Del-Desiran Phase III Miss: Endpoint Failure or Mechanism Vindication Hinges on Undisclosed Secondary Data

Novartis' HARBOR Study for Del-desiran in DM1 Misses Primary Endpoint

Novartis announced that its global Phase III HARBOR study, evaluating delpacibart etedesiran (del-desiran) for myotonic dystrophy type 1 (DM1), did not achieve statistical significance on its primary endpoint of video hand opening time (vHOT). Despite this, the investigational antibody oligonucleotide conjugate (AOC) showed evidence of clinical activity in secondary endpoints and exploratory analyses. Novartis is currently analyzing the full dataset and plans to engage with health authorities to determine the future development path for del-desiran, a therapy for which there are currently no approved treatment options. The company also highlighted progress in its AOC pipeline, including delpacibart zotadirsen for DMD44, which received FDA priority review, and delpacibart braxlosiran for FSHD, based on positive Phase I/II biomarker data.

• The Phase III HARBOR study for delpacibart etedesiran (del-desiran) in myotonic dystrophy type 1 (DM1) failed to meet its primary endpoint of video hand opening time (vHOT), a novel measure of hand myotonia, showing no statistically significant improvement over placebo. This outcome impacts the immediate development trajectory for this investigational therapy.
• Despite missing the primary endpoint, del-desiran demonstrated evidence of clinical activity in several secondary endpoints and exploratory analyses. Safety findings were generally consistent with previously reported data, suggesting potential benefits that require further evaluation and discussion with health authorities to determine the most appropriate development path.
• Novartis's broader antibody oligonucleotide conjugate (AOC) pipeline continues to advance. Delpacibart zotadirsen (del-zota) for Duchenne muscular dystrophy with exon 44 skipping mutations (DMD44) received FDA priority review, and delpacibart braxlosiran (del-brax) for facioscapulohumeral muscular dystrophy (FSHD) is slated for an FDA meeting following positive Phase I/II biomarker data.
• Myotonic dystrophy type 1 (DM1) remains a progressive, multisystem neuromuscular disease with a high unmet need and no currently approved treatment options. The complexity of developing therapies for DM1 underscores the challenges faced in addressing such rare and debilitating conditions.

Del-desiran's HARBOR Study: Mixed Efficacy Signals in DM1

Two recent studies in myotonic dystrophy type 1 (DM1) offer meaningful insights into both quantitative outcome measurement and remote assessment methodology. The END-DM1 natural history study evaluated video hand opening time (vHOT) as a quantitative measure of myotonia across 22 international sites in 591 adult DM1 patients. The primary procedure involved video-recorded hand opening after a maximum 3-second grip, scored blindly at a central site. From an efficacy standpoint, vHOT demonstrated good intra-visit reproducibility (intraclass correlation coefficient 0.84 [95% CI 0.81–0.86]) and captured a broad spectrum of myotonia severity (median 3.9 seconds, interquartile range 1.8–7.9 seconds). However, vHOT correlated relatively weakly with self-reported myotonia (ρ = 0.39) and even lower with grip strength (ρ = −0.21) and 9-hole pegboard (ρ = 0.12). Among the 270 patients who completed 1-year follow-up, vHOT showed no progression (mean difference 0.4 ± 4.7 seconds, p = 0.34), suggesting the measure may be better suited to detecting improvement than tracking decline.

A second study evaluated the feasibility of remote study visits (RSVs) for quantitative assessment of muscle function in DM1. Twenty-three subjects with DM1 were consented remotely and provided toolkits containing a tablet computer, grip dynamometer, and spirometer. Assessments included grip strength, forced vital capacity, peak cough flow, timed-up-and-go (TUG), and grip myotonia (hand opening time). All 23 subjects completed RSVs, with 95% able to complete all components. Grip strength and TUG demonstrated moderate to strong correlations with self-reported inventories of upper and lower extremity impairment (ρ = 0.7 and ρ = −0.52, respectively). A total of 91% of subjects expressed interest in participating in future RSVs, supporting the feasibility of portable devices and video-conferencing for remote data collection in DM1.

The Persistent Unmet Need in Myotonic Dystrophy Type 1

Despite decades of research into its molecular underpinnings, DM1 remains without approved disease-modifying therapies, and the management of its multisystemic manifestations continues to rely on symptomatic interventions with inconsistent outcomes. The challenges span from the absence of validated treatment options to the heterogeneity of disease expression and the limitations of available outcome measures.

• No approved disease-modifying treatment exists. DM1 is described as the most prevalent form of muscular dystrophy in adults and yet there are currently no treatment options targeting the underlying pathology — the CTG repeat expansion and its downstream RNA toxicity cascade involving MBNL sequestration and CELF1 dysregulation.

