Phase 1/2 trial of exon 44 skipping therapy for DMD cleared in UK
Two-part clinical study of ENTR-601-44 expected to launch this year
Entrada Therapeutics announced it has been cleared in the U.K. to start a Phase 1/2 clinical trial of ENTR-601-44, at increasing doses, in Duchenne muscular dystrophy (DMD) patients with a mutation in the DMD gene amenable to exon 44 skipping.
With this decision by U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), which follows positive findings from a study in healthy adults, Entrada plans to initiate the trial later this year.
“The clearance by the MHRA marks a new phase in Entrada’s growth and, most importantly, moves us closer to realizing our commitment to families living with Duchenne muscular dystrophy,” Dipal Doshi, Entrada’s CEO, said in a company press release.
Exon-skipping therapies aim for a shorter, but working, dystrophin protein
The planned two-part trial, called ELEVATE-44-201, will test multiple ascending doses of ENTR-601-44 against a placebo in patients amenable to exon 44 skipping therapy who are ambulatory (can walk), starting “at what we believe to be an effective therapeutic dose,” Doshi said.
For Doshi, “this is even more important since families living with Duchenne do not have time on their side as the progressive decline in function profoundly impacts the quality of life for patients and their care partners.”
In the U.S., clinical testing of ENTR-601-44 remains on hold. The U.S. Food and Drug Administration has declined to lift its order, issued in 2022 in response to an application for the right to open a first clinical test of an experimental therapy. The company noting that the same package of data supported the Phase 1 study it sponsored in the U.K. in 2023.
DMD is caused by a mutation in the DMD gene, the largest in the body. Most commonly, one or more exons (parts of the gene) are missing, causing errors in the instructions for producing the dystrophin protein. Without enough dystrophin, muscle cells become damaged over time.
The goal of exon-skipping therapy is to allow the body to make a shorter but functional form of the dystrophin protein by skipping over a specific exon on the DMD gene. ENTR-601-44 is being developed for patients who have a genetic mutation amenable to exon 44 skipping.
With ENTR-601-44, exon 44 is “patched” with a short strand of DNA, called an oligonucleotide, that allows it to be skipped during production of the dystrophin protein. It uses Entrada’s Endosomal Escape Vehicle (EEV) technology to improve delivery to muscle tissue and prevent degradation by a cell’s natural clearing systems.
“There is a significant unmet medical need in this population, with limited therapeutic options available. The unique properties of Entrada’s EEV therapeutic candidates offer the potential to provide tangible benefits for people with this life-shortening disease,” said Francesco Muntoni, MD, a pediatric neurologist at the Great Ormond Street Hospital in London.
Two-part trial will assess 3 ascending doses, followed by optimal dose
In the Phase 1 drug safety and tolerability study, involving 33 healthy men in the U.K., ENTR-601-44 was well tolerated with no serious side effects when given as a single intravenous (into-the-vein) injection at doses ranging from 0.75 to 6 mg/kg, the company reported in 2024. All six men given the highest dose showed detectable levels of a breakdown product of the therapy in muscle, where it resulted in significant exon 44 skipping compared with a placebo.
ELEVATE-44-201 will comprise two parts. The first will evaluate ENTR-601-44’s safety in about 24 patients, with multiple doses, likely ranging from 6 to 18 mg/kg, given at six-week intervals across three patient groups. It also will test how ENTR-601-44 moves into, through, and out of the body (its pharmacokinetics) and its effects, including exon 44 skipping and dystrophin production, with a goal of establishing an optimal dose.
In its second part, researchers will test that optimal dose for safety and efficacy, including patient-reported outcomes. An open-label extension study is expected to follow for enrolled patients, where the safety and efficacy of ENTR-601-44 will be examined over a longer period of time.
“The MHRA authorization of ELEVATE-44-201 is an exciting development in the clinical progress of ENTR-601-44, a new and very encouraging treatment option for boys and young men living with Duchenne muscular dystrophy who are exon 44 skipping amenable,” Muntoni said.
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