Dyne therapies showing benefit for MD patients, per clinical trial data

New data show DYNE-101, DYNE-251 may lead to improvements in function

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

A bell with the word 'update' on it in all capital letters is flanked by two smaller ringing bells.

DYNE-101 and DYNE-251, Dyne Therapeutics’ investigational therapies for forms of muscular dystrophy, continue to work as intended and may lead to functional improvements for patients, according to new clinical trial data.

These findings come from ongoing Phase 1/2 studies, which may still be recruiting. DELIVER (NCT05524883), launched in 2022, is testing DYNE-251 in boys ages 4-16 with Duchenne muscular dystrophy (DMD). ACHIEVE (NCT05481879), begun the same year, is testing DYNE-101 in adults, ages 18-49, with myotonic dystrophy type 1 (DM1).

Both studies are intended to support regulatory applications seeking their respective treatment’s approval. An update on the pathway toward that goal is due by year’s end.

“We are excited to report new clinical data from both our ACHIEVE and DELIVER trials demonstrating meaningful impact on key biomarkers and functional improvement in multiple clinical endpoints that matter to patients,” John Cox, Dyne’s president and CEO, said in a company press release.

“We believe these data reflect the best-in-class potential for these product candidates and reinforce the opportunity to transform the treatment of DM1 and DMD,” Cox added.

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Both Dyne treatments are comprised of oligonucleotides — short strands of genetic material that influence gene activity — linked to an antibody that directs it specifically to muscle cells.

In Duchenne muscular dystrophy, known as DMD, mutations in the DMD gene lead to a lack of the dystrophin protein that’s important for muscle health. An exon-skipping therapy, DYNE-251 aims to skip over a protein-coding portion of the gene called exon 51 to allow production of a shorter but functional version of dystrophin.

DELIVER is testing various into-the-vein (intravenous) doses of DYNE-251 in boys with DMD who have a mutation expected to be responsive to exon 51 skipping.

In the new clinical trial data, Dyne reports efficacy findings from eight patients enrolled in a once-monthly 10 mg/kg dosing group. Six of the participants received active treatment while two were given a placebo.

Relative to previous reports from a lower dose group, the treatment was associated with dose-dependent exon 51 skipping and subsequent dystrophin increases, as the therapy’s mechanism intends.

The treatment at the 10 mg/kg dose led to a level of dystophin of about 3% of normal after six months — which is about 10 times higher than observations in clinical trials for the approved weekly exon 51-skipping therapy Exondys 51 (eteplirsen), according to Dyne.

When adjusting for muscle content, DYNE-251 was associated with a mean 7.6% dystrophin level, which compares favorably to other treatments in development, the press release states.

The company also reported trends toward functional improvements across several measures, which Dyne’s chief medical officer, Wildon Farwell, MD, noted happened “earlier than expected.”

Farwell said the therapy “led to an improvement in muscle strength, function, and patient-reported outcomes.”

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In DM1, mutations in the DMPK gene cause the production of an abnormal version of RNA — a template molecule used to make protein — that builds up and disturbs the production of muscle proteins. DYNE-101 aims to bind to these clumps and facilitate their degradation.

ACHIEVE is designed similarly to DELIVER, but is testing various intravenous doses of DYNE-101 in adults with DM1.

For this clinical trial, Dyne reported efficacy data from 40 patients treated thus far. Among the information were one-year data from the lowest dose group — those given 1.8 mg/kg monthly — six-month data from patients receiving 3.4 mg/kg monthly, and three-month data from patients given 5.4 mg/kg once every two months.

Consistent with earlier analyses, DYNE-101 was shown at the cellular level to be working as intended, leading to dose-dependent corrections in splicing. Splicing is a faulty cellular process that’s linked to protein disruptions in DM1.

The findings corresponded with observed reductions in myotonia, a DM1 symptom characterized by difficulty relaxing muscles, as well as increased muscle strength and improved mobility.

Patient-reported outcomes indicated reduced overall disease burden and improved abilities, with the treatment, to go about daily activities.

Safety and tolerability data from 48 patients treated with DELIVER’s highest dose so far — up to 40 mg/kg every other month — and 56 people treated with ACHIEVE’s highest dose to date, of up to 6.8 mg/kg every other month, have found both treatments to be safe, with most side effects being mild or moderate in severity.

We believe the breadth and depth of these data are truly differentiating. … We look forward to continuing to engage with global regulatory authorities throughout this year to pursue expedited approval pathways and address the urgent unmet medical needs in these [MD] communities.

These higher dose groups, which Dyne indicated it was moving forward with earlier this year, are now finished enrolling. The company believes the positive data so far support testing the therapies at even higher doses.

“We believe the breadth and depth of these data are truly differentiating,” Farwell said, adding that “the DM1 and Duchenne communities have waited too long for new and better therapeutic options.”

Dyne wants to seek clearance of these therapies under an accelerated approval pathway, which uses early clinical trial findings, like biomarker data, to seek conditional marketing clearance while confirmatory studies are still ongoing.

In DMD, dystrophin levels are an established surrogate biomarker for a therapy’s efficacy. Based on recent discussions with the FDA, the company will pursue the use of splicing as a possible surrogate biomarker in DM1.

“We look forward to continuing to engage with global regulatory authorities throughout this year to pursue expedited approval pathways and address the urgent unmet medical needs in these communities,” Farwell said.