Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (ESSENCE)

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

The main objective of this study is to evaluate the efficacy of SRP-4045 (casimersen) and SRP-4053 (golodirsen) compared to placebo in participants with DMD with out-of-frame deletion mutations amenable to skipping exon 45 and exon 53, respectively.

Study Overview

• Status: Active, not recruiting
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Drug: SRP-4045; Drug: SRP-4053; Drug: Placebo

Detailed Description

This is a double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of SRP-4045 and SRP-4053. Eligible participants with out-of-frame deletion mutations amenable to exon 45 or 53 skipping will be randomized to receive once weekly intravenous (IV) infusions of 30 milligrams/kilograms (mg/kg) SRP-4045 or 30 mg/kg SRP-4053 respectively (combined-active group) or placebo for up to 96 weeks (the placebo-controlled period of the trial). This will be followed by an open-label extension period in which all participants will receive open-label active treatment for 48 weeks (up to Week 144 of study).

The study will enroll approximately 222 participants. Twice as many participants will be randomized to receive active treatment as will receive placebo (2:1 randomization).

Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests, such as the 6-minute walk test (6MWT). All participants will undergo a muscle biopsy at baseline and a second muscle biopsy either at Week 48 or Week 96.

Safety will be assessed through the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations throughout the study.

Blood samples will be taken periodically throughout the study to assess the pharmacokinetics of both drugs.

• Study Type: Interventional
• Enrollment (Actual): 228
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sarepta Therapeutics Inc., For Clinical Trial Information, Select Option 4; Phone Number: 1-888-SAREPTA (1-888-727-3782); Email: SareptAlly@sarepta.com

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aires, Argentina, 1111
    • DOM Centro de Reumatología
• Australia
  • South Brisbane, Australia, 4101
    • Queensland Children's Hospital
  • Westmead, Australia, 2145
    • Children's Hospital at Westmead
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital Melbourne
• Belgium
  • Ghent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Leuven
  • Liège, Belgium, 4000
    • CHR de la Citadelle
• Bulgaria
  • Sofia-Grad
    • Sofia, Sofia-Grad, Bulgaria, 1431
      • University Multiprofile Hospital for Active Treatment Aleksandrovska EAD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Childrens Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's and Women's Health Centre of British Columbia
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
• Czechia
  • Brno, Czechia, 61300
    • University Hospital Brno
  • Praha, Czechia, 15008
    • Fakultni Nemocnice V Motole
• Denmark
  • København Ø, Denmark, 2100
    • Rigshospitalet Copenhagen University Hospital
• France
  • Nantes, France, 44093
    • Reference Centre for Neuromuscular Diseases
  • Paris, France, 75012
    • Hôpital Armand Trousseau
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Hopital des Enfants
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
  • Essen, Germany, 45122
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • University Hospital Freiburg
• Greece
  • Maroussi, Greece, 15123
    • IASO Children's Hospital
  • Thessaloniki, Greece, 54642
    • Ippokratio General Hospital of Thessaloniki
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem Genomikai Medicina és Ritka Betegsegek Intezete
• India
  • Gujarat
    • Ahmedabad, Gujarat, India, 380054
      • Royal Instituite of Child Neurosciences
  • Maharashtra
    • Pune, Maharashtra, India, 411004
      • Deenanth Mangeshkar Hospital
• Ireland
  • Dublin, Ireland, D1
    • The Children's University Hospital
• Israel
  • Petah Tikvah, Israel, 49102
    • Schneider Children's Medical Center of Israel
• Italy
  • Ferrara, Italy, 44124
    • Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant' Anna
  • Genoa, Italy, 16147
    • Istituto Giannina Gaslini
  • Messina, Italy, 98125
    • Az Ospedaliera Universitaria Policlinico G Martino
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Rome, Italy, 00168
    • Policlinico Universitario A Gemelli
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Yangsan, Korea, Republic of, 50612
    • Pusan National University Yangsan Hospital
• Mexico
  • Culiacán, Mexico, 80020
    • Neurociencias Estudios Clínicos S.C
  • Durango, Mexico, 34000
    • Instituto de Investigaciones Clinicas para la Salud A.C
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 02-097
      • Samodzielny Publiczny Centralny Szpital Kliniczny
• Russian Federation
  • Moscow, Russian Federation, 125412
    • Federal state budget educational institution of higher education "Russian national research medical university n.a. N.I. Pirogov" of Ministry of healthcare of Russian Federation
  • Yekaterinburg, Russian Federation
    • State Autonomous Healthcare Institution of Sverdlovsk Region Children's Clinical Hospital No. 9 City of Ekaterinburg
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic for Neurology and Psychiatry for Children and Youth
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Valencia, Spain
    • Hospital Universitari i Politecnic La Fe de Valencia
• Sweden
  • Göteborg, Sweden, SE-41685
    • Drottning Silvias Barn Och Ungdomssjukhus
• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Royal Hospital for Children (Glasgow)
  • Leeds, United Kingdom, LS1 3EX
    • Leeds Teaching Hospitals NHS Trust
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Childrens Hospital
  • London, United Kingdom, WC1N 1EH
    • Great Ormond Street Hospital (GOSH)
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85028
      • Neuromuscular Research Center
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine, UCLA
    • San Diego, California, United States, 92123
      • Rady Children's Hospital San Diego/ UCSD
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine/Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Gulf Breeze, Florida, United States, 32561
      • NW Florida Clinical Research Group, LLC
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Center for Integrative Rare Disease Research (CIRDR)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas, Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89145
      • Las Vegas Clinic
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Clinical Research Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center (CCHMC)
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Shriners Hospital for Children
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 13 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Genotypically confirmed DMD, with genetic deletion amenable to exon 45 or exon 53 skipping
• Stable dose 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).
• Intact right and left biceps or 2 alternative upper muscle groups
• Mean 6MWT ≥300 meters and ≤450 meters
• Stable pulmonary function: forced vital capacity (FVC) ≥50% predicted

