FDA Places Hold on DYNE-251 Clinical Trial Launch in DMD

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by Steve Bryson, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a hold on Dyne Therapeutics’ application to launch a clinical trial evaluating DYNE-251, an experimental exon-skipping therapy for Duchenne muscular dystrophy (DMD).

Dyne now hopes to have that Phase 1/2 trial underway by June, the company said in a press release.

In a clinical hold letter to Dyne dated Jan. 14, the FDA requested additional clinical and non-clinical information regarding the potential therapy.

“The company expects to submit to the FDA its response with data from existing and ongoing studies in the second quarter of 2022, and if satisfactory to the FDA, to be dosing patients in a Phase 1/2 multiple ascending dose (MAD) clinical trial of DYNE-251 by mid-2022,” Dyne said in the statement.

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DYNE-251 works by allowing exon 51 of the DMD gene to be “skipped,” which could benefit around 13% of DMD patients. Exon 51 is a segment within the gene that carries part of the instructions to make dystrophin, a protein that helps maintain the integrity and structure of muscle fibers. Mutations in DMD result in a defective dystrophin protein, leading to progressive muscle damage and weakness.

The exon-skipping therapy is made from phosphorodiamidate morpholino oligomers, which are short, lab-made (synthetic) molecules designed to allow exon 51 to be “skipped,” resulting in the production of a smaller, but functional version of the dystrophin protein to help protect and maintain muscle fibers.

DYNE-251 uses the proprietary FORCE platform, which links the therapeutic payload to an antibody that binds to specific receptors on muscle cells. This approach offers several advantages over existing alternatives, the company said, such as extended time between doses, the ability to re-dose, and targeting the genetic basis of disease.

According to Dyne’s website, DYNE-251 treatment resulted in durable exon skipping and dystrophin production in the heart and skeletal muscles — attached to bones and movement-related — in a DMD mouse model.

The therapy reportedly was well-tolerated and showed robust exon skipping in non-human primates, particularly in the heart and diaphragm, the dome-shaped muscle that plays a key role in breathing.

Dyne also is planning to advance exon-skipping therapies for DMD patients with mutations in exons 53, 45, 43, and is working on treatments for other forms of muscular dystrophy, including myotonic dystrophy type 1, or DM1, and facioscapulohumeral muscular dystrophy, known as FSMD.

Currently, there are four exon-skipping therapies approved for use in DMD patients: Exondys 51 (eteplirsen) for those amenable to exon 51 skipping, Vyondys 53 (golodirsen) and Viltepso (viltolarsen), for patients amenable to exon 53 skipping, and Amondys 45 (casimersen) for people amenable to exon 45 skipping.