• Symptomatic management of excessive daytime sleepiness (EDS) is inconsistent. Modafinil, used off-label for EDS in DM1, has shown inconsistent results in published studies. A European Medicines Agency review concluded that evidence was insufficient to outweigh potentially serious side-effects — including severe skin reactions and cardiac arrhythmia — restricting its use to narcolepsy. In a prospective cohort of 120 DM1 patients offered modafinil for EDS, only 12 continued with benefit while 10 experienced intolerance or no benefit. Similarly, a randomized crossover trial of methylphenidate (20 mg/d) demonstrated significant reductions in Daytime Sleepiness Scale and Epworth Sleepiness Scale scores, but no significant change in mean sleep latency test results, energy/vitality, or mood — and three patients discontinued due to treatment-emergent adverse events.

• Respiratory and cardiac interventions show high rates of intolerance or non-response. Among DM1 patients with respiratory failure offered non-invasive ventilation (NIV), 18 had intolerance or no benefit versus 12 who continued with benefit. For obstructive sleep apnoea managed with continuous positive airway pressure (CPAP), 14 of 21 patients had intolerance or no benefit. Cardiac conduction disorders — including PQ interval ≥240 ms and QRS duration ≥120 ms — are independent markers associated with cardiac events, yet prediction of sudden death remains an unresolved challenge warranting further investigation.

• Outcome measure heterogeneity limits clinical trial design. A systematic review of 80 studies found substantial heterogeneity in methods used to assess muscle strength across cardiac, skeletal, and respiratory domains, with no consensus core outcome set established. Functional capacity measures proposed by the Outcome Measures for Myotonic Dystrophy (OMMYD) group — including the 6-minute walk test, 30-second sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine-hole peg test — showed that the nine-hole peg test failed to detect change after 1 year, and grip strength and manual dexterity measures showed poorer responsiveness over a 9-year longitudinal study.

• Mortality burden remains unchanged over time. DM1 patients carry a hazard ratio of 2.9 versus matched DM1-free controls and a standardized mortality ratio of 8.1 versus the UK general population, with excess risk driven by respiratory failure, aspiration pneumonia, and arrhythmia/conduction defects. No significant calendar time-related changes in overall survival were observed (p trend = 0.19), indicating that current clinical approaches have not meaningfully altered the disease's mortality trajectory.

Understanding DM1's Genetic Roots and Del-desiran's Approach

Myotonic dystrophy type 1 (DM1) originates from an unstable CTG repeat expansion in the 3' untranslated region (3'UTR) of the DM1 Protein Kinase (DMPK) gene. When transcribed, these expanded repeats produce toxic gain-of-function CUG-expansion RNA that forms ribonuclear foci comprised of auto-complementary CUG hairpin structures. These foci sequester the muscleblind-like (MBNL) family of RNA-binding proteins, depleting their availability, while simultaneously driving the abnormal stabilisation of CUGBP Elav-like family member 1 (CELF1). The combined loss of MBNL function and upregulation of CELF1 — two key alternative splicing regulators — disrupts normal splicing of secondary genes, including CLCN1, TNNT2, INSR, and SERCA1, producing fetal isoforms of proteins unable to fulfill the physiological requirements of adult tissues. Bidirectional transcription over the DMPK gene and repeat-associated non-ATG (RAN) translation represent additional molecular events that broaden the pathogenic landscape beyond canonical RNA toxicity.

Several signalling cascades further amplify DM1 pathogenesis. Impairment of protein kinase B (AKT) signalling increases autophagy, apoptosis, and ubiquitin-proteasome activity, while AMP-activated protein kinase (AMPK) downregulation may compound these effects. AKT also regulates CELF1 directly by affecting its subcellular localisation, and indirectly by inhibiting glycogen synthase kinase 3 beta (GSK3β), which stabilises the repressive form of CELF1 in DM1. Protein kinase C (PKC)-dependent signalling has been implicated in CELF1 hyperphosphorylation, contributing to its mis-regulation, although studies in transgenic mice lacking both PKCα and PKCβ demonstrated that disease phenotypes and CELF1 expression levels were not affected by deficiency of these two isoforms. Additionally, fibroblast growth factor-inducible 14 (Fn14) is induced in DM1 and is associated with downstream signalling through the nuclear factor κB (NFκB) pathway, linking inflammation to disease progression. In glial cells, transcriptome analyses have identified altered expression of immune mediators — including CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9 — with inflammation and immune response emerging as major deregulated processes, suggesting a role for glia in the central nervous system symptoms of DM1.

At the cellular level, MBNL1 and CELF1 dysregulation extends into cytoplasmic processes, altering proteostasis and sarcomere structure. Increased proteasome activity has been demonstrated to affect muscle function in mouse models carrying large CTG expansions, and calcium dysregulation — linked to impaired sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) activity and ryanodine receptor dysfunction — contributes to the oxidative stress and mitochondrial dysfunction observed in DM1 models. Cellular senescence, driven by telomere shortening, mitochondrial dysfunction, and oxidative stress, has been implicated in DM1 cellular pathophysiology and is associated with the premature aging phenotypes characteristic of the disease. Additional contributors to the muscular phenotype include alterations to satellite cells, non-coding RNA and microRNA metabolism — with deregulation of miR-222 and miR-448 identified in glial DM1 models — and aberrant polyadenylation, collectively underscoring the multifactorial nature of DM1 disease progression.

