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

NCT04141670 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 2000051ZIANS003129-08Bench-to-bedside award 551673
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

RYR-1 Myopathy

Keywords

RYR1; Myopathy

Outcome Measures

Primary Outcomes (1)

• Number of Participants Experiencing Adverse Events When Treated With S48168 (ARM210)

  Composite safety and tolerability profile of S48168 (ARM210) based on adverse event reporting

  42 days

Study Arms (2)

Low dose group

EXPERIMENTAL

Experimental: 120 mg S48168 (ARM210; 6 x 20 mg tablets) daily for 29 days

Drug: S48168

High dose group

EXPERIMENTAL

Experimental: 200 mg S48168 (ARM210; 10 x 20 mg tablets) daily for 28 days (1 participant) or 29 days (3 participants)

Drug: S48168

Interventions

S48168 DRUG

A novel oral small molecule which is designed to repair leaky RYR1 channels

Also known as: ARM 210

High dose group; Low dose group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet all the following conditions to be eligible for enrollment into the study:
• Body mass index (BMI) ≥ 18.0 and ≤ 36.0 kg/m2 at screening.
• Confirmed genetic diagnosis of RYR1-RM and supporting clinical phenotype.
• Ambulatory. Able to walk ten meters (with or without assistance e.g. with a cane).
• Prior muscle biopsy with demonstrated leaky RyR1 channel.
• Must have a CYP2C8 extensive or intermediate metabolizer genotype.
• For male subjects: is sterile or agrees to use an appropriate method of contraception, including a condom with spermicide, from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug administration. No restrictions are required for a vasectomized male subject provided the subject is at least 1-year post-bilateral vasectomy procedure prior to study drug administration on first day of the first dose. A male subject whose vasectomy procedure was performed less than 1 year prior to study drug administration on the first day of dosing must follow the same restrictions as a non-vasectomized male. Appropriate documentation of surgical procedure should be provided.
• For male subjects: agrees to not donate sperm from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug.
• For female subjects of childbearing potential: uses one of the following highly effective birth control methods:
• Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Depot/implantable hormone (e.g., Depo-provera®, Implanon).
• Bilateral tubal occlusion/ligation.
• Sexual abstinence:

You may not qualify if:

• The presence of any of the following conditions will exclude a patient from study enrollment:
• Patient is mentally or legally incapacitated at the time of the screening visit or during the conduct of the study.
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.
• Positive urine drug or alcohol results at screening.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
• Patients with baseline ALT levels three times above the upper limits of normal (ULN) or baseline AST levels five times the ULN (isolated elevations of total bilirubin \<2 X ULN with direct bilirubin below the ULN will be included).
• Patients with severe pulmonary dysfunction at screening (Forced Vital Capacity (FVC) \< 50% predicted) or evidence of pulmonary exacerbation. Pulmonary exacerbations refer to an acute worsening of respiratory symptoms that result from a decline in lung function.
• Patients with a history of a seizure.
• Patients with uncontrolled diabetes defined as HbA1c \> 7% or diabetic neuropathy.
• Estimated creatinine clearance \<40 mL/minute at screening, which may be calculated using the Chronic Kidney Disease Epidemiology Collaborative method (CKD-EPI), due to reduced muscle mass often seen in RYR1-RM patients.
• Patients with a clinically significant abnormality on their ECG other than hypertensive related, or heart failure (ejection fraction \<30%) or other clinically significant structural heart disease on echocardiogram.
• Patients with a history of myocardial infarction in the last five years, or evidence of congestive heart failure.
• Pregnant and breastfeeding women.
• Patients who have taken Aspirin, Ibuprofen, or Naproxen within the 3 days prior to the muscle biopsy procedure, and/or patients who have taken Plavix (clopidogrel) or Brilinta (ticagrelor) 5 days prior to the muscle biopsy.

Sponsors & Collaborators

• RyCarma Therapeutics, Inc.: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• National Institute of Nursing Research (NINR): collaborator
• Celerion: collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Todd JJ, Lawal TA, Chrismer IC, Kokkinis A, Grunseich C, Jain MS, Waite MR, Biancavilla V, Pocock S, Brooks K, Mendoza CJ, Norato G, Cheung K, Riekhof W, Varma P, Colina-Prisco C, Emile-Backer M, Meilleur KG, Marks AR, Webb Y, Marcantonio EE, Foley AR, Bonnemann CG, Mohassel P. Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial. EClinicalMedicine. 2024 Jan 25;68:102433. doi: 10.1016/j.eclinm.2024.102433. eCollection 2024 Feb.

  PMID: 38318125 DERIVED

MeSH Terms

Conditions

Muscular Diseases

Condition Hierarchy (Ancestors)

Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Results Point of Contact

• Title: Eugene Marcantonio MD PhD
• Organization: ARMGO Pharma, Inc

gmarcantonio@armgo.com

2014633634

Study Officials

• Payam Mohassel, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2019
• First Posted: October 28, 2019
• Study Start: August 25, 2020
• Primary Completion: December 30, 2022
• Study Completion: July 30, 2023
• Last Updated: August 22, 2024
• Results First Posted: April 19, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: six months after publication
• Access Criteria: published results and associated data will be available to academic medical researchers and patient advocacy groups upon request from ARMGO Pharma, INC

Locations

US (1)