Novartis Reports HARBOR Phase 3 Study of Del-Desiran in Myotonic Dystrophy Type 1 Misses Primary Endpoint
Novartis announced that the global Phase 3 HARBOR study evaluating del-desiran in people living with myotonic dystrophy type 1 (DM1) did not achieve its primary endpoint, failing to demonstrate a statistically significant improvement compared with placebo on video hand opening time (vHOT), a novel measure designed to assess hand myotonia.
The company said evidence of clinical activity was observed in several secondary endpoints and exploratory analyses, although the primary endpoint result means the overall Phase 3 study did not meet its main efficacy objective. Safety findings from HARBOR were generally consistent with previously reported data for del-desiran.
Novartis is now conducting a comprehensive evaluation of the full HARBOR dataset. The company plans to engage with health authorities to determine the most appropriate development path for del-desiran and assess what the results mean for the future of the program.
The outcome represents a setback for the development of a potential treatment for DM1, a serious neuromuscular disorder for which there are currently no approved disease-modifying treatment options. At the same time, Novartis said it remains committed to advancing therapies for people living with DM1 and other serious neuromuscular diseases.
HARBOR Study Fails to Meet Primary Endpoint
The HARBOR Phase 3 study was designed to evaluate the efficacy and safety of del-desiran in people living with DM1. The primary endpoint focused on video hand opening time, or vHOT, a novel functional measure intended to capture the severity of hand myotonia.
Hand myotonia is one of the characteristic manifestations of DM1 and can interfere with everyday activities. Patients may experience difficulty relaxing muscles after contraction, affecting tasks that require hand movement and coordination.
In HARBOR, del-desiran did not demonstrate a statistically significant improvement versus placebo on vHOT. As a result, the study did not meet its primary efficacy endpoint.
Despite the primary endpoint outcome, Novartis reported evidence of clinical activity in secondary endpoints and exploratory analyses. The company did not provide detailed numerical results from these analyses in its announcement and said it is continuing to assess the complete dataset.
The distinction between the primary endpoint and the secondary findings will be important as Novartis evaluates the next steps for the program. The company will review the totality of the clinical evidence, including efficacy outcomes, safety findings and exploratory observations, before determining the appropriate development strategy.
Safety Findings Generally Consistent With Previous Data
Novartis reported that safety findings from HARBOR were generally consistent with previously reported data for del-desiran.
The company did not identify new safety concerns in its announcement. The continued assessment of the full safety dataset will form part of the ongoing analysis as Novartis determines the future of the program.
Safety and tolerability are particularly important considerations in the development of treatments for chronic neuromuscular diseases such as DM1, where patients may require long-term management.
The company will assess the HARBOR safety profile alongside efficacy findings and other clinical measures as it prepares to engage with regulatory authorities.
Novartis Acknowledges Challenges in DM1 Drug Development
Shreeram Aradhye, president, Development and chief medical officer at Novartis, acknowledged the significance of the HARBOR results while emphasizing the continuing need for effective treatments for DM1.
“Despite decades of research, there are still no approved treatment options for DM1, and patients and caregivers continue to face a significant daily burden,” Aradhye said.
He noted that developing therapies for a complex disease such as DM1 remains challenging and described setbacks as part of scientific progress.
“As we continue to evaluate the full HARBOR dataset, we remain committed to identifying the most appropriate development path for the del-desiran program and advancing innovative approaches for people living with DM1 and other serious neuromuscular diseases,” Aradhye added.
The comments underscore the company’s intention to complete its assessment before making decisions about the next stage of development.
DM1 Remains an Unmet Medical Need
Myotonic dystrophy type 1 is a genetic neuromuscular disorder characterized by progressive muscle weakness and myotonia, or delayed muscle relaxation. The disease can affect multiple systems of the body and may substantially interfere with patients’ mobility, daily activities and overall quality of life.
The chronic and progressive nature of DM1 can create a significant burden not only for patients but also for caregivers. Symptoms can vary widely between individuals, adding complexity to both disease management and clinical development.
Despite decades of scientific research into the underlying mechanisms of DM1, there are currently no approved treatment options specifically addressing the disease-modifying needs of this patient population.
As a result, development programs such as HARBOR have attracted significant interest because of the potential to address an important unmet medical need.
The failure of the primary endpoint in HARBOR highlights the challenges associated with translating promising scientific approaches into clinically meaningful outcomes in complex neuromuscular diseases.
Del-Desiran Came to Novartis Through Avidity Acquisition
Del-desiran is one of three antibody oligonucleotide conjugate, or AOC, therapies that became part of Novartis’ neuromuscular pipeline through its acquisition of Avidity Biosciences.
AOC therapies are designed to combine antibody-based targeting with oligonucleotide-based mechanisms, with the goal of delivering genetic medicines to specific tissues. Novartis has been expanding its neuromuscular development efforts around this technology following the acquisition.
The HARBOR outcome therefore has implications beyond the individual DM1 program, as Novartis continues to evaluate the potential of its broader AOC portfolio in other serious neuromuscular disorders.
The company is advancing two additional AOC-based programs: delpacibart zotadirsen, also known as del-zota, in Duchenne muscular dystrophy (DMD), and delpacibart braxlosiran, or del-brax, in facioscapulohumeral muscular dystrophy (FSHD).
Del-Zota Program Advances in Duchenne Muscular Dystrophy
Novartis is developing del-zota for patients with Duchenne muscular dystrophy who have mutations amenable to exon 44 skipping, commonly referred to as DMD44.
