A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy (HOPE-3)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Human Allogeneic Cardiosphere-Derived Cells for the Treatment of Duchenne Muscular Dystrophy

HOPE-3 is a two cohort, Phase 3, multi-center, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of a cell therapy called CAP-1002 in study participants with Duchenne muscular dystrophy (DMD) and impaired skeletal muscle function. Non-ambulatory and ambulatory boys and young men who meet eligibility criteria will be randomly assigned to receive either CAP-1002 or placebo every 3 months for a total of 4 doses during the first 12-months of the study. All participants will be eligible to receive 4 doses of CAP-1002 for an additional 12 months as part of an open-label extended assessment period.

Up to 102 eligible study subjects will participate in this two cohort study. Cohort A will enroll approximately 58 subjects randomized in a 1:1 ratio (active:placebo). Subjects randomized to the active treatment group in Cohort A will receive CAP-1002A (manufactured at Capricor's manufacturing facility in Los Angeles, CA). Once Cohort A enrollment is completed, Cohort B enrollment will begin. Cohort B will enroll approximately 44 participants randomized in a 1:1 ratio (active:placebo). Subjects randomized to the active treatment group in Cohort B will receive CAP-1002B (manufactured at Capricor's manufacturing facility in San Diego, CA). Both cohorts will include visits at Screening, Baseline/Day 1, Month 1, and Months 3, 6, 9, and 12. Subjects will receive IV infusions of CAP-1002 or placebo on Day 1 and Months 3, 6, and 9. All subjects will then be eligible to receive additional IV infusions of CAP-1002 at Month 12, 15, 18, and 21 as part of the open-label phase of the study. A primary analysis of efficacy and safety will be performed for each individual cohort at Month 12 following 4 administrations of CAP-1002 or placebo. The primary efficacy endpoint is the mean change from baseline in upper limb function as assessed by Performance of the Upper Limb test, version 2.0 [PUL 2.0] Total Score at the 12-month time point. Secondary endpoints evaluated at the 12-month time point include assessment of changes in cardiac muscle function and structure by cardiac magnetic resonance imaging [cMRI], changes in hand-to-mouth function [eat 10-bites assessed by the Duchenne Video Assessment (DVA)], quality of life assessments, and biomarker analysis for creatine kinase MB isoenzyme (CK-MB). Safety evaluations will include adverse events, concomitant medications, physical exam, vital signs, and clinical laboratory testing. Following the initial 4 infusions in Cohort A or Cohort B, all subjects will be eligible to participate in a 12-month open label extended assessment period and receive up to 4 additional IV infusions of CAP-1002 once every 3 months. An analysis of extended safety and efficacy will be conducted after all subjects have completed the Month 24 visit.

Muscular Dystrophies, Muscular Dystrophy, Duchenne, Muscular Disorders, Atrophic, Muscular Diseases, Neuromuscular Diseases, Genetic Diseases, X-Linked, Genetic Diseases, Inborn, Nervous System Diseases

Cohort A: placebo-controlled, double-blind, randomized 1:1 (active:placebo); Cohort B: placebo-controlled, double-blind, randomized 1:1 (active:placebo)

Cohort A: Approximatetly 29 subjects will receive CAP-1002A active treatment consisting of 150 million cardiosphere-derived cells (CDCs) via intravenous infusion every 3 months Cohort B: Approximately 22 participants will receive CAP-1002B active treatment consisting of 150 million cardiosphere-derived cells (CDCs) via intravenous infusion every 3 months

Cohort A: Approximately 29 subjects will receive a Placebo solution via intravenous infusion every 3 months Cohort B: Approximately 22 participants will receive a Placebo solution via intravenous infusion every 3 months

Cohort A: CAP-1002A manufactured in Los Angeles, CA; Cohort B: CAP-1002B manufactured in San Diego, CA

Mean change from baseline in Performance of the Upper Limb test, version 2 (PUL 2.0) Total Score. Items are scored on a three-point scale: 0=unable to perform the item, 1=impaired or performs with compensation, 2=performs task without compensation

Mean change from baseline in left ventricular ejection fraction as assessed by Cardiac Magnetic Resonance (cMRI)

Change in cardiac muscle function and structure by assessment of left ventricular end-systolic volume

Mean change from baseline in left ventricular end-systolic volume as assessed by Cardiac Magnetic Resonance (cMRI)

Change in cardiac muscle function and structure by assessment of left ventricular end-diastolic volume

Mean change from baseline in left ventricular end-diastolic volume as assessed by Cardiac Magnetic Resonance (cMRI)

Mean change from baseline in mid [elbow] plus distal level upper limb function in Performance of the Upper Limb test, version 2 (PUL 2.0); items are scored on a three-point scale: 0=unable to perform the item, 1=impaired or performs with compensation, 2=performs task without compensation

Mean change from baseline in the functional ability of eating 10 bites evaluated by Duchenne Video Assessment (DVA) using a video record of patient performing the task at home. Physical therapists score the patient's quality of movement in the video using scorecards with pre-specified compensatory movement criteria.

Mean change from baseline in item 7 [hand-to-mouth] in Performance of the Upper Limb test, version 2 (PUL 2.0); items are scored on a three-point scale: 0=unable to perform the item, 1=impaired or performs with compensation, 2=performs task without compensation

Proportion of patients with total loss of hand-to-mouth function as assessed by item 7 [hand-to-mouth] in Performance of the Upper Limb test, version 2 (PUL 2.0)

Mean change from baseline in Duchenne Muscular Dystrophy Upper Limb Patient-Reported Outcome Measures (DMD UL PROM) questionnaire. Patient or caretaker evaluates the perceived difficulty in performing activities of daily living on a 3-level scale: 0=impossible without help, 1=can do task with difficulty, 2= can do task easily.

