Evaluating Zeleciment Basivarsen in Myotonic Dystrophy Type 1: The Phase 3 HARMONIA Trial

Welcome to NeurologyLive's Clinical Trial in Focus. Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month's spotlight is the phase 3 HARMONIA trial (NCT07486934) assessing zeleciment basivarsen (z-basivarsen, formerly DYNE-101; Dyne Therapeutics), an investigational antisense oligonucleotide (ASO) conjugate, in individuals with myotonic dystrophy type 1 (DM1).^1,2

DM1 is a rare, progressive, genetic neuromuscular disease that affects an estimated 40,000 people in the US and 55,000 in the European Union. Although its genetic cause is well characterized, there are currently no approved disease-modifying treatments.²

Mechanism of Action

DM1 is caused by mutations in the DMPK gene that lead to widespread disruption of RNA splicing, known as spliceopathy, which drives the disease's multisystem manifestations. Clinical features include muscle weakness throughout the body, myotonia, excessive daytime sleepiness, fatigue, dysregulated sleep, cognitive impairment, cardiac arrhythmias, respiratory issues, and gastrointestinal dysfunction.²

Z-basivarsen consists of an ASO conjugated to an antigen-binding fragment (Fab) that binds transferrin receptor 1 (TfR1), enabling delivery to skeletal muscle and the central nervous system (CNS). Once internalized, the ASO is designed to reduce toxic nuclear DMPK RNA, releasing sequestered splicing proteins and allowing normal mRNA processing. By targeting the mutant transcript upstream of the splicing defect, the agent aims to address the shared mechanism behind DM1's muscular and CNS manifestations rather than individual symptoms.

That rationale is reflected in HARMONIA's end point structure. A lower-extremity functional measure serves as the primary outcome, while myotonia, strength, gait, patient-reported disease burden, and a broad set of exploratory CNS assessments capture the multiple tissues the conjugate is designed to reach.

Study Design

HARMONIA is a global, randomized, double-blind, placebo-controlled, confirmatory phase 3 trial assessing the multisystem efficacy, safety, and tolerability of z-basivarsen.^1,3 The trial will enroll approximately 150 participants aged 16 years and older, who will be randomly assigned 1:1 to intravenous z-basivarsen 6.8 mg/kg or placebo every 8 weeks (Q8W).²

The design of the study was presented at the 2026 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held September 29 to October 2, 2026, in Orlando, Florida, by senior author Doug Kerr, MD, PhD, and colleagues. "HARMONIA is a larger and longer-term study utilizing a clinically meaningful functional measure as the primary endpoint," Kerr chief medical officer at Dyne, said in a statement.²

The study consists of a screening period of up to 8 weeks, a 48-week placebo-controlled period, and a 24-week long-term extension in which all participants receive z-basivarsen 6.8 mg/kg Q8W. An independent data monitoring committee will review safety and tolerability data at regular intervals. Enrollment began in the first half of 2026, with estimated study completion in January 2029.⁴

The primary end point is the change from baseline in the 5xSTS test at week 49. The sponsor selected the 5xSTS as a reliable and responsive measure reflecting lower-extremity strength, balance, and trunk strength, which are critical to daily activities. Secondary end points include video hand opening time (vHOT), quantitative muscle testing (QMT), the 10-Meter Walk/Run test, the Myotonic Dystrophy Health Index (MDHI), and additional patient- and clinician-reported outcomes. The trial also includes a broad set of exploratory end points assessing multiple domains of DM1-related CNS involvement.

Dyne has aligned with the FDA on the HARMONIA design and protocol. The trial is intended to serve as a confirmatory study to support conversion of a potential accelerated approval to traditional approval in the US, and to support marketing applications outside the US.² The accelerated approval pathway is being pursued through the registrational expansion cohort of the phase 1/2 ACHIEVE trial (NCT05481879), which uses change in middle-finger myotonia on vHOT at 6 months as its primary end point.³

Inclusion Criteria

Eligible participants are individuals aged 16 years and older with a diagnosis of DM1 confirmed by molecular genetic testing showing a trinucleotide repeat size greater than 100; historical results from clinical testing are acceptable.⁴ Requiring genetic confirmation above this repeat threshold defines a population with established DMPK expansion, the molecular target of the therapy.

Participants must be able to walk 10 meters and complete the 5xSTS independently, with inserts or supports that do not extend above the ankle permitted. This functional requirement ensures that participants can perform the primary end point and the 10-Meter Walk/Run secondary end point at baseline, so that change over 48 weeks can be measured. A body mass index below 35 kg/m is also required. The lower age limit of 16 years extends enrollment to adolescents, a broader range than the ACHIEVE registrational expansion cohort, which enrolled adults aged 18 to 65 years.⁵

Exclusion Criteria

Individuals with a known diagnosis of congenital DM1 are excluded. Congenital DM1 has a distinct clinical course and severity profile, and its exclusion keeps the trial population focused on noncongenital forms of the disease.