Duchenne muscular dystrophy is a severe genetic disorder characterized by progressive muscle degeneration and weakness. The disease is associated with mutations in the dystrophin gene, and exon-skipping approaches are intended to enable production of a shortened but potentially functional dystrophin protein in eligible patients.
Novartis has filed del-zota for accelerated approval in the United States. The U.S. Food and Drug Administration has granted the application Priority Review designation.
The regulatory progress of del-zota provides Novartis with another important development opportunity within its neuromuscular pipeline as the company evaluates the broader potential of its AOC technology.
The company will continue to work with regulators as the review process advances.
Del-Brax Program in FSHD
Novartis is also evaluating del-brax in patients with facioscapulohumeral muscular dystrophy, or FSHD.
The company recently reported positive Phase 1/2 biomarker data for the program and is planning to meet with the FDA to discuss potential next steps.
FSHD is another inherited neuromuscular disease characterized by progressive muscle weakness. The condition can affect muscles of the face, shoulder blades and upper arms, although disease manifestations and progression can vary considerably among patients.
The planned regulatory discussions for del-brax indicate that Novartis is continuing to evaluate opportunities across different neuromuscular diseases even as it reassesses the development strategy for del-desiran following the HARBOR results.
Full HARBOR Dataset Under Evaluation
Following the topline Phase 3 outcome, Novartis will now conduct a detailed review of the complete HARBOR dataset.
The company has not announced a final decision regarding the future of del-desiran. Instead, it said it will evaluate the full results and engage with health authorities to determine the most appropriate development path.
This process could include a detailed assessment of the secondary endpoints and exploratory analyses in which evidence of clinical activity was observed. Understanding the magnitude, consistency and clinical relevance of those findings will be important in determining whether further development could be justified.
The company will also consider the safety profile and the performance of the novel vHOT endpoint, which was selected as the primary measure of hand myotonia in the study.
The eventual regulatory and development strategy will depend on the totality of the evidence and discussions with health authorities.
Broader Implications for Neuromuscular Drug Development
The HARBOR results illustrate the challenges of developing treatments for complex genetic and neuromuscular diseases. Even when a therapeutic approach is supported by a compelling biological rationale, demonstrating statistically significant and clinically meaningful benefits in a large Phase 3 trial can be difficult.
Functional measures are particularly important in neuromuscular clinical development because changes in symptoms and disease biology do not always translate directly into improvements in everyday function.
The use of vHOT as the primary endpoint reflects the effort to develop objective and clinically relevant measures for hand myotonia. The HARBOR outcome may therefore also provide valuable information for future research into DM1 and the development of outcome measures for the disease.
For Novartis, the next step will be to understand why the primary endpoint did not reach statistical significance while signals of clinical activity emerged across secondary and exploratory measures.
Novartis Continues Focus on Serious Neuromuscular Diseases
Although the HARBOR results represent a setback for del-desiran, Novartis continues to pursue multiple programs in neuromuscular medicine.
The company’s AOC pipeline now includes programs targeting DM1, DMD and FSHD, providing a broad development platform across several serious inherited muscle disorders.
Del-zota has advanced to the regulatory stage in DMD44, with the FDA granting Priority Review following Novartis’ accelerated approval filing. Meanwhile, del-brax is moving toward regulatory discussions following positive Phase 1/2 biomarker data in FSHD.
These programs demonstrate Novartis’ broader commitment to developing genetic medicines for conditions where significant treatment gaps remain.
For del-desiran, the immediate focus will be on the detailed evaluation of HARBOR. The company has not ruled out further development and will work with health authorities before determining the next steps.
The Phase 3 outcome reinforces the complexity of developing therapies for DM1 but does not diminish the significant unmet need faced by patients and caregivers. Novartis said it remains committed to identifying the most appropriate path forward for del-desiran while continuing to advance its wider neuromuscular pipeline.
About DM1
Myotonic dystrophy type 1 (DM1) is a progressive, multisystem, heterogeneous neuromuscular disease caused by an expansion of CTG repeats in the DM1 protein kinase (DMPK) gene.³,⁴,⁵ People living with DM1 may experience a range of internal and systemic symptoms, including myotonia, muscle weakness and impaired hand function, which can affect everyday activities, independence, and quality of life.³
About Del-desiran
Del-desiran is an investigational antibody oligonucleotide conjugate (AOC) designed to target the underlying cause of DM1. The therapy consists of a muscle-targeting monoclonal antibody that binds to the transferrin receptor 1 (TfR1) and is conjugated to a small interfering RNA (siRNA) designed to induce degradation of disease-causing toxic DMPK messenger RNA (mRNA).⁶ Del-desiran received Orphan Drug, Fast Track and Breakthrough Therapy Designations from the US Food and Drug Administration (FDA), and Orphan Medicinal Product Designation in the European Union (EU).
About the HARBOR study
HARBOR (NCT06411288) is a global Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of del-desiran over 54 weeks in approximately 150 people living with DM1. Participants were randomized to receive del-desiran or placebo every eight weeks. The study assesses the impact of del-desiran across multiple functional aspects of DM1. The primary endpoint is vHOT and key secondary endpoints include muscle strength as measured by hand grip strength and quantitative muscle testing (QMT) total score, activities of daily living as measured by DM1-Activ, and mobility and physical function as measured by the 10-meter walk/run test (10mWRT).¹