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

Primary Purpose

RYR-1 Myopathy

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
S48168
Sponsored by
Armgo Pharma, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for RYR-1 Myopathy focused on measuring RYR1, Myopathy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

Patients must meet all the following conditions to be eligible for enrollment into the study:

  1. Body mass index (BMI) ≥ 18.0 and ≤ 36.0 kg/m2 at screening.
  2. Confirmed genetic diagnosis of RYR1-RM and supporting clinical phenotype.
  3. Ambulatory. Able to walk ten meters (with or without assistance e.g. with a cane).
  4. Prior muscle biopsy with demonstrated leaky RyR1 channel.
  5. Must have a CYP2C8 extensive or intermediate metabolizer genotype.
  6. Daily use of medicines and dietary supplements need to be approved by the PI and Sponsor, or a drug/supplement-dependent wash-out prior to inclusion.
  7. 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.
  8. 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.
  9. 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:
    • Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements.
    • If the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used.
  10. For female subjects of non childbearing potential; defined by at least 1 of the following criteria:

    • Postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated documentation of FSH levels is required.
    • Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.
    • Has a congenital condition resulting in no uterus.
  11. Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and study procedures (muscle biopsies and PK sampling).
  12. Able to provide written informed consent and understands the study procedures in the informed consent form (ICF).

EXCLUSION CRITERIA:

The presence of any of the following conditions will exclude a patient from study enrollment:

  1. Patient is mentally or legally incapacitated at the time of the screening visit or during the conduct of the study.
  2. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
  3. History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.
  4. Positive urine drug or alcohol results at screening.
  5. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
  6. 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).
  7. 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.
  8. Patients with a history of a seizure.
  9. Subject has a history of cancer (malignancy) Exceptions: (1) Subjects with adequately treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in the trial (2) Subjects with other malignancies who have been successfully treated > 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the screening except those identified at the beginning of the exclusion criterion or (3) Subjects who in the opinion of the investigator are highly unlikely to sustain a recurrence for the duration of the trial.
  10. Patients with uncontrolled diabetes defined as HbA1c > 7% or diabetic neuropathy.
  11. 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.
  12. 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.
  13. Patients with a history of myocardial infarction in the last five years, or evidence of congestive heart failure.
  14. Pregnant and breastfeeding women.
  15. 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.
  16. Unable to refrain from or anticipates the use of:

    • Any non-approved medicines and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. Thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug. Medicines that would contraindicate the skeletal muscle needle biopsy procedure, and therefore would be considered non- approved, include but are not limited systemic anticoagulants or oral direct thrombin inhibitors.
    • Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 28 days prior to the first dose of study drug and throughout the study. Any substrates of breast cancer resistance protein (BCRP).
  17. Is currently taking any drug which raises gastric pH, including proton pump inhibitors or H2 antagonists. Antacids may be used if taken at night.
  18. Donation of blood or significant blood loss within 56 days prior to the first dose of study drug.
  19. Plasma donation within 7 days prior to the first dose of study drug.
  20. Participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug.
  21. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the subject.
  22. Is an NIH employee who is a subordinate/relative/coworker of a study investigator.

Sites / Locations

  • National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Low dose group

High dose group

Arm Description

Experimental: Low dose group Group of three participants who are treated with a low dose of S48168 (ARM210) for 28 days.

Experimental: High dose group Group of seven participants who are treated with a high dose of S48168 (ARM210) for 28 days.

Outcomes

Primary Outcome Measures

Safety and tolerability of S48168 (ARM210) treatment in RYR1-RM affected individuals
Composite safety and tolerability profile of S48168 (ARM210)

Secondary Outcome Measures

Full Information

First Posted
October 24, 2019
Last Updated
January 9, 2023
Sponsor
Armgo Pharma, Inc.
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Nursing Research (NINR), Celerion
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1. Study Identification

Unique Protocol Identification Number
NCT04141670
Brief Title
S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
Official Title
Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 25, 2020 (Actual)
Primary Completion Date
December 30, 2022 (Actual)
Study Completion Date
June 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Armgo Pharma, Inc.
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Nursing Research (NINR), Celerion

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
RYR-1 Myopathy
Keywords
RYR1, Myopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Low dose group
Arm Type
Experimental
Arm Description
Experimental: Low dose group Group of three participants who are treated with a low dose of S48168 (ARM210) for 28 days.
Arm Title
High dose group
Arm Type
Experimental
Arm Description
Experimental: High dose group Group of seven participants who are treated with a high dose of S48168 (ARM210) for 28 days.
Intervention Type
Drug
Intervention Name(s)
S48168
Other Intervention Name(s)
ARM 210
Intervention Description
A novel oral small molecule which is designed to repair leaky RYR1 channels
Primary Outcome Measure Information:
Title
Safety and tolerability of S48168 (ARM210) treatment in RYR1-RM affected individuals
Description
Composite safety and tolerability profile of S48168 (ARM210)
Time Frame
42 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: 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. Daily use of medicines and dietary supplements need to be approved by the PI and Sponsor, or a drug/supplement-dependent wash-out prior to inclusion. 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: Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements. If the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used. For female subjects of non childbearing potential; defined by at least 1 of the following criteria: Postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated documentation of FSH levels is required. Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure. Has a congenital condition resulting in no uterus. Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and study procedures (muscle biopsies and PK sampling). Able to provide written informed consent and understands the study procedures in the informed consent form (ICF). EXCLUSION CRITERIA: 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. Subject has a history of cancer (malignancy) Exceptions: (1) Subjects with adequately treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in the trial (2) Subjects with other malignancies who have been successfully treated > 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the screening except those identified at the beginning of the exclusion criterion or (3) Subjects who in the opinion of the investigator are highly unlikely to sustain a recurrence for the duration of the trial. 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. Unable to refrain from or anticipates the use of: Any non-approved medicines and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. Thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug. Medicines that would contraindicate the skeletal muscle needle biopsy procedure, and therefore would be considered non- approved, include but are not limited systemic anticoagulants or oral direct thrombin inhibitors. Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 28 days prior to the first dose of study drug and throughout the study. Any substrates of breast cancer resistance protein (BCRP). Is currently taking any drug which raises gastric pH, including proton pump inhibitors or H2 antagonists. Antacids may be used if taken at night. Donation of blood or significant blood loss within 56 days prior to the first dose of study drug. Plasma donation within 7 days prior to the first dose of study drug. Participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the subject. Is an NIH employee who is a subordinate/relative/coworker of a study investigator.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Payam Mohassel, M.D.
Organizational Affiliation
National Institute of Neurological Disorders and Stroke (NINDS)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
all IPD that underlie results in a publication
IPD Sharing Time Frame
six months after publication
IPD Sharing Access Criteria
published results and associated data will be available to academic medical researchers and patient advocacy groups upon request from ARMGO Pharma, INC

Learn more about this trial

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

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