S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)

Phase 1

Completed

Conditions: RYR-1 Myopathy

Interventions: Drug: S48168

Registration Number: NCT04141670

Lead Sponsor: Armgo Pharma, Inc.

Brief Summary: This study proposes to test S 48168 (ARM210) in a Phase 1 trial in RYR1-RM patients, specifically. The objectives of this study are to explore the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD)/target engagement (TE) of S 48168 (ARM210), as well as effects on muscle/motor function, and fatigue in RYR1-RM patients. The study population will include adult patients (≥18 years of age) who have demonstrated leaky RyR1 channels that are responsive to S48168 (ARM210) ex vivo.

Detailed Description: RYR1- related myopathy comprises a group of rare neuromuscular diseases. Affected individuals generally present with delayed motor milestones, muscle weakness, impaired ambulation, and, in severe cases, scoliosis, ophthalmoplegia, and respiratory distress all due to skeletal muscle weakness.

Causative variants in RYR1, which encodes the major calcium (Ca2+) release channel in skeletal muscle, RyR1, exert different effects on the RyR1 channel. They generally disrupt the normal Ca2+ flow between the sarcoplasmic reticulum (SR) and muscle cell cytosol and commonly result in excessive Ca2+ leak into the cytosol. Persistent Ca2+ leaks reduce its availability in the SR that is necessary for excitation-contraction coupling leading to the muscle weakness characteristic of this disease.

This open-label study consists of ten participants, randomized to two dose groups. All participants will have a diagnosis of RYR1-RM. In addition they have a prior muscle biopsy demonstrating a leaky RYR1 channel which responds to S48168 (ARM210) ex vivo. The first group of three participants will receive a low dose of S 48168 (ARM210) daily for 28 days. The second group of seven participants will receive a higher dose for 28 days. The decision to escalate to the higher dose will be made by an independent Data and Safety Monitoring Board (DSMB) after review of safety, tolerability and PK of the low daily dose. Safety and tolerability will be the primary objective in this study. In addition, exploratory objectives will include PK, PD/TE as well as measures of muscle/motor function and fatigue.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Low dose group	S48168	Experimental: 120 mg S48168 (ARM210; 6 x 20 mg tablets) daily for 29 days
High dose group	S48168	Experimental: 200 mg S48168 (ARM210; 10 x 20 mg tablets) daily for 28 days (1 participant) or 29 days (3 participants)

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Adverse Events When Treated With S48168 (ARM210)	42 days	Composite safety and tolerability profile of S48168 (ARM210) based on adverse event reporting

Secondary Outcome Measures