A Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy

Study ID: STU 082015-050

Summary

This is a double-blind, placebo-controlled, multicenter study with an open-label extension to evaluate the efficacy and safety of 2 phosphorodiamidate morpholino oligomers (PMos), SRP-4045 and SRP-4053, in approximately 99 patients with genotypically confirmed Duchenne muscular dystrophy (DMD) with deletion mutations amenable to correction by skipping exon 45 and 53, respectively. a placebo group will be employed, and patients will be randomized in a double-blind fashion in a 2:1 ratio, combined active (SRP-4045 or SRP-4053) to placebo. a minimum enrollment target of 45 patients per genotype is planned. Patients will be evaluated for inclusion during a Screening period of up to 8 weeks. eligible patients who have out-of-frame deletions amenable exon 45 or 53 skipping will be randomized in a 2:1 ratio between the active group and the placebo group to receive once weekly intravenous (iV) infusions of 30 mg/kg SRP-4045 or 30 mg/kg SRP-4053 respectively, or placebo for up to 96 weeks. Randomization will be stratified by genotype and age (7 to 8.5 years vs [Greater Than]8.5 to13 years). Screening and Baseline assessments, and after eligibility is confirmed by both the Local Site and the Sponsor,all patients undergo a muscle biopsy at Baseline. a second biopsy will be performed at Week 48. all patients may participate in the open-label extension treatment period of the study for up to an additional 96 weeks. Patients who received placebo in the double-blind treatment period of the study will receive open-label active treatment via weekly infusions with either SRP-4045 or SRP-4053 according to their genotype. Following the end of the weekly infusions, patients will be required to return to the study site for end of Study safety evaluations approximately 4 weeks after the last infusion at Week oL100.. The total duration is approximately 204 weeks. Functional assessments of 6MWT, nSaa, and PFTs will be videotaped. The primary efficacy endpoint is: * -Change from Baseline at Week 96 on the 6MWT for the combined-active group compared to placebo. Secondary efficacy endpoints are: * - Change from Baseline at Week 48 in the quantity of dystrophin protein expression as measured by Western blot of biopsied muscle tissue. * - Change from Baseline at Week 48 in the intensity of dystrophin expression in biopsied muscle tissue, as measured by iHC. * - ability to rise independently from the floor (without external support) at Week 96, as indicated by an nSaa subscore of [Quote]2[Quote] (without modification) or [Quote]1[Quote] (Gower's maneuver). * - Loa status at Week 96, as defined by the inability to perform the 6MWT, resulting in a [Quote]0[Quote] value for the 6MWT. * -Change from Baseline at Week 96 in: - - nSaa total score - - FVC% predicted - - Frequency of falls - - LVeF additional efficacy endpoints are: * - Change from Baseline at Week 48 dystrophin protein expression in biopsied muscle tissue as measured by iHC (PDPF). * - Change from Baseline at Week 96 for the combined-active group in: - - nSaa time to complete 10-meter run - -Timed 4-step test - - 9-hole peg test - - PuL - - QMT by hand-held myometry/dynamometry and MViCT - - MiP%p and MeP%p - - PoDCi score The safety and tolerability of SRP-4045 and SRP-4053 will be assessed through a review and evaluation of: * - aes, Saes, deaths, and discontinuations due to aes * - Laboratory testing including hematology, coagulation, chemistry (including serum cystatin C), and urinalysis (including urinary kidney injury olecule-1 [KiM-1]) * - immunogenicity * - eCG * - Vital signs * - Physical examination findings Standard population PK parameters will be estimated by population PK analysis. The effects of potential covariates such as standard dosing, demographic characteristics, concomitant medications, laboratory values, and others on SRP-4045 and SRP-4053 PK will be evaluated.

Participant Eligibility

1. Is a male with an established clinical diagnosis of DMD and an out-of-frame deletion amenable to: *Exon 45 skipping (including but not limited to deletions of exons such as 12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, or 46-55) OR *Exon 53 skipping (including but not limited to deletions of exons such as 42-52, 45-52, 47-52, 48-52, 49-52, 50- 52, 52, or 54-58) as documented by a genetic report from an accredited laboratory confirming deletion endpoints by multiplex ligation-dependent probe amplification or sequencing. *As documented prior to screening by a genetic report from an accredited laboratory defining deletion endpoints by multiplex ligation-dependent probe amplification or sequencing. The patient's amenability to exon 45 or 53 skipping must be confirmed prior to first dose using the genotyping results obtained during Screening. 2. Is between 7 and 13 years of age, inclusive, at randomization. 3. Has stable pulmonary function (FVC% >=50% and no requirement for nocturnal ventilation) that, in the Investigator[Single Quote]s opinion, is unlikely to decompensate over the duration of the study. 4. Has intact right and left biceps brachii muscles (the preferred biopsy site) or 2 alternative upper arm muscle groups. 5. Has been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight). 6. If taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), [BETA] adrenergic blockers, aldosterone receptor antagonists, potassium, or coenzyme Q, has been on a stable dose for at least 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight). 7. Achieved a mean 6MWT distance of >=300 to <=450 meters (without assistance) at both the Screening and Baseline visits (prior to Week 1). The mean 6MWT distance at the Screening and Baseline visits is the average of 2 separate assessments on 2 consecutive days at each visit. The Baseline mean (average of Baseline Days 1 and 2) must be within 15% of the Screening mean distance (average of Screening Days 1 and 2). 8. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive (eg, male condom or female oral contraceptives) during this time frame. 9. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements. 10. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.

Cancer Related: No
Healthy Volunteers: No
UT Southwestern Principal Investigator: Susan Theresa Iannaccone

Contact:

Holly Lawrence

Holly.Lawrence@UTSouthwestern.edu