DM1 therapy shows promise over year of testing, trial data suggest
Dyne’s Z-basivarsen linked to physical function gains
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Dyne Therapeutics‘ experimental therapy zeleciment basivarsen (z-basivarsen) may help improve multiple measures of physical function in people with myotonic dystrophy type 1 (DM1), new clinical trial data suggest.
“What’s encouraging is that we observed improvements across multiple measures, including strength and functional assessments,” Doug Kerr, MD, PhD, chief medical officer at Dyne, said in an interview with Muscular Dystrophy News. “Rather than seeing a change in just one endpoint, we’re seeing evidence of functional improvement across multiple measures.
“For people living with DM1, that may suggest the potential for improvements across multiple aspects of physical function, which is particularly important given the broad and progressive nature of the disease,” Kerr said.
DM1 is a type of muscular dystrophy caused by mutations in the DMPK gene. These mutations lead to problems with how cells process RNA, a molecule that’s normally produced as an intermediary when genes are read to make proteins. Specifically, DMPK mutations lead to the production of an abnormal RNA molecule that forms clumps in the nucleus (the compartment that houses most of the cell’s DNA), which disrupts the cell’s ability to process a range of other RNA molecules.
Targeting ‘underlying biology’
Z-basivarsen is designed to clear toxic clumps of DMPK RNA, normalizing RNA processing. The therapy is administered by infusion into the bloodstream.
“DM1 is caused by toxic DMPK RNA that disrupts normal RNA processing and splicing,” Kerr said. “Z-basivarsen is designed to target that underlying biology by reducing toxic nuclear DMPK RNA and correcting splicing abnormalities.”
Z-basivarsen is being tested in the Phase 1/2 ACHIEVE trial (NCT05481879). The first part of the study tested various doses of the therapy against a placebo for about six months, after which all patients could opt to receive z-basivarsen treatment at various doses in a long-term extension study.
The new analysis covers one year of data from more than two dozen patients in this part of the trial. The patients were given different regimens of z-basivarsen, mostly at lower doses than are being tested in further studies.
“A key strength of this analysis is that the pooling of participants across multiple ACHIEVE cohorts provides a larger dataset for evaluating the treatment effect across participants and clinical measures,” Kerr said. “At the same time, these findings should be interpreted in the context of the analysis design. The dataset is still relatively small and represents pooled data from participants across dose cohorts and treatment histories.”
A hallmark symptom of DM1 is myotonia, in which muscles cannot relax easily after contraction. In the ACHIEVE study, myotonia is being tracked using a measure called video hand opening time (vHOT).
“For patients, myotonia can affect many everyday activities, particularly those that require repetitive hand movements and grip,” Kerr said.
The new data showed that, after six months of treatment with z-basivarsen, vHOT decreased by a mean of 3.2 seconds, reflecting a decrease in myotonia. Among patients given the placebo in the first part of the trial, vHOT increased by 0.4 seconds over six months of follow-up.
“Improvements in vHOT may provide evidence that z-basivarsen is affecting the underlying disease process,” Kerr said.
Improvements in standing, grip strength
One-year data also suggested that z-basivarsen led to improvements in a functional assessment called the five times sit to stand (5xSTS) test. After a year on various doses of the therapy, 5xSTS improved by more than one second on average.
“The five times sit-to-stand test is a well-established functional assessment that measures a person’s ability to repeatedly rise from a seated position,” Kerr said, adding that the test “requires strength, balance, coordination, mobility, and stamina, all of which can be affected as DM1 progresses.”
Improvements were also seen on measures of grip strength and walking ability. Scores on the Myotonic Dystrophy Health Index (MDHI) — a patient-reported assessment of cognitive impairment, sleep disturbances, fatigue, communication, emotional issues, and pain — improved by 25.2% on average after a year on z-basivarsen. Safety data from the trial have shown no serious issues so far, according to Dyne.
Kerr said this analysis “further supports our confidence in the potential of z-basivarsen.”
“We’ve observed sustained improvement across myotonia, functional assessments, muscle strength and patient-reported outcomes, which provides an encouraging foundation as we look ahead to the registrational expansion cohort,” Kerr added.
That cohort, a subgroup of 71 patients in the ACHIEVE study, is testing a high dose (6.8 mg/kg of z-basivarsen administered every eight weeks) against a placebo. This part of the study primarily hopes to confirm z-basivarsen’s effect on vHOT. Results are expected early next year.
“For the upcoming readout, we’ll be looking at whether the improvements in vHOT observed in the [first part] of ACHIEVE are replicated in a larger population, while also evaluating the broader data across functional and safety measures,” Kerr said
Dyne hopes to use findings from this group of patients to apply for accelerated approval in the U.S. Accelerated approval is a type of conditional approval that allows a therapy to be brought to market based on early evidence that it is likely to benefit patients.
If z-basivarsen is granted accelerated approval, Dyne would be obligated to conduct additional testing aimed at proving clinical benefit. The company is running a Phase 3 trial, HARMONIA (NCT07486934), which aims to do just that. Its main goal is to show that z-basivarsen outperforms the placebo at improving 5xSTS after about one year. The HARMONIA trial is currently recruiting participants at sites across the U.S., Europe, Japan, and Australia.
“We’re looking forward to the upcoming ACHIEVE registrational expansion cohort data and the continued advancement of the Phase 3 HARMONIA study as we continue evaluating the potential of z-basivarsen in DM1,” Kerr said.
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