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

• ClinicalTrials.gov Identifier: NCT02310906
• Recruitment Status: Completed
• First Posted: December 8, 2014
• Results First Posted: October 19, 2020
• Last Update Posted: October 19, 2020
• Sponsor: Sarepta Therapeutics, Inc.
• Collaborators: Institut de Myologie, France; Consultants for Research in Imaging and Spectroscopy; Great Ormond Street Hospital for Children NHS Foundation Trust; Catholic University of the Sacred Heart; Royal Holloway University; Sysnav; University College, London; University of Newcastle Upon-Tyne
• Information provided by (Responsible Party): Sarepta Therapeutics, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: Placebo; Drug: SRP-4053	Phase 1; Phase 2

Detailed Description:

Part 1: Randomized, placebo-controlled dose-titration to assess safety, tolerability and pharmacokinetics of 4 dose levels of SRP-4053 in genotypically-confirmed DMD patients with deletions amenable to exon 53 skipping.

Part 2: Open-label evaluation of SRP-4053 in patients from Part 1, along with newly enrolled DMD patients with deletions amenable to exon 53 skipping and an untreated group of DMD patients with deletions not amenable to exon 53 skipping.

Safety, including adverse event monitoring and routine laboratory assessments, will be followed on an ongoing basis for all patients.

Clinical efficacy, including functional tests such as the six-minute walk test (6MWT), will be assessed at regularly scheduled study visits. Patients in the treated groups will undergo one baseline and one follow-up muscle biopsy. Patients in the untreated group will not undergo biopsies and will follow an abbreviated schedule of study assessments.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Masking Description: Part 1 is double-blind and randomized; Part 2 is open-label.
• Primary Purpose: Treatment
• Official Title: A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping
• Actual Study Start Date: January 13, 2015
• Actual Primary Completion Date: March 25, 2019
• Actual Study Completion Date: March 25, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: SRP-4053; 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; SRP-4053 (golodirsen) solution for IV infusion.
Placebo Comparator: Part 1: Placebo; 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; SRP-4053 placebo-matching solution for IV infusion.
Experimental: Part 2: SRP-4053; 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; SRP-4053 (golodirsen) solution for IV infusion.
No Intervention: Part 2: Untreated Group; 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.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Discontinuation [ Time Frame: Baseline up to Week 12 ]
   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.
2. Part 1: Number of Participants With Potentially Clinically Significant (PCS) Laboratory Abnormalities Reported as TEAEs [ Time Frame: Baseline up to Week 12 ]
   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.
3. Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs Reported as TEAEs [ Time Frame: Baseline up to Week 12 ]
   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.
4. Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Physical Examinations [ Time Frame: Baseline up to Week 12 ]
   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.
5. Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Reported as TEAEs [ Time Frame: Baseline up to Week 12 ]
   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.
6. Part 1: Number of Participants With Potentially Clinically Significant Abnormalities in Echocardiograms (ECHO) [ Time Frame: Baseline up to Week 12 ]
   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.
7. Part 2a: Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 144 in Total Golodirsen Group [ Time Frame: Baseline and Week 144 ]
   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.
8. 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) [ Time Frame: Baseline and Week 144 ]
   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.
9. Part 2a: Change From Baseline in Dystrophin Protein Levels Determined by Western Blot at Week 48 in Total Golodirsen Group [ Time Frame: Baseline, Week 48 ]
   Change from baseline in dystrophin protein levels (in muscle biopsy samples) was determined by Western blot in total golodirsen group.

Secondary Outcome Measures :

