Phase 2 Open‑Label Extension of ENTR‑601‑45 (with ENTR‑601‑44) in Exon‑Skipping‑Amenable Duchenne Muscular Dystrophy: Safety, Tolerability, PK and Efficacy

Primary objective: to evaluate the long‑term safety and tolerability of the study drug in participants with Duchenne Muscular Dystrophy, addressing the essential need for sustained safety data in this progressive neuromuscular disorder.

Secondary objectives:

• Characterize the pharmacokinetic profile of the study drug after prolonged dosing.
• Assess the impact of long‑term treatment on functional performance measures.
• Evaluate the immune response to the study drug during extended administration.

The trial enrolled 24 participants diagnosed with Duchenne muscular dystrophy. All subjects were male and classified as a vulnerable population. The age range of enrolled individuals spanned from 2 to 3 years. Participants were required to have completed a prior clinical study (ENTR‑601‑44‑201 or ENTR‑601‑45‑201) and to be capable of providing consent (or assent if a minor). Males who were sexually active with a female partner of childbearing potential were required to use condoms during intercourse. The cohort consisted of patients in generally stable health status appropriate for evaluation of the study drug’s long‑term safety and tolerability.

The study is a Phase 2 open‑label long‑term extension assessing the safety, tolerability, pharmacokinetics, and efficacy of the endosomal escape vehicle phosphorodiamidate morpholino oligomer platform products ENTR‑601‑44 and ENTR‑601‑45 in males with Duchenne Muscular Dystrophy amenable to exon skipping. Eligible participants must have completed the preceding ENTR‑601‑44‑201 or ENTR‑601‑45‑201 studies and provide appropriate consent; sexually active males with partners of childbearing potential are required to use condoms. After an initial screening visit to confirm eligibility, participants receive the study drug by intravenous infusion (18 mg/kg for ENTR‑601‑44 and 20 mg/kg for ENTR‑601‑45) at baseline and at scheduled follow‑up visits throughout the extension period, which extends from the estimated recruitment start on 26 August 2026 to an estimated end date of 31 March 2032. At each visit, vital signs, clinical laboratory tests, electrocardiograms, and physical examinations are performed to monitor the primary safety endpoints, which include the incidence and severity of treatment‑emergent adverse events, changes in vital signs, laboratory results, ECG parameters, and physical findings. Secondary efficacy assessments comprise plasma drug concentrations and functional measures such as the 10‑Meter Walk/Run, timed rise from floor, timed 4‑Stair Climb, stride velocity 95th centile, North Star Ambulatory Assessment, Performance of the Upper Limb v2.0, and immunogenicity markers (anti‑drug and anti‑dystrophin antibodies). Participants remain in the study until the end‑of‑study visit, at which point final safety and efficacy evaluations are conducted.

The trial evaluates two investigational products, ENTR-601-45 and ENTR-601-44, both classified as test agents. ENTR-601-45 is supplied as a solution for infusion for intravenous administration. The prescribed dose is 20 mg/kg, delivered by intravenous infusion. Dosing is performed according to the study schedule, with each infusion calculated based on the participant’s current body weight and recorded in the infusion log to ensure compliance.

ENTR-601-44 is also provided as a solution for infusion for intravenous delivery. The assigned dose is 18 mg/kg, administered by intravenous infusion. As with ENTR-601-45, dosing follows the protocol‑defined schedule, with weight‑based calculations documented prior to each infusion and infusion records maintained for monitoring adherence.

All participants continue any standard‑of‑care therapies for Duchenne muscular dystrophy as prescribed by their treating physicians. Concomitant medications are recorded at each visit, and adherence to the investigational product regimen is verified through infusion documentation, weight assessments, and review of dosing logs.

Efficacy in the long‑term extension will be assessed by comparing functional and biomarker outcomes measured at the extension baseline with those obtained at the end‑of‑study. Functional assessments include the 10‑Meter Walk/Run (10MWR), timed rise from floor (TRF), timed 4‑Stair Climb (4SC), stride velocity at the 95th centile (SV95C), the North Star Ambulatory Assessment (NSAA), and Performance of the Upper Limb version 2.0 (PUL 2.0). Changes are expressed as the difference from the parent study Part A and open‑label period baselines to the LTE end‑of‑study values in participants with Duchenne muscular dystrophy.

Biomarker efficacy will be evaluated through serum analysis for anti‑drug antibodies and anti‑dystrophin antibodies. All functional tests are performed using validated protocols, and laboratory assays follow established analytical methods. Data will be analyzed with appropriate statistical techniques to quantify the magnitude and significance of change from baseline.