FDA Removes Clinical Hold on Duchenne Muscular Dystrophy Agent ENTR-601-44

Dipal Doshi

(Credit: LinkedIn)

The FDA has lifted its clinical hold on Entrada Therapeutics’ investigational new drug (IND) application for ENTR-601-44 in Duchenne muscular dystrophy (DMD) and provided authorization to initiate ELEVATE-44-102, a randomized, double-blind placebo-controlled, multiple ascending dose (MAD) phase 1b study assessing the investigational therapy in adult patients with a confirmed mutation in the DMD gene amenable to exon 44 skipping.¹

The phase 1b trial is investigating the safety and tolerability of ENTR-601-44 in approximately 32 nonambulatory and ambulatory adult patients with DMD who are exon 44 skipping amenable. Entrada noted that MAD study is also designed to assess target engagement as measured by exon skipping and dystrophin production, and pharmacokinetics. Dosing for the trial will be administered every 6 weeks, with the planned doses across 4 cohorts anticipated to range from 0.16 mg/kg up to 1.28 mg/kg.

Participants in the study may be eligible to enter an open label extension study (OLE), in which the safety, efficacy and tolerability of ENTR-601-44 will be assessed over a longer period of time. Entrada announced in its recent update that it plans to initiate study enrollment in the first half of 2026, which would enable a seamless transition into an OLE. Overall, the company noted the global ELEVATE-44 program, which includes the ELEVATE-44-102 study and ELEVATE-44-201, aims to cover a broad population of patients with DMD and potentially support the evaluation of ENTR-601-44 among patients who may be early and advanced in the disease progression.

“Given the strength of our safety and target engagement data from our Phase 1 clinical study and the profound unmet need in adults living with Duchenne, we are pleased to have obtained FDA clearance for the ELEVATE-44-102 study,” Dipal Doshi, CEO at Entrada Therapeutics, said in a statement.¹ “The study will help assess the potential of ENTR-601-44 in both non-ambulatory and ambulatory adult patients who are unfortunately often left out of clinical studies due to the advanced stage of their disease. Nearly half of those living with Duchenne who are amenable to exon 44 skipping are adults. ELEVATE-44-102 will provide clinical experience from this important population for our growing data package in support of what we believe will be a best-in-class therapy.”

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Previously, in November 2023, the FDA declined to lift the clinical hold on the IND application for the phase 1 clinical trial of ENTR-601-44 despite the company providing additional information to the agency.² At the time, the company noted that the information submitted to the FDA at least supported the initiation of a United Kingdom-based phase 1 clinical trial of ENTR-601-44 among healthy volunteers, which was announced in August 2023.³

The initial hold from the FDA was placed in December 2022.⁴ At the time, the agency indicated they would provide an official clinical hold letter to Entrada in 30 days and the company planned to share additional updates pending further communications with the FDA. ENTR-601-44, an exon 44 skipping oligonucleotide developed with Entrada’s Endosomal Escape Vehicle (EEV) platform, aims to target the underlying genetic cause of DMD to allow muscle cells to produce functional dystrophin. For context, roughly 7.5% of the DMD population are considered exon 44 skipping amenable.

At TIDES USA 2022: Oligonucleotide and Peptide Therapeutics Conference, the company presented nonhuman primate data on the agent where it showed robust exon 44 skipping in nonhuman primate biceps through 12 weeks following a single intravenous infusion, demonstrating durability of response.⁵ That data built on a previously reported nonhuman primate study indicating similar robust exon 44 skipping across different muscle groups at 7 days following a single intravenous infusion. Specifically, treatment with the agent resulted in exon skipping in the quadriceps, biceps, deltoid, tibialis anterior, diaphragm, and cardiac ventricle.

Entrada announced both of these analyses, as well as other analyses in hDMD mice expressing full length human DMD gene and patient-derived muscle cells, at the 2022 New Directions in Biology and Disease of Skeletal Muscle conference. In patient cells, robust dose-dependent exon 44 skipping and dystrophin protein production were observed after 5 days of differentiation. Similarly, the agent resulted in high and durable levels of exon 44 skipping across major muscle groups in hDMD mice for at least 12 weeks.⁶

REFERENCES
1. Entrada Therapeutics Announces FDA Removal of Clinical Hold on ENTR-601-44. News Release. Entrada Therapeutics. Published February 24, 2025. Accessed February 24, 2025. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-fda-removal-clinical-hold-entr
2. Entrada Therapeutics Announces Updates on ENTR-601-44 in Duchenne Muscular Dystrophy. News Release. Entrada Therapeutics. Published November 22, 2023. Accessed February 24, 2025. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-updates-entr-601-44-duchenne
3. Entrada Therapeutics Receives Authorization in the United Kingdom to Initiate Phase 1 Clinical Trial of ENTR-601-44 for the Potential Treatment of Duchenne Muscular Dystrophy. News Release. Entrada Therapeutics. Published August 1, 2023. Accessed February 24, 2025. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-receives-authorization-united-kingdom
4. Entrada Therapeutics announces clinical hold on IND application for ENTR-601-44 in Duchenne muscular dystrophy. News release. December 19, 2022. Accessed February 24, 2025. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-clinical-hold-ind-application
5. Entrada Therapeutics presents new data supporting its growing pipeline of endosomal escape vehicle (EEV) therapeutics at TIDES USA 2022. News release. May 11, 2022. Accessed February 24, 2025. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-presents-new-data-supporting-its-growing
6. Estrella NL, Hicks AN, Kumar A, et al. Development of ENTR-601-44, a novel EEV-conjugated PMO for Duchenne muscular dystrophy. Presented at: New Directions in Biology and Disease of Skeletal Muscle Conference; Ft. Lauderdale, FL.