1. Part 1: Maximum Plasma Concentration (Cmax) of Golodirsen [ Time Frame: 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) ]
   Maximum Concentration (Cmax) of golodirsen in plasma was evaluated.
2. Part 1: Time to Reach Maximum Plasma Concentration (Tmax) of Golodirsen [ Time Frame: 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) ]
   Time to reach maximum plasma concentration (Tmax) of golodirsen was evaluated.
3. Part 1: Area Under the Concentration-Time Curve From Time Zero Extrapolated to the Infinity (AUCinf) of Golodirsen in Plasma [ Time Frame: 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) ]
   Area under the concentration-time curve from time zero extrapolated to the infinity was evaluated.
4. Part 1: Apparent Volume of Distribution at Steady State (Vss) of Golodirsen [ Time Frame: 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) ]
   Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution at steady state of golodirsen was evaluated.
5. Part 1: Elimination Half-life (T1/2) of Golodirsen [ Time Frame: 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) ]
   T1/2 is the time measured for the plasma concentration of drug to decrease by one half. T1/2 of golodirsen was evaluated.
6. Part 1: Total Clearance (CL) of Golodirsen [ Time Frame: 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) ]
   Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
7. Part 1: Mean Residence Time (MRT) of Golodirsen [ Time Frame: 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) ]
   MRT= AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. Mean residence time of golodirsen was evaluated.
8. Part 1: Renal Clearance (CLR) of Golodirsen [ Time Frame: 0 to 1440 min after initiation of dosing on Day 1 ]
   Renal clearance was calculated using the partial AUC0-24 from the non-compartmental analysis in plasma and AE0-24. AUC0-24 was defined as area under the plasma concentration-time curve, from time 0 to 24 hours after completion of dosing. AE0-24 was defined as total cumulative amount excreted from 0 to 24 hours. Summarized data of all urine collection intervals are reported.
9. Part 2a: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Total Golodirsen Group [ Time Frame: Baseline, Week 144 ]
   FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and the most important measurement of lung function. This test required participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which was used to dilate participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%.
10. Part 2b: Percent Change From Baseline in Forced Vital Capacity Predicted (FVC%p) at Week144 in Untreated Group (Non-exon 53 Amenable Participants) [ Time Frame: Baseline, Week 144 ]
    FVC was the total amount of air exhaled during the forced expiratory volume test that was measured during spirometry and is the most important measurement of lung function. This test requires participant to breath into a tube connected to a machine that measures the amount of air that can be moved in and out of the lungs after taking an inhaled bronchodilator medicine which was used to dilate participant bronchial (breathing) tubes. Percent of predicted FVC = (observed value)/ (predicted value) * 100%.
11. Part 2a: Change From Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group [ Time Frame: Baseline, Week 48 ]
    Change from baseline in dystrophin Intensity levels (in muscle biopsy samples) was determined by Immunohistochemistry in total golodirsen group.
12. Part 2a: Percent Change From Baseline in Exon 53 Skipping Determined by Reverse Transcription Polymerase Chain Reaction (PCR) at Week 48 in Total Golodirsen Group [ Time Frame: Baseline, Week 48 ]
    Percent change from baseline in Exon 53 skipping (in muscle biopsy samples) was determined by reverse transcription polymerase chain reaction in total golodirsen group.
13. Part 2a: Percent Change From Baseline in Dystrophin Positive Fibers Determined by Immunohistochemistry (IHC) at Week 48 in Total Golodirsen Group [ Time Frame: Baseline, Week 48 ]
    Percent change from baseline in dystrophin positive fibers (in muscle biopsy samples) were determined by Immunohistochemistry at Week 48 in total golodirsen group.

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 15 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Other inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02116

France

Institute de Myologie

Paris, France, 75013

Italy

Policlinico Universitario A Gemelli

Rome, Italy, 00168

United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust

London, United Kingdom, WC1N 3JH

Newcastle University Hospital

Newcastle, United Kingdom

Sponsors and Collaborators

Sarepta Therapeutics, Inc.

Institut de Myologie, France

Consultants for Research in Imaging and Spectroscopy

Great Ormond Street Hospital for Children NHS Foundation Trust

Catholic University of the Sacred Heart

Royal Holloway University

Sysnav

University College, London

University of Newcastle Upon-Tyne

Investigators

• Study Director: Medical Director; Sarepta Therapeutics, Inc.

  Study Documents (Full-Text)

Documents provided by Sarepta Therapeutics, Inc.:

Study Protocol  [PDF] November 8, 2017

Statistical Analysis Plan  [PDF] May 30, 2018

More Information

Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sarepta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02310906
• Other Study ID Numbers: 4053-101
• First Posted: December 8, 2014
• Results First Posted: October 19, 2020
• Last Update Posted: October 19, 2020
• Last Verified: October 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sarepta Therapeutics, Inc.:

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

Additional relevant MeSH terms:

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