Mean change from baseline between patients initially randomized to either CAP-1002 or placebo in full Performance of the Upper Limb test, version 2 (PUL 2.0) at Month 24 in the open label phase of the trial. items in PUL 2.0 are scored on a three-point scale: 0=unable to perform the item, 1=impaired or performs with compensation, 2=performs task without compensation

Inclusion Criteria: Male subjects at least 10 years of age at time of consent who are willing and able to provide informed consent to participate in the trial if ≥ 18 years of age or assent with parental or guardian informed consent if < 18 years of age. If a third-party caregiver is involved, they must provide informed consent. Diagnosis of DMD based on clinical and phenotypic manifestations consistent with DMD (e.g., family history of DMD, elevated creatine kinase, dystrophin muscle biopsy, calf pseudohypertrophy, history of Gowers' sign, and gait impairment before 7 years of age) as confirmed by the Investigator. Confirmatory genetic testing performed to have reached a diagnosis of DMD at any time in the past or currently performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent. Performance of the Upper Limb test (PUL) entry item scores 2-6 and total PUL score less than or equal to 40. For Cohort A only: enrollment of patients with PUL entry score 6, Exon 44 skipping amenable, and/or Exon 3 through 7 deletions will be capped at no more than 10% of the total study population (approximately 6 patients with these characteristics). Reduced ability to walk/run (if ambulatory): subjects must take more than 10 seconds for the 10-meter walk/run (i.e., velocity < 1 meter/second). If non-ambulatory, loss of independent ambulation between 10th and 18th year birthday (standing unassisted or ability to take, at most, several steps independently is not considered ambulation). Subjects who are considered non-ambulatory between the ages of 9 and10 may be enrolled with prior approval from the sponsor. Receiving standard of care therapy at an experienced, multidisciplinary DMD center as evidenced by regular cardiac and pulmonary monitoring, systemic glucocorticoid treatment, and at-home range of motion exercises. Treatment with systemic glucocorticoids for at least 12 months and at a stable dose at least 6 months prior to study participation, except for either weight-based dose adjustment or a decrease in steroid dose of ≤ 10% for toxicity. For patients on chronic deflazacort, treatment with an equivalent dose of prednisone or prednisolone for a period of ≤ 30 days to bridge lack of availability of deflazacort during the 6 months prior to randomization is acceptable. Current and up-to-date immunizations according to children and adolescent Centers for Disease Control and Prevention immunization schedule at the discretion of the Investigator. Adequate venous access for parenteral IP infusions and routine blood collection. Assessed by the Investigator as willing and able to comply with the requirements of the trial. Sexually active subjects and their partners who are fertile must agree to use effective method(s) of contraception. Exclusion Criteria: Left ventricular ejection fraction (LVEF) less than or equal to 35% prior to randomization. Elbow-flexion contractures > 30° in both extremities. Body mass index (BMI) > 45. Percent predicted forced vital capacity (FVC%) < 35% within 6 months prior to randomization. Inability to perform consistent PUL 2.0 measurement within ± 2 points without shoulder domain or within ± 3 points with shoulder domain during paired testing at screening. Risk of near-term respiratory decompensation in the judgment of the Investigator, or the need for initiation of day and night non-invasive ventilator support as defined by serum bicarbonate ≥ 29 mmol/L at screening. History of non DMD-related chronic respiratory disease requiring ongoing or intermittent treatment, including, but not limited to, asthma, bronchitis, and tuberculosis. Acute respiratory illness within 30 days prior to screening and during screening. Initiation of nocturnal non-invasive ventilation within 30 days prior to screening. Planned or anticipated thoracic or spinal surgery within the 6 months following randomization. Planned or anticipated lower extremity surgery within the 6 months following randomization, if ambulatory. Known hypersensitivity to dimethyl sulfoxide (DMSO) or bovine products. Initiation of treatment with metformin or insulin within 3 months prior to randomization. Initiation of treatment with an FDA-approved exon skipping therapy for the treatment of DMD and/or non-weight based adjustments within 12 months prior to randomization. Treatment with human growth hormone within 3 months prior to randomization, unless on a stable dose allowing for weight-based dose adjustments (as determined by the site Investigator) for at least 24 months prior to randomization. Treatment with a cell therapy product within 12 months prior to randomization; any prior exposure to CAP-1002 will be excluded. Treatment with an investigational product within 6 months prior to randomization. History, or current use, of drugs or alcohol that could impair the ability to comply with participation in the trial. Inability to comply with the investigational plan and follow-up visit schedule for any reason, in the judgment of the investigator. Inability to undergo a cardiac MRI. For Cohort B Only - Subjects with a known hypersensitivity to gadolinium may forgo the LGE assessment but must complete a cardiac MRI without contrast. For Cohort B Only - Subjects who are unable to tolerate gadolinium due to renal insufficiency as measured by an estimated Glomerular Filtration Rate (eGFR) less than 60 mL/min/1.73 m2 may forgo the LGE assessment but must complete a cardiac MRI without contrast. For Cohort B: Subjects with PUL entry score 6, Exon 44 skipping amenable, or Exon 3 through 7 deletions are excluded from participation.