2 Dyne treatments for muscular dystrophy do well in early trials
Both DYNE-251 for DMD and DYNE-101 for DM1 seen to work as designed
Both DYNE-251 for Duchenne muscular dystrophy (DMD), being tested in a trial dubbed DELIVER, and DYNE-101 for myotonic dystrophy type 1 (DM1), under evaluation in the ACHIEVE trial, showed proof-of-concept, according to the company.
“These compelling initial data from our ACHIEVE and DELIVER trials highlight the exciting opportunity we have to advance our investigational therapeutics for devastating diseases with no or limited treatment options,” Wildon Farwell, MD, chief medical officer at Dyne, said in a company press release.
Further data from both trials are expected to be reported in the second half of this year, per Dyne. Both investigational treatments were developed using Dyne’s platform, called FORCE.
Dyne testing treatments for 2 types of muscular dystrophy in Phase 1/2 trials
DYNE-251 is an exon-skipping treatment being developed for Duchenne, the most common type of muscular dystrophy. It’s expected to facilitate production of a shortened but functional version of the dystrophin protein, whose defects cause DMD. Specifically, this treatment is intended for patients amenable for skipping exon 51 of the DMD gene — an approach expected to benefit about 13% of patients with the disease. Exons are segments within the DMD gene that encode dystrophin, a protein essential for muscle health.
Meanwhile, DYNE-101 is designed to reduce levels of toxic messenger RNA (mRNA) from the DMPK gene, which causes DM1, a type of muscular dystrophy in which the symptoms begin during adulthood.
“We are excited that Dyne’s first clinical data in two programs have demonstrated proof-of-concept and validated the promise of the FORCE platform in developing targeted therapeutics for rare muscle diseases,” said Joshua Brumm, president and CEO of Dyne.
The Phase 1/2 clinical trial DELIVER (NCT05524883) is testing DYNE-251 in boys with DMD who have mutations amenable to exon 51 skipping. Initial efficacy data were based on findings from six patients; four of these boys received DYNE-251 at a dose of 5 mg/kg every four weeks, while the other two were given a placebo.
The results after six months showed that the mean absolute exon skipping level was 0.9%, with a 0.8% increase in exon skipping relative to the trial’s start. Similarly, dystrophin protein levels were 0.88% of normal with a 0.28% increase from the start of the trial; a mean 22.2% of evaluated muscle fibers had dystrophin, a 19.8% change from the trial’s start.
We are excited that Dyne’s first clinical data in two programs have demonstrated proof-of-concept and validated the promise of the FORCE platform in developing targeted therapeutics for rare muscle diseases.
According to Dyne, these data suggest that DYNE-251’s ability to promote exon skipping and dystrophin production may be superior to that of Exondys 51 (eteplirsen), an exon 51-skipping therapy that’s already approved in the U.S.
“Treatment with DYNE-251 surpassed the level of dystrophin production reported for the standard of care for DMD exon 51 with a fraction of the dose,” Farwell said.
“Underpinning these results are favorable safety profiles, which are critical in the development of therapies for chronic diseases,” Farwell added.
Safety data from the DELIVER study, covering 37 patients treated with DYNE-251 at doses up to 20 mg/kg, have been positive to date: Thus far, no serious side effects related to the experimental therapy have been reported.
Also, all participants who have completed the placebo-controlled part of the study have since opted to continue into an open-label extension, in which they are being treated with DYNE-251 for about six months.
Positive trial results support dose escalation in both clinical trials
The interim data from the Phase 1/2 ACHIEVE trial (NCT05481879) — testing DYNE-101 in adults with DM1 — covered data from 32 patients. Six-month data were available from a group of patients given the therapy at a dose of 1.8 mg/kg, while three-month data were reported from patients on a dose of 3.4 mg/kg every four weeks.
In both groups, most patients are given the active therapy and a few are given a placebo. For six patients, meanwhile, DYNE-101 was given for the first two doses, and then the placebo for the rest of the study.
The findings demonstrated that, after six months, patients in the group given 1.8 mg/kg of DYNE-101 experienced a mean 3.8-second benefit in myotonia — a hallmark symptom of DM1, marked by difficulty relaxing muscles. Individuals in this group also reported overall improvements in a patient-reported measure called the Myotonic Dystrophy Health Index (MDHI). Dyne noted that patients reported less severe fatigue.
Data also indicated that DYNE-101 is decreasing DMPK mRNA as designed. Specifically, after three months, mean levels were reduced by 25% in the 1.8 mg/kg group, and by 40% in the 3.4 mg/kg group. Treated participants also showed corrections in splicing, which is a process that occurs when genes are read to make proteins that are disrupted in DM1.
“DYNE-101 demonstrated early dose-dependent results, including in correction of splicing, the key biomarker for DM1, as well as meaningful improvement in myotonia at the lowest dose,” Farwell said.
Safety data, covering 45 patients treated at doses up to 5.4 mg/kg every other month, have shown no serious side effects related to the experimental therapy.
According to Brumm, “the safety profiles for both DYNE-101 and DYNE-251 have supported dose escalation to a combined 10 cohorts and the administration of nearly 600 doses across both the ACHIEVE and DELIVER trials.”
Dyne is expecting to provide another update on these trials later in the year that will include data from higher dosage groups.
Brumm said the company is hoping to launch registrational trials — studies that could potentially support applications for the treatments’ approval for each of these types of muscular dystrophy — before the end of 2024.
“We anticipate reporting data for multiple, higher dose cohorts from both trials in the second half of 2024, while continuing to pursue expedited regulatory pathways and working to help address the urgent need for therapeutics for people living with DM1 and Duchenne,” Brumm said.
Dyne expressed its appreciation for everyone taking part in these clinical trials.
“We are grateful to the participants, clinicians and the community for their ongoing partnership as we collectively strive to transform the treatment of rare muscle diseases,” Farwell said.