Dyne's Exon-51 Skipping DMD Therapy Moves Forward on FDA Go Sign

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The U.S. Food and Drug Administration has lifted the clinical hold on Dyne Therapeutics’ clinical study of DYNE-251 in Duchenne muscular dystrophy (DMD) patients amenable to skipping exon 51. They expect the Phase I/II trial to launch by mid-year.

The agency placed a hold on the company’s Investigational New Drug (IND) application in January, requesting more clinical and non-clinical data for the therapy.

DMD is a genetic disease marked by progressive muscle degeneration and weakness. It is caused by mutations to the dystrophin protein, which codes for muscle. It is the largest gene in the body, which is why traditional gene therapy technology is not utilized - the gene is too large for the typical viral vectors. The disease primarily occurs in boys and typically leads to impaired pulmonary function and acute respiratory failure and death.

Dyne is Targeting Exon 51

Most of the treatments in existence and experimental therapies involve a technology known as exon skipping. These therapies are a type of RNA splicing that causes cells to “skip” over mutated or misaligned segments (exons) of genetic code. This results in a truncated but still functional protein. Dyne-251 is being developed for DMD amenable to exon 51 skipping. It is made up of a phosphorodiamidate morpholino oligomer (PMO) conjugated to a proprietary Fab (antibody fragment).

“Today marks a significant step in our journey to build a DMD franchise to serve people across the globe with Duchenne mutations amenable to exon skipping,” said Joshua Brumm, Dyne’s president and chief executive officer. “The clearance of our first IND is an important achievement for Dyne and we appreciate the partnership with the FDA throughout this process. Our team has worked extensively with key opinion leaders, patient advocacy groups and individuals living with DMD to thoughtfully design and executive our global multiple-ascending dose Phase I/II clinical trial of DYNE-251.”

The study will be global and is a multiple ascending dose (MAD) study with a long-term extension study. Dyne plans to enroll 30 to 50 ambulant and non-ambulant males with Duchenne ages four to 16 years whose dystrophin mutations are amenable to exon 51 skipping therapy.

“We believe we are well-positioned to deliver on our commitment of initiating dosing in both of our DMD and DM1 programs in mid-2022. The entire Dyne team is proud of the progress we have made to advance our mission and address the urgent need to bring new therapeutic options to people living with serious muscle diseases,” Brumm added.

The Current DMD Treatment Space

As of March, there were five drugs approved by the FDA to treat DMD. They include Sarepta Therapeutics’ Amondys 45 (casimersen), Vyondis 53 (golodirsen) and Exondys 51 (eteplirsen), which was the first drug to be approved in the space. The others are NS Pharma’s Viltepso (viltolarsen) and PTC Therapeutics’ Emflaza (deflazacort).

Other companies working on treatments for DMD include Pfizer, Genethon and Solid Biosciences, which are developing gene therapies. However, they have been finding serious side effects.

In May, Pfizer, Sarepta, Genethon and Solid partnered with academic experts to work on ways of minimizing the side effects they are finding with the adeno-associated virus (AAV)-based gene therapies for DMD. All of their experimental therapies use the AAV to deliver different versions of a shortened dystrophin transgene driven by different promoters.

All four companies had observed serious adverse events (SAEs) with these therapies, marked by muscle weakness and variable cardiac involvement. However, all had similar clinical presentations and time courses. The SAEs involved five patients across three clinical trials, all occurring about three to seven weeks after the initial gene therapy infusion.

The group believes these SAEs are a “specific transgene/genotype-related ‘class effect.’” The SAEs only occurred in patients with specific genomic deletions, including N-terminal epitopes, which are present in the transgene protein. Pfizer had one death associated with its Phase Ib study in 2021, but the hold has since been lifted.