Exclusion Criteria:

• Treatment with gene therapy at any time
• Previous treatment with SMT C1100 within 1 week prior to Week 1 and previous treatment with PRO045 (BMN 045), PRO053 (BMN 053), or PRO051 (BMN 051) within 24 weeks prior to Week 1
• Current or previous treatment with any other experimental treatment within 12 weeks prior to Week 1
• Major surgery within 3 months prior to Week 1
• Presence of other clinically significant illness

Other inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SRP-4045; Participants amenable to exon 45 skipping will receive SRP-4045 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045; SRP-4045 solution for IV infusion; Other Names: Casimersen; AMONDYS 45
Experimental: SRP-4053; Participants amenable to exon 53 skipping will receive SRP-4053 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4053; SRP-4053 solution for IV infusion; Other Names: Golodirsen; VYONDYS 53
Placebo Comparator: Placebo followed by SRP-4045 or SRP-4053; Participants amenable to exon 45 or 53 skipping will receive SRP-4045 or SRP-4053 placebo-matching IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 or SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045; SRP-4045 solution for IV infusion; Other Names: Casimersen; AMONDYS 45; Drug: SRP-4053; SRP-4053 solution for IV infusion; Other Names: Golodirsen; VYONDYS 53; Drug: Placebo; SRP-4045 or SRP-4053 placebo-matching solution for IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in the Total Distance Walked During 6MWT at Week 96	Baseline, Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Total Distance Walked During 6MWT at Week 144 (Week 48 of the Open-Label Extension Period)		Baseline, Week 144
Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96		Baseline, Week 48 or Week 96
Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96		Baseline, Week 48 or Week 96
Participant's Ability to Rise Independently From the Floor, as indicated by a North Star Ambulatory Assessment (NSAA) Subscore	The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, the participant's ability to rise independently from the floor (without external support) will be reported as an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver).	Week 96, Week 144
Time to Loss of Ambulation (LOA)		Baseline, Week 96, and Week 144
Change From Baseline in the NSAA Total Score at Week 96 and Week 144	The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, participants will be asked to perform 17 different functional activities, including a 10 meter walk/run, rising from a sit to standing, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. Participants will be graded as follows: 2 = achieves goal without any assistance; 1 = modified method but achieves goal independent of physical assistance from another person; and 0 = unable to achieve goal independently. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function.	Baseline, Week 96 and Week 144
Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 96 and Week 144		Baseline, Week 96 and Week 144

Collaborators and Investigators

• Sponsor: Sarepta Therapeutics, Inc.
• Investigators: Study Director: Medical Director, Sarepta Therapeutics, Inc.

Publications and helpful links

General Publications

• Wagner KR, Kuntz NL, Koenig E, East L, Upadhyay S, Han B, Shieh PB. Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve. 2021 Sep;64(3):285-292. doi: 10.1002/mus.27347. Epub 2021 Jun 29.

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2016
• Primary Completion (Estimated): October 3, 2025
• Study Completion (Estimated): October 3, 2025

Study Registration Dates

• First Submitted: July 14, 2015
• First Submitted That Met QC Criteria: July 14, 2015
• First Posted (Estimated): July 16, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pediatric; DMD; Duchenne; Duchenne muscular dystrophy; Exon Skipping; Exon 53; Ambulatory; Exon 45
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: 4045-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No