Navigating the Evolving Treatment Landscape for Myotonic Dystrophy Type 1

Over the past five years, the DM1 treatment landscape has been substantially shaped by advances in antisense oligonucleotide (ASO) technology targeting the root molecular pathology of the disease. IONIS-486178, an ASO directed against mutant DMPK transcripts, achieved ~90% DMPK knockdown in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a DM1 patient, reduced toxic nuclear foci, corrected SCN5A mis-splicing toward the adult isoform, fully restored ionic currents reduced in DM1 hiPSC-CMs, normalized action potential kinetics and durations, and significantly reduced the incidence of arrhythmogenic events. Separately, research in primary DM1 myoblasts bearing repeat lengths of 800, 1,200, or >3,000 triplets demonstrated that both blocking and gapmer ASOs achieved DMPK downregulation, with the gapmer ASO leading to substantial downregulation and essentially normalized splicing levels throughout — though the study underscored that repeat length is central to therapeutic effectiveness and that genotypic heterogeneity must be considered in clinical trial design.

Beyond direct DMPK targeting, complementary molecular strategies have advanced. An autoregulated MBNL1 overexpression system — in which an MBNL-sensitive alternative exon containing a stop codon governs the production of active versus inactive MBNL1 — demonstrated beneficial effects on alternative splicing patterns in DM1 models and in cells derived from DM1 patients, offering a self-limiting approach to avoid excessive MBNL activity. In parallel, antagomiR-23b, which blocks microRNA-23b to boost MBNL1 protein levels, showed dose-dependent rescue of splicing alterations, grip strength, and myotonia in HSA mice following subcutaneous administration, with effects on grip strength and myotonia still slightly notable after 45 days. Research into MBNL deficiency specifically in motor neurons further revealed that MBNL activity in motor neurons is crucial for neuromuscular junction maintenance, identifying mis-splicing events in genes associated with synaptic transmission as a distinct therapeutic consideration.

On the clinical and rehabilitative side, published data from DM1 mouse models demonstrated that ASO monotherapy alone did not reverse fatigue despite correcting the molecular phenotype for 3 months, whereas ASO treatment combined with a treadmill walking regimen of 30 minutes per day, 6 days per week for 3 months reversed all measures of fatigue in old DM1 mice — highlighting exercise as a necessary adjuvant to targeted molecular therapies. At the clinical outcomes level, the Myotonic Dystrophy Health Index (MDHI) has been validated longitudinally in 451 DM1 patients, with a Minimal Detectable Change for the total score ranging from ±4.24 to ±9.72 points and a Minimal Clinically Important Difference ranging from small changes (−0.12 improvement/+1.25 worsening) to large changes (−2.17 improvement/+4.71 worsening), supporting its use as a potential additional outcome measure at subgroup levels in clinical trials. The OPTIMISTIC trial's retrospective analysis further identified nine variables potentially associated with Cognitive Behavioural Therapy response — including measures of disease severity, executive cognitive functioning, and perceived social support — reinforcing the heterogeneity of treatment response that any emerging DM1 therapy must account for.

Navigating the Nuances of Neuromuscular Drug Development

The recent announcement from Novartis regarding its HARBOR study for delpacibart etedesiran (del-desiran) in myotonic dystrophy type 1 (DM1) offers a poignant illustration of the complexities inherent in developing therapies for rare, progressive neuromuscular diseases. DM1, a debilitating condition with no approved treatments, represents a significant unmet need, making any therapeutic advancement highly anticipated. Del-desiran, an antibody-oligonucleotide conjugate (AOC), was designed to address the root cause of DM1 by targeting toxic DMPK mRNA, a mechanism supported by earlier studies showing reductions in mutant DMPK mRNA and correction of aberrant splicing.

While the HARBOR study did not achieve statistical significance on its primary functional endpoint, video hand opening time (vHOT), the reported evidence of clinical activity in secondary and exploratory analyses presents a nuanced picture. This outcome underscores a critical challenge in drug development: translating robust molecular and pharmacodynamic improvements into statistically significant, clinically meaningful functional benefits. The path forward for del-desiran in DM1 will now involve careful analysis of the full dataset and engagement with health authorities, potentially requiring a re-evaluation of clinical endpoints or trial design to better capture the therapy's impact.

This situation also has broader implications for Novartis's innovative AOC platform. While del-desiran's journey faces a hurdle, the platform itself continues to show promise with other assets, such as delpacibart zotadirsen for DMD44, which has received FDA priority review, and delpacibart braxlosiran for FSHD, backed by positive biomarker data. These developments suggest the AOC modality holds potential across various neuromuscular indications by enhancing targeted delivery to muscle. However, the DM1 results serve as a reminder that even with a sophisticated delivery mechanism and clear molecular targets, the clinical validation of functional improvement remains the ultimate arbiter of success. The industry will be watching closely to see how Novartis navigates this complex data, as it could set precedents for future AOC development in this challenging therapeutic area.