and chief executive officer at ARTHEx, said in a statement.1 "We believe that the market opportunity for a new DM1 therapy is very attractive, given the important unmet medical need and the lack of an approved agent that is disease-modifying."
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To be included in the study, patients must have a documented clinical diagnosis of DM1, with a CTG expansion of at least 150 repeats in DMPK gene measured in peripheral blood monuclear cells. In addition, patients must be ambulatory, defined as able to complete a 10-meter walk/run test at screening without the use of assistive devices such as canes, walkers, or orthoses, except for ankle-foot orthoses. Furthermore, patients must have a presence of at least 3 seconds of grip myotonia as confirmed by a central ready.
The study has only a few exclusions, including patients with congenital DM1. Additionally, the study excludes those with Medical Research Council Muscle Scale score of less than 4 on ankle dorsiflexion or significant tibialis anterior atrophy that prevents a muscle biopsy. Lastly, patients who use mexiletine or other agents for myotonic within 21 days or 5 half-lives, whichever is longer, are also not included in the study.
"The ArthemiR™ trial is designed to assess the safety and tolerability of ATX-01 in persons with DM1, as well as its activity on the disease pathophysiology and clinical outcomes. We are very pleased with the non-clinical safety profile of ATX-01 and are excited about moving this agent to clinic as it offers a fresh approach to the disease due to its dual mechanism of action," Judy Walker, chief medical officer at ARTHEx, said in a statement.1 "We sincerely hope that ATX-01 will lead to functional benefits for patients with DM1, offer a well-tolerated safety profile, and improve quality of life for those with the condition. We look forward to continuing to enroll participants and initiating more sites across the globe."
In July 2022, the FDA granted orphan drug designation for ATX-01 in DM1.2 The treatment was discovered through the company’s in-house discovery engine, which is developed to recognize and optimize novel microRNA modulators and ensure preferential delivery to target tissues, for the treatment of diseases in which microRNAs are involved in the disease pathogenesis such as DM1.
