A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-DM1 in Subjects With Type 1 Myotonic Dystrophy Who are ≥18 to ≤65 Years

This phase 1/2a dose-escalation study evaluates ARO-DM1, an investigational agent, in adults with Type 1 Myotonic Dystrophy aged 18 to 65 years. The primary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single and multiple doses of ARO-DM1 in subjects with this neuromuscular disorder. Additionally, the study aims to evaluate the efficacy of multiple doses of ARO-DM1 specifically in Cohort 5. These objectives are clinically relevant as Type 1 Myotonic Dystrophy is a progressive genetic condition characterized by myotonia, muscle weakness, and multisystem involvement, for which limited therapeutic options currently exist. Understanding the safety profile, dose-response relationship, and preliminary efficacy signals of ARO-DM1 is essential for determining its potential as a disease-modifying therapy in this patient population.

The clinical trial enrolled a total of **32 participants** diagnosed with **Type 1 Myotonic Dystrophy**. The study population included both **male and female subjects** aged **18 to 65 years** at the time of informed consent. Participants were required to have a genetically confirmed diagnosis of DM1 with DMPK CTG repeat length of at least 100, verified through screening evaluation or source documentation. All subjects presented clinician-assessed signs of DM1, including clinically apparent myotonia equivalent to a hand opening time of at least 2 seconds. The onset of clinically significant symptoms must have occurred after the age of 12 years. Functional mobility was assessed, requiring participants to be capable of walking independently for at least 10 meters at screening, with orthoses permitted but canes and walkers excluded. Subjects of childbearing potential were required to adhere to highly effective contraception methods in addition to condom use throughout the study period and for at least 90 days following study completion or the last dose of study drug. The trial population was selected based on specific diagnostic, clinical, and functional criteria to ensure appropriate evaluation of the investigational treatment's safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in this patient population.

This is a Phase 1/2a, dose-escalating clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-DM1 in subjects with Type 1 Myotonic Dystrophy. The study investigates both single and multiple escalating doses of the investigational medicinal product. The trial employs a placebo-controlled design, with the comparator being Sodium Chloride 9 mg/ml (0.9%) solution for injection. ARO-DM1 is formulated as a powder for solution for injection containing the active substance ADS-019, a nucleic acid, and is administered via intravenous infusion.

The primary objective is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single and multiple doses of ARO-DM1 in subjects with Type 1 Myotonic Dystrophy. An additional objective for Cohort 5 specifically is to evaluate the efficacy of multiple doses of ARO-DM1. The primary endpoint is the incidence, frequency, and severity of treatment-emergent adverse events and treatment-related adverse events over time through the end of study. The secondary endpoint focuses on the plasma pharmacokinetics of ARO-DM1 in subjects with Type 1 Myotonic Dystrophy.

Eligible participants are males and females aged 18 to 65 years at the time of informed consent with a genetically confirmed diagnosis of Type 1 Myotonic Dystrophy. Subjects must have DMPK CTG repeat length of 100 or greater based on screening evaluation or source verifiable medical records. Additional inclusion criteria require clinician-assessed signs of Type 1 Myotonic Dystrophy including clinically apparent myotonia equivalent to hand opening time of at least 2 seconds. Subjects must have had the onset of clinically significant symptoms after the age of 12 years and must be able to walk at least 10 meters independently at screening, with orthoses allowed but canes and walkers not permitted. Subjects of childbearing potential must agree to use highly effective contraception in addition to a condom during the study and for at least 90 days following the end of the study or last dose of study drug, whichever is later, and must not donate sperm or eggs during this period.

The estimated recruitment start date for the trial is January 31, 2026, with an estimated end date of September 30, 2026. The overall trial duration encompasses the screening phase, treatment period with dose escalation across multiple cohorts, and follow-up assessments through the end of study visit. Participant involvement extends from the initial screening visit through the completion of all scheduled follow-up visits and safety assessments. Conditions that may lead to early termination from the study include the occurrence of treatment-emergent adverse events of sufficient severity, withdrawal of consent, protocol violations, or other safety concerns as determined by the investigator or sponsor.

The experimental treatment in this clinical trial is **ARO-DM1**, a powder for solution for injection containing the active substance **ADS-019**, which is a nucleic acid-based compound. The investigational medicinal product is manufactured by Arrowhead Pharmaceuticals Inc. and is administered via **intravenous infusion**. The study evaluates escalating single and multiple doses of ARO-DM1 in subjects with **type 1 myotonic dystrophy**. The specific dosage amounts, frequency of administration, and duration of treatment periods are determined according to the dose-escalation protocol design, with different cohorts receiving varying dose levels to assess safety, tolerability, **pharmacokinetics**, and **pharmacodynamics** of the investigational product.

The comparator treatment used in this study is a **placebo** consisting of sodium chloride 9 mg/ml (0.9%) solution for injection. The placebo is administered to control subjects to enable comparison with the active treatment and to maintain the integrity of the study design. The placebo formulation is designed to be indistinguishable from the reconstituted experimental medication to ensure appropriate blinding where applicable in the trial protocol.

The primary efficacy endpoint will assess the incidence, frequency, and severity of treatment-emergent adverse events and treatment-related adverse events in subjects with Type 1 Myotonic Dystrophy over time through the end of study. This evaluation will provide data on the safety and tolerability profile of ARO-DM1 during the treatment period. Additionally, plasma pharmacokinetics of ARO-DM1 will be evaluated as a secondary endpoint in subjects with Type 1 Myotonic Dystrophy. The study aims to evaluate the efficacy of multiple doses of ARO-DM1 specifically in subjects enrolled in Cohort 5.