DYNE-251 leads to improvements in motor function in DMD: Update
Phase 1/2 DELIVER trial enrolling boys with DMD, ages 4-16, at sites globally
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Up to a year of treatment with DYNE-251, Dyne Therapeutics’ investigational exon 51-skipping therapy, led to improvements in motor function for boys with Duchenne muscular dystrophy (DMD), according to a clinical trial update.
Based on these positive data from the Phase 1/2 DELIVER clinical trial (NCT05524883), Dyne is launching registrational groups of trial participants, the data from which are expected to support regulatory applications seeking DYNE-251’s approval.
The trial may still be enrolling boys with DMD, ages 4-16, at sites in the U.S., Australia, Europe, and Canada.
“We believe these data reinforce the opportunity to transform the treatment paradigm for individuals living with Duchenne,” Wildon Farwell, MD, chief medical officer of Dyne, said in a company press release.
Update on plan to seek DYNE-251’s approval expected by year’s end
“With these exciting data, we are moving quickly to initiate registrational cohorts in DELIVER, and we continue to pursue expedited approval pathways and plan to provide an update on our path to registration by the end of this year,” Farwell added.
Boys with DMD are lacking in dystrophin, a protein important for protecting muscles from injury, due to mutations in the DMD gene.
Exon skipping is a therapeutic strategy for DMD wherein certain protein-coding portions of DMD are skipped over when the gene is being read to make dystrophin protein. This essentially allows a shorter-than-normal but still functional version of dystrophin to be produced for patients with disease-causing mutations that affect the DMD gene in certain ways.
DYNE-251 is an investigational exon-skipping therapy designed to skip over exon 51 of DMD. It consists of an oligonucleotide, which is a short strand of genetic material that can influence gene activity, that is bound to an antibody that directs the therapy specifically to muscle cells. The treatment is given via infusions directly into the bloodstream.
DELIVER is testing various doses of DYNE-251 against a placebo in boys with DMD who have mutations expected to be responsive to exon 51 skipping.
Preliminary data from boys who received monthly infusions of DYNE-251 at a dose of 5 mg/kg or 10 mg/kg indicated the therapy led to increases in dystrophin levels, as the therapy’s mechanism intends. Monthly treatment at the 10 mg/kg dose increased dystrophin levels to an average of just over 3% of normal after six months.
In the recent update, Dyne provided six-month biomarker and functional data from eight boys enrolled in a monthly 20 mg/kg dosing group, some of whom received active treatment and some who were given the placebo. The company also provided a one-year functional update from six boys in the 10 mg/kg group.
DYNE-251 led to increases in dystrophin levels
DYNE-251 at the 20 mg/kg dose led to increases in dystrophin levels (consistent with earlier reports) reaching a mean absolute dystrophin level of 3.71% of normal. That’s more than 10-fold higher than the 0.3% that was observed in a clinical trial of Exondys 51 (eteplirsen), an approved exon 51-skipping therapy.
When adjusting for muscle content, DYNE-251 achieved mean dystrophin levels at 8.72% of normal.
Notably, these dystrophin increases corresponded with meaningful improvements in motor function for patients treated at the 10 mg/kg and at the 20 mg/kg doses after six months, with continued improvements observed up to a year in patients in the 10 mg/kg group.
Benefits were observed across a range of functional assessments, including the North Star Ambulatory Assessment, 10-Meter Walk/Run Time, and Time to Rise From the Floor tests.
In particular, improvements were observed in the Stride Velocity 95th Centile (SV95C), a digital outcome measure that looks at patients’ walking abilities in their normal daily environment.
SV95C is used as a primary outcome measure for DMD clinical trials in Europe. The improvement in this measure observed with either dose of DYNE-251 met the threshold that the European Medicines Agency considers to be a clinically meaningful change, according to Dyne.
Goal to ‘drive dystrophin levels that lead to functional benefit for patients’
“Our goal has always been to drive dystrophin levels that lead to functional benefit for patients,” Farwell noted, adding the new data suggest that earlier preclinical findings are “translating in the clinic.”
Safety data from 54 boys enrolled in DELIVER, with around 675 doses delivered, have indicated the treatment was well tolerated, with most side effects being mild or moderate in severity.
Two boys treated at a higher dose level (40 mg/kg) experienced side effects considered potentially related to DYNE-251, from which both participants have recovered.
As DELIVER continues, Dyne is also moving forward with its Phase 1/2 ACHIEVE trial (NCT05481879) that’s testing investigational therapy DYNE-101 in adults with myotonic dystrophy type 1.
Data so far have indicated the treatment is safe and leads to functional benefits for patients. An update on the ACHIEVE trial, which is still recruiting participants, is anticipated by year’s end.
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