Novartis HARBOR Phase III trial misses primary endpoint in DM1
Novartis has reported that its Phase III HARBOR study evaluating del-desiran (delpacibart etedesiran) in myotonic dystrophy type 1 (DM1) did not meet its primary endpoint. The trial, which enrolled approximately 150 patients over 54 weeks, assessed improvement in video hand opening time (vHOT), a novel digital measure of hand myotonia. The drug failed to achieve a statistically significant improvement versus placebo on that measure.
The company said safety findings were consistent with previously reported data and that evidence of clinical activity was seen across secondary endpoints and exploratory analyses, including measures of hand grip strength, activities of daily living, and a 10-metre walk/run test. Novartis said it is reviewing the full dataset and intends to engage with regulatory authorities before deciding on the most appropriate next step for the programme.
Shreeram Aradhye, President of Development and Chief Medical Officer at Novartis, said: "Developing therapies for a complex disease like DM1 remains challenging, and setbacks are part of scientific progress."
Pipeline context
Del-desiran is one of three antibody oligonucleotide conjugate (AOC) therapies Novartis acquired through its purchase of Avidity Biosciences. The AOC platform works by coupling a muscle-targeting monoclonal antibody, directed at transferrin receptor 1 (TfR1), with a small interfering RNA (siRNA) designed to degrade toxic DMPK messenger RNA, the molecular driver of DM1. Prior to the Phase III readout, del-desiran held FDA Orphan Drug, Fast Track and Breakthrough Therapy designations, as well as Orphan Medicinal Product Designation in the EU, reflecting the genuine medical need in a disease with no approved treatments.
The setback does not derail the broader AOC programme. A second asset from the same platform, delpacibart zotadirsen (del-zota) targeting Duchenne muscular dystrophy patients with exon 44-amenable mutations, has been filed for US accelerated approval and granted FDA priority review. A third candidate, delpacibart braxlosiran (del-brax) in facioscapulohumeral muscular dystrophy, is advancing towards an FDA meeting following positive Phase I/II biomarker data. Novartis said it maintains its five-to-six per cent five-year sales compound annual growth rate guidance for 2025 to 2030.
Market landscape and regulatory read-across
DM1 remains one of the most intractable targets in rare neuromuscular disease. The condition is caused by an expansion of CTG repeats in the DMPK gene and presents with a wide and heterogeneous symptom burden, which has historically made endpoint selection difficult. The choice of vHOT as a primary endpoint was novel and, while it has been explored using machine-learning techniques, it had not previously supported a pivotal approval. Regulators and investigators may now scrutinise whether the endpoint was sufficiently sensitive or validated for a Phase III setting, a question that will shape discussions with the FDA and EMA.
The broader antibody-oligonucleotide conjugate space is increasingly competitive. Wave Life Sciences and others have pursued RNA-targeting approaches in DM1, and Dyne Therapeutics has an AOC platform of its own in development for overlapping indications. A failed Phase III primary endpoint in DM1 will focus attention on whether muscle-directed RNA knockdown can translate into robust functional improvements in a disease with substantial systemic involvement, or whether composite endpoints that capture more of the disease burden are required. Novartis's willingness to press on with regulatory discussions suggests it sees salvageable value in the secondary data, but the path to approval is materially less clear than it was before the HARBOR readout.