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Ryanodine receptor isoform 1-related congenital myopathies (RYR1-RM) are a group of
rare neuromuscular diseases. RYR1-RM first develops in children. People with RYR1-RM may have muscle weakness, impaired walking, and other problems. There is no treatment for RYR1-RM. Researchers hope the drug S48168 can help by fixing leaky RyR1 channels.
To test if S48168 is safe for people with RYR1-RM, if the dose given reaches muscle, and if S48168 improves muscle function and fatigue.
Otherwise healthy people age 18-65 with RYR1-RM.
Participants will have 3 study visits at NIH Clinical Center, including screening. Visit 1 will last 3-5 days; visit 2, 1-2 days; visit 3, 3-4 days.
Participants will be screened with a medical history and physical exam. Their heart rate, blood pressure, and heart and lung function will be checked. They will give blood and urine samples. A small tube may be inserted in a vein to collect blood. They will take movement function tests. They will complete questionnaires about their fatigue symptoms. They will answer questions about suicidal thoughts. These tests will be repeated during the study. Photographs/videos may be taken to document symptoms.
Participants will have 2 needle muscle biopsies.
Participants will take S48168 by mouth daily for 28 days. They will keep a medication diary. A study investigator will make lifestyle recommendations.
Between visits and after treatment, participants will be contacted by email or telephone. They will talk about how they are feeling.
One week after the last dose of S48168, participants will give a blood sample at a local facility.
Participation lasts about 2 months....
Ryanodine receptor isoform 1-related congenital myopathies (RYR1-RM) comprise a group of rare neuromuscular diseases estimated to affect at least 1/90,000 pediatric individuals in the United States. 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. Additionally, chronic SR Ca2+ leak results in elevated cytosolic Ca2+ concentration, and mitochondrial-related oxidative stress and cellular injury. The oxidative stress, in turn, can further contribute to RyR1 Ca2+ leak by channel oxidation and nitrosylation. Although RYR1-RM have been associated with significant morbidities and early mortality, there remains no FDA-approved treatment.
A new class of Ca2+ channel stabilizers, Rycals , were developed by Dr. Andrew Marks at Columbia University. Under normal physiological conditions, Calstabin1 binds and stabilizes the RyR1 closed state. Rycals function as Ca2+ channel stabilizers by restoring RyR1- Calstabin1 binding when it is deficient, thereby stabilizing the RyR1 closed state. To date, Dr. Marks laboratory has tested Rycals pre-clinically in at least 20 RYR1-RM patient muscle biopsies in vitro, including ten obtained during a previous clinical trial (NCT02362425). All untreated samples initially showed decreased RyR1-Calstabin1 binding (<10- 40% of healthy control muscle), which improved to 70-90% of control levels upon treatment with Rycals ex vivo. This work has demonstrated that Rycal treatment can restore RyR1-Calstabin1 binding and rescue leaky RyR1 channels in human biopsies ex vivo. In addition, a few muscle disease mouse models demonstrated that Rycal treatment improved muscle strength and muscle cell survival and may therefore offer a promising treatment for RYR1-RM. S 48168 may also have benefit for malignant hyperthermia susceptibility, a condition allelic to RYR1-RM, by restoring the conformational integrity of mutant RyR1 channels. The lead Rycal, S 48168 (ARM210), has completed Phase I clinical studies in healthy volunteers. In those studies, S 48168 (ARM210) was safe and well tolerated in single and multiple dose studies up to now but has not been tested in patients with RYR1-RM. This study proposes to test S 48168 (ARM210) for the first time in a Phase I trial in RYR1-RM patients, specifically, in the same patients who have exhibited loss of RyR1-Calstabin1 binding based on previous ex vivo studies.
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 (greater than or equal to 18 years of age) who have demonstrated loss of RyR1-Calstabin1 binding ex vivo. The proposed open-label study design consists of ten participants, randomized to two dose groups. The first group of three participants are to receive 120 mg S 48168 (ARM210) second group of seven participants will receive a dose less than or equal to 200 mg daily for 28 days. The decision to escalate to a top dose of less than or equal to 200 mg daily will be made by an independent Data and Safety Monitoring Board (DSMB) after review of safety, tolerability and PK of the 120 mg 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.
National Institutes of Health Clinical Center
National Institutes of Health Clinical Center (CC)
Published on BioPortfolio: 2019-10-31T14:29:37-0400
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