MDA 2024: Dyne trials raising doses after early positive results

Investigational therapies are aimed at treating Duchenne and DM1

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

DYNE-251 and DYNE-101, Dyne Therapeutics’ investigational therapies for forms of muscular dystrophy, appear safe and are showing signs of preliminary efficacy in Phase 1/2 clinical trials.

These proof-of-concept data, announced by Dyne in January, were discussed in two oral presentations at the recent 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference.

The DELIVER trial (NCT05524883) is evaluating DYNE-251 in boys ages 4-16 with Duchenne muscular dystrophy (DMD) while ACHIEVE (NCT05481879) is testing DYNE-101 in adults ages 18-49 with myotonic dystrophy type 1 (DM1).

Based on these very early analyses, the company is moving forward with testing higher doses of the treatments, with both trials enrolling new participants. Additional trial data are expected this year.

“We’re excited to present to the rare muscle disease community initial clinical data from our co-lead programs in DM1 and DMD, where there remains an urgent and significant need for new and better treatment options,” Wildon Farwell, MD and chief medical officer of Dyne, said in a February press release.

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DYNE-251 and DYNE-101 were designed using the company’s FORCE platform, which targets the delivery of therapeutic oligonucleotides — short strands of genetic material that work to modulate gene activity — directly to muscle cells. That is achieved by linking a therapeutic payload to an antibody that specifically binds to a protein on muscle cells.

An exon-skipping therapy, DYNE-251 is intended for certain patients with DMD, in whom mutations in the DMD gene lead to a lack of the dystrophin protein, which is important for muscle health. Particularly, the treatment aims to skip over a protein-coding portion of DMD called exon 51, producing a shorter but functional version of dystrophin.

In DM1, an adult-onset form of muscular dystrophy, mutations in the DMPK gene cause production of an abnormal version of RNA — a template molecule for making protein — that accumulates and disrupts normal muscle-related protein production. DYNE-101 binds to these faulty clumps and causes them to degrade.

The DELIVER and ACHIEVE trials are designed similarly. Each is testing multiple doses of its respective therapy, delivered via into-the-vein infusions, against a placebo over a six-month period.

DYNE-101 data presentation

Valeria Sansone, MD, PhD, of the NEuroMuscular Omnicenter and University of Milan, described interim findings from the ACHIEVE trial in the presentation “Initial Data from the ACHIEVE Trial of DYNE-101 in Adults with Myotonic Dystrophy Type 1 (DM1).”

Efficacy data are so far only available for five DM1 patients treated with a 1.8 mg/kg monthly dose of DYNE-101, followed for six months, and five patients treated with 3.4 mg/kg, followed for three months, as well as eight placebo-given patients.

Although there was some variability “consistent with the complexity of the disease,” Sansone said, the data generally showed that DYNE-101 worked as intended, decreasing DMPK RNA levels and correcting a faulty cellular process called splicing that’s implicated in the disease.

Reductions in myotonia — a hallmark DM1 symptom characterized by difficulty relaxing muscles — were also observed in the 1.8 mg/kg group.

“I’d like to point out that this is just with the lower dose,” Sansone noted. “So this is an encouraging result because already … with the lowest dose we are seeing something in our patients.”

Patient-reported outcome measures also indicate benefits at the lower dose, including reductions in overall disease burden and fatigue.

We’re showing the fatigue domain because that’s one of the symptoms patients often complain of, but the other measures go in the same direction,” Sansone explained. “So again, this is encouraging.”

Safety data indicated DYNE-101 was safe up to doses of 5.4 mg/kg, given every two months. A high-dose group (6.8 mg/kg every two months) is now enrolling.

DYNE-251 data presentation

In the presentation “Initial Data from the DELIVER Trial of DYNE-251 in Males with DMD Mutations Amenable to Exon 51 Skipping,” Kevin Flanigan, MD, of Nationwide Children’s Hospital in Ohio, discussed preliminary efficacy data from six DMD patients enrolled in DELIVER, four who received monthly infusions of DYNE-251 at a dose of 5 mg/kg and two who received placebo.

The therapy led to exon 51 skipping, as well as an associated increase in dystrophin levels and the number of dystrophin-positive muscle fibers.

Although the sets of data can’t directly be compared, Flanigan noted that DYNE-251 here generally outperformed what was observed after six months in clinical trials of Exondys 51 (eteplirsen), an approved exon 51-skipping therapy.

Safety findings so far have indicated that the treatment was safe up to 20 mg/kg monthly doses. A new group of patients is being enrolled, and it will receive DYNE-251 at a dose of 40 mg, given once every eight weeks.

“These initial data support the continued clinical development of DYNE-251 for the treatment of DMD,” Flanigan said.

After completion of either trial, participants will be able to enter a six-month, open-label extension phase, followed by a nearly two-year, long-term extension, in which all will receive their respective investigational therapy at the highest tolerable dose.