Laurie Gutmann, MD, chair of the Department of Neurology at Indiana University School of Medicine, discusses one-year pooled ACHIEVE data for z-basivarsen (DYNE-101), an investigational antisense oligonucleotide, in myotonic dystrophy type 1 (DM1).
Zeleciment basivarsen (z-basivarsen; DYNE-101) is an investigational antisense oligonucleotide conjugated to a Fab that binds transferrin receptor 1, designed to deliver the drug to muscle and the central nervous system. It aims to reduce toxic nuclear DMPK RNA and restore normal splicing in myotonic dystrophy type 1 (DM1), a multisystem disease with no approved disease-modifying treatments.
Additional one-year data from the phase 1/2 ACHIEVE trial were presented at the
Following the meeting, NeurologyLive spoke with Laurie Gutmann, MD, chair of the Department of Neurology at Indiana University School of Medicine, about the findings. Gutmann answered questions on the mechanism behind z-basivarsen, the durability of response in the pooled group and in participants who crossed over from placebo, and the safety profile so far. She also covered next steps, including the confirmatory phase 3 HARMONIA trial.
Laurie Gutmann, MD: Myotonic dystrophy type 1 is a disorder caused by a prolonged repeat in the DMPK gene. Because of that prolonged repeat, the abnormal MBNL protein gets stuck and collects within the nucleus. It is an abnormal sequestration of the protein. That protein is important for downstream splicing of multiple genes and systems, and it matters for much more than what we think of as muscle disease in myotonic dystrophy. It is probably the source of the beginning of all the other abnormalities that happen in this disease.
The thought is that if you can release that protein and allow appropriate splicing downstream, you will reduce the effects of the disease. So, the antisense oligonucleotide goes in and breaks up the DMPK gene itself, allowing the release of the MBNL proteins into the system and all that downstream splicing to occur. That’s the theory behind it.
There was an original report looking at just the first 6 participants, and the question was whether we could still see changes down the road by pooling some of this data. The idea was to take people from this larger group who had been on intervention for a year. Some of those people were in the placebo group and then switched over, which is another interesting point. The original 6 were all at the highest, registrational dose. This pool includes people at lower doses who were still followed over a year as the dosing study went on. Only 8 of them were on the full dose for the full 12 months.
In the whole pooled group, there was clearly improvement. The outcome being looked at is myotonia, which is measured through what’s called the video hand opening time. You have a patient make a fist and then release it, and you count how long it takes for them to fully open their hand. It is looking specifically at myotonia, and there was clear improvement and then sustained improvement. Those on placebo showed no improvement and then showed improvement with the changeover, so pooling all of that together really made a difference. When you look at the people on placebo alone, there was no change, which is also a nice signal for that particular outcome.
It’s an infusion, and there actually have not been any serious adverse events, which is a great thing. I agree with you that this always depends on the ASO itself and its downstream effects. Some people withdrew from treatment, and they withdrew because of infusion reactions. So, we know that some people did have mild infusion reactions, such as fever and headache, which could be mitigated primarily with anti-inflammatories. Those were the only reasons people withdrew. There were serious adverse events, but they were unrelated to the study drug and related more to the disease itself or unrelated to the disease.
I always worry about giving false hope this early in a trial. This really was looking at safety and at this particular outcome, a reduction of myotonia, which is felt to be directly related to the change in RNA splicing that happens in this disease. We are also measuring other things, such as strength, sit to stand, and patient-reported outcomes, and those are all important. But the number of people in this pooled data is not enough to draw any significant conclusions, except that they did not show worsening. They were compared with a pooled natural history study to look at change over the same period of time in propensity-matched individuals, and there definitely is a signal of improvement, but it is way too early to draw conclusions like that. The next step is hopefully a phase 2b or phase 3 trial.
I did want to give a clarifying point. We have already initiated a phase 3 for this drug, our HARMONIA trial. I should have said the next step is already underway.
The phase 3 study is now looking at efficacy. We feel that safety is not a major concern, so now we are going to look more at efficacy, which includes motor function as well as patient-reported outcomes for a signal for cognition. As I mentioned earlier, this is a very multisystem disease, and we focused for many years on the muscle part of it. For patients, there are so many more functional concerns that are sometimes difficult to measure. So it is very exciting to be recruiting now for the phase 3 trial, and we look forward to seeing the outcomes.
Transcript edited for clarity. For more AANEM 2026 coverage,
