A Study in Participants With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping to Evaluate the Safety and Efficacy of ENTR-601-45

Official title

A 2-Part, Randomized, Double-Blind, Placebo-Controlled Study in Participants With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping With an Initial Multiple Ascending Dose Part A to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ENTR-601-45, Followed by Part B to Evaluate the Safety and Efficacy of ENTR-601-45 (ELEVATE-45)

Overview

This is a study of the investigational medicine ENTR-601-45 in participants who have Duchenne muscular dystrophy (DMD), a rare genetic condition. The researchers want to: Test how safe ENTR-601-45 is, learn about any side effects, and look at the potential positive effects of ENTR-601-45, compared to placebo. Placebo looks like the investigational medicine but does not contain any active ingredient. In this summary ENTR-601-45 and placebo are both called study treatments. The study has 2 parts: Part A: to evaluate if ENTR-601-45 is safe and to determine the best dose of ENTR-601-45 for Part B. Part B: to further evaluate the effect and safety of ENTR-601-45 at the dose determined in Part A. Participants will be able to roll into an open-label treatment period during which the safety and efficacy of extended dosing will be evaluated. Participants will: * Receive study treatment in the form of multiple intravenous (IV) infusions (slow injection) into a vein over the course of several weeks in Part A and in Part B * Visit the clinic regularly for checkups and tests such as: blood and urine tests, physical examinations, questionnaires, muscle biopsies and exercise tests. Participants will have a muscle biopsy at the beginning of their participation and after their last dose to allow researchers to compare whether there have been changes in the muscle as a result of the study drug. Participants are allowed to continue receiving their standard of care therapy for DMD during the study, as long as their health remains stable.

Interventions

• Drug ENTR-601-45
  intravenous infusion
• Drug ENTR-601-45 - matching placebo
  intravenous infusion

Primary outcome measures

• Number of participants with Treatment Emergent Adverse Events (TEAEs) according to study protocol (Part A and OL Period). [Time frame: From baseline through End of Study (up to 62 weeks).]

Secondary outcome measures (11)

• Plasma, muscle, and urine concentration of ENTR-601-45 and its final metabolite (Part A and OL Period) [Time frame: From baseline through End of Study (Up to 62 weeks).]
• Change from baseline to End of Part A in dystrophin by Western blot from muscle biopsy (Part A). [Time frame: Baseline, End of Study (Up to 25 weeks)]
• Change from baseline to End of Part A in dystrophin expression and localization from muscle biopsy (Part A). [Time frame: Baseline, End of Study (Up to 25 weeks)]
• Percent change from baseline to end of Part A in exon 45 skipping measured in muscle biopsy (Part A) [Time frame: Baseline, End of Study (Up to 25 weeks)]
• Anti-drug antibody (ADA) and anti-dystrophin antibody in serum (Part A and OL Period) [Time frame: From baseline through End of Study (Up to 62 weeks).]
• Change from baseline to End of OL Period in 10-Meter Walk/Run (10MWR) (Part A and OL Period). [Time frame: Baseline, End of Study (up to 62 weeks)]
• Change from baseline to End of OL Period in Timed Rise from Floor (Part A and OL Period). [Time frame: Baseline, End of Study (up to 62 weeks)]
• Change from baseline to End of OL Period in Timed 4-Stair Climb (4SC) (Part A and OL Period). [Time frame: Baseline, End of Study (up to 62 weeks)]
• Change from baseline to End of OL Period in 95th centile Stride Velocity (SV95C) (Part A and OL Period). [Time frame: Baseline, End of Study (up to 62 weeks)]
• Change from baseline to End of OL Period in North Star Ambulatory Assessment (NSAA) (Part A and OL Period) [Time frame: Baseline, End of Study (up to 62 weeks)]
• Change from baseline to End of OL Period in Performance of the Upper Limb v2.0 (PUL 2.0) (Part A and OL Period). [Time frame: Baseline, End of Study (up to 62 weeks)]

Eligibility criteria

Inclusion criteria

• Genetic diagnosis of DMD and confirmed pathologic variant in the dystrophin gene amenable to exon 45 skipping as reviewed by a central genetic counselor.
• Assigned male at birth with clinical signs compatible with Duchenne muscular dystrophy as determined by the investigator.
• Part A: 4-20 years of age, inclusive.
• Ambulatory Status Part A: ambulatory with a Performance of the Upper Limb v2.0 (PUL 2.0) Entry as per protocol at Screening.
• Adequate muscle for obtaining tissue biopsy as assessed by the investigator.
• Other protocol-defined criteria apply.

Exclusion criteria

• Any significant concomitant medical condition that might interfere with the ability to comply with protocol requirements.
• Has an acute illness within 4 weeks prior to the first dose of study drug which may interfere with study measurements or jeopardize participant's safety.
• Use of the following medications :

• Prior or current treatment with any exon skipping therapy within the previous 12 months
• Prior or current treatment with any gene therapy
• Use of anti-coagulants, anti-thrombotics, or anti-platelet agents from 30 days prior to screening and until the end of the study
• Use of an immunosuppressant (other than systemic or oral corticosteroid for DMD condition) from 30 days prior to screening until the end of the study.
• Treatment with a histone deacetylase (HDAC) inhibitor, including (but not limited to) givinostat from 30 days prior to screening until the end of the study
• Laboratory abnormalities.
• Daytime ventilator dependence or any use of invasive mechanical ventilation via tracheostomy.
• Has an abnormal electrocardiogram (ECG) reading assessed as clinically significant by the investigator, and/or a QT interval with Fridericia correction method (QTcF) >450 msec at Screening or prior to the first dose of study drug on Day 1.
• Received any experimental or investigational drug, etc. within 3 months prior to first dose or within 5 half-lives (whichever is longer).
• Other protocol-defined criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United Kingdom · 5 centers

• Leeds General Infirmary — Leeds
• Alder Hey Children's NHS Foundation Trust — Liverpool
• Great Ormond Street Hospital for Children — London
• Royal Manchester Children's Hospital — Manchester
• Oxford University Hospitals NHS Foundation Trust — Oxford

Belgium · 3 centers

• University Hospital Gent — Ghent
• UZ Leuven — Leuven
• Centre Hospitalier Régional de la Citadelle — Liège

Italy · 3 centers

• IRCCS Ospedale San Raffaele — Milan
• Ospedale Pediatrico Bambino Gesu — Rome
• Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuo — Rome

Netherlands · 2 centers

• Leids Universitair Medisch Centrum — Leiden
• Stichting Radboud Universitair Medisch Centrum — Nijmegen

Spain · 2 centers

• Hospital Universitario Vall d'Hebron — Barcelona
• Hospital Sant Joan de Deu — Barcelona

Identifiers

NCT: NCT07038824 · ENTR-601-45-201 · 2024-517499-39-00 · U1111-1316-6093

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