Phase I/II Study of SRP-4053 in DMD Patients

NCT02310906 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 4053-101
• Study Type: interventional
• Target: 39
• Locations: 4 countries
• Sites: 5

Brief Summary

This is a first-in-human, multiple-dose 2-part study to assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in Duchenne muscular dystrophy (DMD) patients with deletions amenable to exon 53 skipping.

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne muscular dystrophy; Exon Skipping; DMD; Exon 53; Ambulatory; Pediatric

Outcome Measures

Primary Outcomes (9)

• Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation

  Adverse event (AE) was any untoward medical occurrence in a clinical trial participant, which does not necessarily have a causal relationship with the investigational drug. A Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as AEs that were reported or worsened on or after the start of study drug dosing through 12 weeks. TEAEs included both Serious TEAEs and non-serious TEAEs.

  Baseline up to Week 12

• Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs

  Laboratory parameters included hematology, serum chemistry (SC), urinalysis and coagulation. Number of participants with at least one potentially clinically significant abnormal finding were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potentially clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care.

  Baseline up to Week 12

• Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs

  Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Number of participants with at least one potentially clinically significant abnormal vital signs findings were reported as TEAEs. The Investigator determined whether abnormal assessment results were potentially clinically significant or not. Potential clinical significance was defined as any variation in assessment results that had medical relevance resulting in an alteration in medical care.

  Baseline up to Week 12

• Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations

  Physical examinations were performed by the Investigator, or qualified study staff. A full physical examination included a review of general appearance, head, eyes, ears, nose and throat, heart, lungs, abdomen, extremities, skin, lymph nodes, musculoskeletal, and neurological systems. Number of participants with potentially clinically significant abnormalities in physical examinations were reported. Potentially clinically significant abnormalities in physical examinations were based on Investigator's discretion.

  Baseline up to Week 12

• Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs

  Twelve-lead ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the participant was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECG reported as TEAEs presented here. The Investigator determined whether abnormal assessment results were potentially clinically significant or not.

  Baseline up to Week 12

• Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO)

  Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. Cardiac function events included cardiomegaly, tachycardia, and dyspnoea. The ECHO was reviewed and interpreted by medically qualified personnel. Number of participants with potentially clinically significant abnormalities in ECHO were reported.

  Baseline up to Week 12

• Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group

  6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in total golodirsen group was reported.

  Baseline and Week 144

• Part 2b: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Untreated Group (Non-exon 53 Amenable Participants)

  6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course of 25 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at Week 144 in untreated group (non-exon 53 amenable participants) was calculated.

  Baseline and Week 144

• Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group

  Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group.

  Baseline, Week 48

Secondary Outcomes (13)

• Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen

  Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

• Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen

  Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

• Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma

  Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

• Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen

  Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

• Part 1: Elimination Half-life (T1/2) of Golodirsen

  Pre-dose, 5 to 10 minutes, 1, 1.5, 2, 4, 6, 8, 12, 16 and 24 hours post-dose at Weeks 1 (for 4 mg/kg arm), 3 (for 10 mg/kg arm), 5 (for 20 mg/kg arm) and 7 (for 30 mg/kg arm)

Study Arms (4)

Part 1: SRP-4053

EXPERIMENTAL

Patients will receive SRP-4053 (golodirsen) intravenous (IV) infusions, weekly, at escalating dose levels as follows: Weeks 1-2, 4 mg/kg/week; Weeks 3-4, 10 mg/kg/week; Weeks 5-6, 20 mg/kg/week; Weeks 7-12, 30 mg/kg/week. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.

Drug: SRP-4053

Part 1: Placebo

PLACEBO COMPARATOR

Patients will receive SRP-4053 placebo-matching IV infusions, weekly, for 12 weeks. Dosing will be interrupted or halted if specific predefined stopping criteria are met or if warranted at the discretion of the Sponsor or Investigator.

