FDA Declines to Lift Clinical Hold on Entrada Therapeutics’ ENTR-601-44 in Duchenne Muscular Dystrophy


Despite additional information submitted, the FDA continues to impose a clinical hold on Entrada Therapeutics' ENTR-601-44 for the potential treatment of Duchenne muscular dystrophy.

Dipal Doshi, president and chief executive officer at Entrada Therapeutics

Dipal Doshi

In recent news, the FDA declined to lift the clinical hold on Entrada Therapeutics' investigational new drug (IND) application for the phase 1 clinical trial of ENTR-601-44 in Duchenne muscular dystrophy (DMD) despite the company providing additional information to the agency.1 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 months ago.

In December 2022, the FDA placed a clinical hold on the IND for ENTR-601-44.3 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.

“We are disappointed that the U.S. clinical hold has not been lifted, especially given the strength of the data package submitted to the FDA. It’s important to emphasize that the ongoing ENTR-601-44 development program continues to progress, with ENTR-601-44-101 clinical data expected in the second half of 2024. We will re-engage the FDA to discuss next steps in due course,” Dipal Doshi, president and chief executive officer at Entrada Therapeutics, said in a statement.

In the same update, the company announced the completion of dosing for the first and second cohorts of its phase 1 clinical trial ENTR-601-44-101.1The primary objective of the double-blind, single ascending dose phase 1 clinical trial is to assess the safety and tolerability of a single dose of ENTR-601-44 in healthy male volunteers. The trial will also evaluate pharmacokinetics and target engagement, as measured by exon skipping in the skeletal muscle. The company noted that the phase 1 trial is expected to enroll approximately 40 participants and plans to announce data from the study in the second half of 2024.

“Our strategy has always been to run a single phase 1 clinical trial for ENTR-601-44 and, notably, that trial is progressing in the United Kingdom. We are pleased to have completed dosing of the first and second cohorts of participants,” Doshi said in a statement.1 “In parallel with the phase 1 clinical trial, we continue to plan for the global development of ENTR-601-44 which will include clinical trials in patients with Duchenne who are 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.4 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.

1. Entrada Therapeutics Announces Updates on ENTR-601-44 in Duchenne Muscular Dystrophy. News Release. Entrada Therapeutics. Published November 22, 2023. Accessed November 28, 2023. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-updates-entr-601-44-duchenne
2. 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 November 28, 2023. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-receives-authorization-united-kingdom
3. Entrada Therapeutics announces clinical hold on IND application for ENTR-601-44 in Duchenne muscular dystrophy. News release. December 19, 2022. Accessed November 28, 2023. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-clinical-hold-ind-application
4. 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 December 20, 2022. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-presents-new-data-supporting-its-growing
5. 3. 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.
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