Investigational Drug Shows Promise in Myotonic Dystrophy Type 1

Investigational zeleciment basivarsen (z-basivarsen) led to functional improvement in patients with myotonic dystrophy type 1 (DM1), data from the phase I/II ACHIEVE trial suggested.

The analysis evaluated whether a larger group experienced similar efficacy trends that were seen in a small cohort of six participants who received the registrational dose of 6.8 mg/kg once every 8 weeks. It included a pooled-dose group of 26 DM1 patients from the multiple ascending dose portion of the ACHIEVE trial who were assessed through 12 months.

At 1 year, participants had sustained improvement from baseline in hand myotonia, measured by video hand-opening time (vHOT), reported Shauna Andersson, MD, PhD, vice president of clinical development at Dyne Therapeutics, at the American Association of Neuromuscular and Electrodiagnostic Medicine meeting in Orlando.

The pooled-dose group had a mean baseline vHOT of 8.2 seconds, which decreased by 3.2 seconds at 6 months. This represented a 3.6 second improvement over the placebo group from the multiple ascending dose portion of ACHIEVE, which increased its vHOT by 0.4 seconds at 6 months.

Participants in the pooled-dose group had sustained improvement from baseline in function assessed by the 5 times sit-to-stand (5xSTS) test, and in strength measured by quantitative muscle testing (QMT) total scores. They also reported improvements in disease burden.

Compared with a natural history cohort, participants treated with z-basivarsen had better functional and strength outcomes and functional improvements in patient-reported Myotonic Dystrophy Health Index scores, Andersson pointed out.

Z-basivarsen continued to demonstrate a favorable safety profile, she said. Treatment-related adverse events included infusion-related reaction, nasopharyngitis, diarrhea, headache, procedural pain, influenza, and back pain. No serious treatment-emergent adverse events related to the study drug were identified.

“These data support answers to two important questions at once,” Andersson noted. “First, even though most participants in this larger group received lower doses than our selected registrational dose, we still saw the same pattern of improvement from baseline at 12 months that we previously saw in a smaller cohort treated at the full registrational dose,” she told MedPage Today.

“Second, when we compared this larger group to a well-matched cohort of untreated DM1 patients, we saw clear divergence at 12 months from the natural course of the disease across every reported endpoint,” she said. “Together, these findings reinforce our confidence in z-basivarsen’s potential to deliver functional improvement for people living with myotonic dystrophy type 1.”

DM1 is a rare progressive disorder caused by mutations in the DMPK gene that lead to a widespread disruption of RNA splicing. Adult-onset DM1 symptoms typically appear between ages 20 and 40. No disease-modifying therapies are currently available for DM1, and treatment is limited to symptom management.

Z-basivarsen (DYNE-101) is an investigational drug consisting of an antisense oligonucleotide conjugated to an antigen-binding fragment that binds to the transferrin receptor 1. It is designed to reduce toxic nuclear DMPK RNA to release splicing proteins and allow normal mRNA processing.

The treatment is being investigated in the phase I/II ACHIEVE trial and the phase III HARMONIA trial, which is currently recruiting. The primary endpoint of HARMONIA will be the change from baseline in 5xSTS at 12 months.

ACHIEVE also has a registrational expansion cohort (REC) to support potential regulatory submissions, including accelerated approval in the U.S. The primary endpoint for this cohort is the change from baseline in middle finger myotonia measured by vHOT at 6 months compared with placebo.

The mean baseline vHOT value of the 71 participants enrolled in the ACHIEVE REC study is 8.3 seconds. Topline data from the registrational expansion cohort are planned for the first quarter of 2027.