RYR-1 MyopathyPhase 1NCT04141670
S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
A Phase 1 study testing S48168 in people with RYR-1 Myopathy, run by RyCarma Therapeutics, Inc. at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- RYR-1 Myopathy
- What is being tested?
- S48168
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Aug 2020to 30 Jul 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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).
Who cannot join
- 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).
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
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.
Read the 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.
- Conditions
- RYR-1 Myopathy
- Being tested
- S48168
- Keywords
- RYR1, Myopathy
- Medical subject headings
- Muscular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
S48168Drug
Also called ARM 210
A novel oral small molecule which is designed to repair leaky RYR1 channels
| Study group | Role | What they receive |
|---|---|---|
| Low dose group | Experimental | Experimental: 120 mg S48168 (ARM210; 6 x 20 mg tablets) daily for 29 days Receives: 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) Receives: Drug: S48168 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Experiencing Adverse Events When Treated With S48168 (ARM210)
Composite safety and tolerability profile of S48168 (ARM210) based on adverse event reporting
Measured: 42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 2019
- Study start25 Aug 2020
- Primary completion30 Dec 2022
- Study completion30 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for RYR-1 MyopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- RyCarma Therapeutics, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Nursing Research (NINR), Celerion
- Responsible party
- Sponsor
- Investigators
- Payam Mohassel, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04141670
- Sponsor's protocol ID
- 200005
- Other IDs
- 1ZIANS003129-08, Bench-to-bedside award 551673
- Status last verified
- Feb 2024
- First submitted
- 24 Oct 2019
- Last updated
- 22 Aug 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: all IPD that underlie results in a publication
Publications
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.
PubMed 38318125
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)
- ClinicalTrials.gov ID
- NCT04141670
- Acronym / sponsor ID
- 200005
- Conditions
- RYR-1 Myopathy
- Keywords
- RYR1, Myopathy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- RyCarma Therapeutics, Inc.Industry (pharma, biotech, devices)
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Nursing Research (NINR), Celerion
- Study start
- 25 Aug 2020 (actual)
- Primary completion
- 30 Dec 2022 (actual)
- Study completion
- 30 Jul 2023 (actual)
- First posted
- 28 Oct 2019 (actual)
- Results
- Posted 19 Apr 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low dose group | Experimental | Drug: S48168Experimental: 120 mg S48168 (ARM210; 6 x 20 mg tablets) daily for 29 days |
| High dose group | Experimental | Drug: S48168Experimental: 200 mg S48168 (ARM210; 10 x 20 mg tablets) daily for 28 days (1 participant) or 29 days (3 participants) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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.
Key exclusion criteria (25 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| S48168Also: ARM 210A novel oral small molecule which is designed to repair leaky RYR1 channels | Drug | High dose group, Low dose group |
Primary outcome
Number of Participants Experiencing Adverse Events When Treated With S48168 (ARM210)
Time frame: 42 days
Composite safety and tolerability profile of S48168 (ARM210) based on adverse event reporting
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38318125Todd 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.
- Individual participant dataSharing planned: Yes. all IPD that underlie results in a publication
Related trials for RYR-1 Myopathy
RecruitingPhase 2
A Trial to Compare Treatment With Surlorian (ARM210, S48168) to Placebo in Effects on Muscle Strength and Safety in Adults With Autosomal Dominant RYR1-related Myopathy
Autosomal Dominant RYR1-Related Myopathy
RecruitingObservational study
A Natural History Study of RYR1-Related Disorders
Ryanodine Receptor 1-Related Myopathy, Ryanodine Receptor 1 Related Disorders
Not yet recruitingObservational study
The Prevalence of RYR1-related Disease
Neuromuscular Disease, Malignant Hyperthermia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Payam Mohassel, M.D. principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing S48168 in people with RYR-1 Myopathy, run by RyCarma Therapeutics, Inc. at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Apr 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Experiencing Adverse Events When Treated With S48168 (ARM210) (time frame: 42 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04141670, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2024.