Drug: Placebo

Part 2: SRP-4053

EXPERIMENTAL

All eligible patients from Part 1, as well as new patients, will receive SRP-4053 (golodirsen) 30 mg/kg/week IV infusions, weekly, for up to 168 weeks.

Drug: SRP-4053

Part 2: Untreated Group

NO INTERVENTION

Patients with DMD who have a genotypically confirmed deletion of exon(s) not amenable to treatment by exon 53 skipping, but who otherwise meet the same eligibility criteria as treated patients newly recruited to Part 2, will undergo the same study assessments as treated Patients (except for pharmacokinetic \[PK\] sampling and muscle biopsies), but at a reduced schedule through Week 144. The untreated patients are not considered as control group.

Interventions

Placebo DRUG

SRP-4053 placebo-matching solution for IV infusion.

Part 1: Placebo

SRP-4053 DRUG

SRP-4053 (golodirsen) solution for IV infusion.

Part 1: SRP-4053; Part 2: SRP-4053

Eligibility Criteria

• Age: 6 Years - 15 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Diagnosed with DMD, genotypically confirmed.
• Intact right and left biceps muscles or an alternative upper arm muscle group.
• Stable pulmonary and cardiac function.
• Minimum performance on 6MWT, North Star Ambulatory Assessment, and rise (Gowers) test as specified in the study protocol.
• On a stable dose of corticosteroids for at least 6 months.

You may not qualify if:

• Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.
• Current or previous treatment with any other experimental treatments within 12 weeks prior to study entry.
• Major surgery within the last 3 months.
• Presence of other clinically significant illness.
• Major change in physical therapy regime within the last 3 months.

Sponsors & Collaborators

• Sarepta Therapeutics, Inc.: lead
• Institut de Myologie, France: collaborator
• Consultants for Research in Imaging and Spectroscopy: collaborator
• Great Ormond Street Hospital for Children NHS Foundation Trust: collaborator
• Catholic University of the Sacred Heart: collaborator
• Royal Holloway University: collaborator
• SYSNAV: collaborator
• University College, London: collaborator
• University of Newcastle Upon-Tyne: collaborator

Study Sites (5)

Boston Children's Hospital

Boston, Massachusetts, 02116, United States

Location

Institute de Myologie

Paris, 75013, France

Location

Policlinico Universitario A Gemelli

Rome, 00168, Italy

Location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Location

Newcastle University Hospital

Newcastle, United Kingdom

Location

Related Publications (2)

• Frank DE, Schnell FJ, Akana C, El-Husayni SH, Desjardins CA, Morgan J, Charleston JS, Sardone V, Domingos J, Dickson G, Straub V, Guglieri M, Mercuri E, Servais L, Muntoni F; SKIP-NMD Study Group. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. Neurology. 2020 May 26;94(21):e2270-e2282. doi: 10.1212/WNL.0000000000009233. Epub 2020 Mar 5.

  PMID: 32139505 BACKGROUND

• Servais L, Mercuri E, Straub V, Guglieri M, Seferian AM, Scoto M, Leone D, Koenig E, Khan N, Dugar A, Wang X, Han B, Wang D, Muntoni F; SKIP-NMD Study Group. Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial. Nucleic Acid Ther. 2022 Feb;32(1):29-39. doi: 10.1089/nat.2021.0043. Epub 2021 Nov 17.

  PMID: 34788571 DERIVED

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Medical Director
• Organization: Sarepta Therapeutics, Inc.

clinicaltrials@sarepta.com

1-800-690-2003

Study Officials

• Medical Director

  Sarepta Therapeutics, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2014
• First Posted: December 8, 2014
• Study Start: January 13, 2015
• Primary Completion: March 25, 2019
• Study Completion: March 25, 2019
• Last Updated: October 19, 2020
• Results First Posted: October 19, 2020

Record last verified: 2020-10

Locations

FR (1); IT (1); US (1); GB (2)