CY 5021 was a Phase 2, double-blind, randomized, placebo-controlled, multiple dose study of reldesemtiv in 2 sequential ascending dose cohorts of patients with SMA. Patients were randomized 2:1 to receive reldesemtiv or placebo twice daily for 8 weeks. Patients randomized to reldesemtiv in Cohort 1 received a dose of 150 mg twice daily and patients randomized to reldesemtiv in Cohort 2 received 450 mg twice daily. Within each cohort, randomization was stratified by ambulatory status (ambulatory versus non ambulatory).

The primary objective of the study was to determine the PD effects of reldesemtiv on measures of pulmonary function, respiratory function, muscle strength, and motor function. Other PD measures included changes in the timed up and go (TUG) test, a 6-minute walk test (6MWT), and patient and investigator global assessments. Secondary objectives included safety of multiple doses of reldesemtiv and an evaluation of the pharmacokinetics of reldesemtiv.

Muscle strength of 3 muscle groups (elbow flexion, knee extension, and shoulder abduction) were measured bilaterally using a hand-held dynamometer. Muscle strength was measured twice for each body location; if the variability between the 2 measures was > 15%, a third measure was obtained.

The maximum muscle strength of the 2 measurements was identified and transformed as a percent change from baseline using the equation: ([postbaseline value - baseline value] / baseline value) × 100.

The mega-score was a composite score that averaged strength across the 3 muscle groups. It was calculated as the mean of the non-missing transformed muscle strength scores among the 3 muscle groups each measure bilaterally (totaling 6 body locations).

Inclusion Criteria:

• Able to comprehend and willing to sign an Informed Consent Form (ICF) for patients 18 years of age and older. For patients less than 18 years of age, parent(s)/legal guardian(s) of patients must provide written informed consent prior to participation in the study and informed assent will be obtained from minors at least 12 years of age when required by regulation.
• Males or females with genetically confirmed diagnosis of SMA who are Type II, III or IV and at least 12 years of age
• Ambulatory patients, once having achieved a standing position independently, must be able to complete at least one lap in the 6-minute walk test (at least 50 meters) within 6 minutes without assistance.
• Non-ambulatory patients (defined as individuals who are effectively requiring a wheelchair for all mobility needs; they may be able to stand or walk short distances, but unable to walk 50 meters without assistance in 6 minutes). Non-ambulatory patients must be able to tolerate an upright sitting position, with support, continuously for 3 hours
• Hammersmith (HFMS-E) score ≥ 10 and ≤ 54
• Contracture of the elbow flexion and knee flexion ≤ 90 degrees
• Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
• Able to swallow an oral suspension and in the opinion of the Investigator, is expected to continue to be able to do so for the duration of the trial. Administration via a feeding tube is not allowed.
• Forced vital capacity (FVC) > 20% predicted
• Male patients who have reached puberty must agree to do either of the following from Screening until 10 weeks after the last dose of the investigational product unless they have had a vasectomy and confirmed sperm count is zero:
  • Abstain from sexual intercourse, OR
  • If having heterosexual intercourse, must use a condom and their female partners who are of childbearing potential must use a highly effective contraception method*
• Female patients who have had their first period will be considered of childbearing potential unless they are anatomically and physiologically incapable of becoming pregnant. If of childbearing potential, the female patients must:
  • Have a negative urine/serum pregnancy test at Screening AND
  • Abstain from heterosexual intercourse from Screening until 10 weeks after the last dose of investigational product OR
  • If having heterosexual intercourse, must use a highly effective contraception method* and require the male partners to use a condom from Screening until 10 weeks after the last dose of investigational product

    *Highly effective contraception methods include:

  • Established use of oral, injected or implanted hormonal methods of contraception
  • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Male patients must agree to refrain from sperm donation from Screening until 10 weeks after the final study drug administration

Exclusion Criteria:

• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator
• Hospitalization within 2 months of Screening
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (appendectomy, hernia repair, and/or cholecystectomy will be allowed)
• A clinically significant illness within 4 weeks of Screening
• History of alcoholism or drug addiction within 2 years prior to Screening
• History of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to Screening
• Patient has used a strong CYP3A4 inhibitor within 7 days prior to first dose of study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug
• Any other medical condition that would interfere with performance of testing including (but not limited to) significant joint pain or arthritis limiting mobility, and chronic neuromuscular pain sufficient to require ongoing analgesic medication
• Participation by two people at the same time that are living in the same household
• Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days or five half-lives of the other investigational study drug, whichever is greater, prior to Screening
• An ALT or AST greater than 2-fold the upper limit of normal (ULN) or has total bilirubin greater than the ULN at screening. These assessments may be repeated once at the investigator's discretion (within the screening window)
• Currently taking nusinersen, or has taken it in the past, or plans to take it during the course the study