Hold Placed on Clinical Testing of Entrada’s Exon 44-skipping Therapy

The FDA decision followed company's investigational new drug application

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a hold on clinical testing of ENTR-601-44, Entrada Therapeutics‘ investigational therapy for people with Duchenne muscular dystrophy (DMD) who have mutations amenable to exon 44 skipping.

The decision was in response to the company’s investigational new drug (IND) application, essentially a request to begin clinical testing of an experimental therapy.

The IND application is on hold and an official clinical hold letter will be sent to Entrada within 30 days. The company plans to provide additional updates after communicating with the regulatory agency.

“The clinical hold on our ENTR-601-44 program is disappointing and we will work to address the FDA’s concerns regarding the IND,” said Dipal Doshi, president and CEO of Entrada, in a company press release. “There are no approved Duchenne therapies for people with exon 44 skippable mutations and we are eager to resolve this hold and continue down the treatment development pathway.”

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Hold Placed on Clinical Testing of Entrada’s Exon 44-skipping Therapy

DMD is caused by mutations in the DMD gene, which lead to no dystrophin protein being produced. Since dystrophin is important for muscle function, people with DMD experience progressive muscle degeneration.

Protein-coding genes, including DMD, are comprised of exons — which contain the information that ultimately yields the protein — interspersed with introns that don’t code for the protein but serve other regulatory functions.

When the information in DNA is used to make protein, it’s first transcribed into a template, called messenger RNA (mRNA). During this process, introns are cut out and exons are strung back together. This now mature template is sent to the cell’s protein-making machinery.

DMD-causing mutations can lead to one or more missing exons. When the introns are removed, the remaining exons don’t fit together properly and dystrophin can’t be produced.

Exon-skipping therapies make cells skip over one or more problematic exons during mRNA splicing, enabling the remaining exons to better fit together. Cells can then produce  a shorter-than-normal, but functional, protein.

Basically, they use short strands of nucleic acids — the building blocks of DNA and RNA — called oligonucleotides, to prompt the cell to remove the exons along with introns during splicing.

ENTR-601-44 was designed to enable skipping of exon 44. About 7.5% of Duchenne patients have mutations amenable to exon 44 skipping, according to Entrada.

The treatment employs the company’s proprietary Endosomal Escape Vehicle (EEV) platform, which is designed to enhance uptake of the treatment by target tissues and prolong its effects by avoiding the cellular compartments that would lead to it degrading.

In cell cultures of DMD patient-derived muscle cells, ENTR-601-44 led to robust skipping of exon 44 and significant increases in dystrophin.

A single into-the-vein injection of the therapy in a DMD mouse model led to sustained exon 44 skipping in key muscle groups, including the heart, diaphragm, legs and arms. In non-human primates, it led to exon-skipping in the skeletal and heart muscles, with effects lasting at least 12 weeks.

According to the company, the levels of dystrophin production observed in preclinical studies are sufficient to result in functional improvements.

The company is also using its EEV platform to develop therapies for myotonic dystrophy type 1. A treatment candidate, ENTR-701, is currently under preclinical evaluation. Entrada said an IND submission for ENTR-701 is planned for the second half of 2023.