A history of a major surgical procedure, based on investigator judgment, within 12 weeks prior to the start of screening is exclusionary, with the exception of an implanted pacemaker or defibrillator. The exception reflects the frequency of cardiac conduction disease in DM1 and prevents excluding patients who have received standard cardiac device care.

Participants are also excluded if they have used glucagon-like peptide-1 (GLP-1) receptor agonist or incretin medications, including semaglutide, dulaglutide, liraglutide, exenatide, or tirzepatide, within 5 half-lives of the medication prior to screening assessments. The publicly posted registry summary notes that additional protocol-defined inclusion and exclusion criteria may apply.

Prior Data

HARMONIA's dose and regimen were selected from the multiple ascending dose (MAD) portion of the ongoing phase 1/2 ACHIEVE trial.³ In the completed 24-week placebo-controlled MAD portion, 56 participants received 1 of 5 intravenous z-basivarsen dose regimens or placebo, and eligible participants subsequently entered a long-term extension at 6.8 mg/kg Q8W.

Findings presented at the 2026 MDA Clinical & Scientific Conference showed that, among 6 participants who received 6.8 mg/kg Q8W in the MAD portion, substantial knockdown of DMPK RNA and improvement in splicing were observed as early as 3 months after treatment. Improvement from baseline in myotonia measured by vHOT was noted at 3 months and sustained through 12 months.

Improvements from baseline in QMT total score, the 10-Meter Walk/Run test, 5xSTS, and the 9-Hole Peg Test were also sustained through 12 months. Investigators reported that these changes were supported by improvements in MDHI total score and subscales assessing CNS manifestations, mobility, ability to do activities, and upper-extremity function. Clinician-reported global impression of change scales showed improvement in 83% of patients at 12 months.

As of April 23, 2025, z-basivarsen demonstrated a favorable safety profile across the MAD portion, with no serious treatment-related treatment-emergent adverse events. Z-basivarsen has received Breakthrough Therapy, Orphan Drug, and Fast Track designations from the FDA, as well as orphan drug designations from the European Medicines Agency and Japan's Ministry of Health, Labour and Welfare for the treatment of DM1.²

The ACHIEVE registrational expansion cohort is fully enrolled, with topline data planned for the first quarter of 2027. At AANEM 2026, Dyne is also presenting 6- and 12-month data from a pooled MAD dose group compared with a propensity-matched cohort from the END-DM1 natural history study, along with updated safety data.³

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REFERENCES
1. Chary S, et al. HARMONIA study design: a global phase 3 trial assessing the efficacy and safety of z-basivarsen in myotonic dystrophy type 1. Presented at: 2026 AANEM Annual Meeting; September 29-October 2, 2026; Orlando, FL.
2.Dyne Therapeutics announces initiation of phase 3 HARMONIA trial of z-basivarsen in myotonic dystrophy type 1 (DM1). News release. Dyne Therapeutics. March 8, 2026. Accessed September 28, 2026. https://investors.dyne-tx.com/news-releases/news-release-details/dyne-therapeutics-announces-initiation-phase-3-harmonia-trial-z
3. Dyne Therapeutics to present additional one-year clinical data from phase 1/2 ACHIEVE trial of z-basivarsen (DYNE-101) for myotonic dystrophy type 1 (DM1) at upcoming medical meetings. News release. Dyne Therapeutics. September 8, 2026. Accessed September 28, 2026. https://www.globenewswire.com/news-release/2026/09/08/3357546/0/en/dyne-therapeutics-to-present-additional-one-year-clinical-data-from-phase-1-2-achieve-trial-of-z-basivarsen-dyne-101-for-myotonic-dystrophy-type-1-dm1-at-upcoming-medical-meetings.html
4. Efficacy, safety, and tolerability of zeleciment basivarsen (DYNE-101) in participants with myotonic dystrophy type 1 (HARMONIA). ClinicalTrials.gov identifier: NCT07486934. Updated September 1, 2026. Accessed September 28, 2026. https://clinicaltrials.gov/study/NCT07486934
5. Andersson S, Bassez G, Diaz-Manera J, et al. Zeleciment basivarsen targets the underlying cause of DM1 to enable functional improvement in the phase 1/2 ACHIEVE trial. Presented at: 2026 MDA Clinical & Scientific Conference; March 2026. Poster 135 M. Accessed September 28, 2026. https://www.mdaconference.org/abstract-library/zeleciment-basivarsen-targets-the-underlying-cause-of-dm1-to-enable-functional-improvement-in-the-phase-1-2-achieve-trial/