Novartis Discontinues Huntington Disease Program Following Phase 2b Study


Branaplam, an mRNA splicing modifier, joins the many unsuccessful agents for Huntington disease as biopharma continues to be challenged with trial holds and failures.

News from Novartis’s year-end report recently announced the discontinuing of several programs, including its Huntington disease (HD) program, based on assessment of potential benefit-riskfrom phase 2b VIBRANT-HD study (NCT05111249).The study, which had dosing temporarily suspended in August 2022, was assessed its lead candidate branaplam (LMI070).2

VIBRANT-HD was a double-blind, placebo-controlled study, that started in early 2022 and was expected to include 75 participants with early manifest HD. The core treatment period, which proceeded screening and baseline assessments, included a dose range finding period of 17 weeks, followed by a blinded extension of 53 weeks. Investigators used reduction percentage of mutant huntingtin (HTT) protein levels at the end of the 17-week treatment period as the primary end point.3

In the summer of 2021, Novartis decided to stop the development of branaplam, originally a treatment for children with spinal muscular atrophy, to focus its efforts on adults with HD. Data in HD animal models and early safety trials of branaplam in healthy adults supported the decision.

READ MORE: FDA Accepts Supplemental NDA for Valbenazine as Therapy for Huntington Disease Chorea

Currently, there are no approved disease-modifying therapies for HD that delay onset or slow disease progression. In December 2021, the FDA granted fast track designation for the agent to speed up the review process. Branaplam, an investigational oral disease-modifying therapy, is an mRNA splicing modifier that targets the underlying pathophysiology in HD by modifying HTT mRNA throughout the brain and body, resulting in lower levels of HTT protein.4

In recent years, the development of therapeutics for HD has been a continuing challenge. Another company in March 2021, Wave Life Sciences, announced the discontinuation of 2 HD agents—WVE-120102 and WVE-120101 —according to early results from a phase 1b/2a study, which demonstrated no dose-response across all dose levels tested.5

Around the same time, Roche’s tominersen was also discontinued although the agent was the first to successfully target and reduce levels of mutant HTT protein. Roche then announced the design for a new phase 2 trial for the drug almost a year later, stating that a post-hoc analysis displayed a possible benefit for a subgroup of younger patients with less disease burden.6

1. Novartis Fourth Quarter and Full Year 2022. Condensed Financial Report - Supplementary Data. Novartis. February 1, 2023. Accessed February 1, 2023.
2. Community update: status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. News release. Novartis. August 24, 2022. Accessed February 1, 2023.
3. Updated August 25, 2022. Accessed February 1, 2023.
4. Novartis receives FDA fast track designation for branaplam (LMI070) for the treatment of Huntington’s disease. News release. Novartis. December 16, 2021. Accessed February 1, 2023.
5. Wave Life Sciences Provides Update on Phase 1b/2a PRECISION-HD Trials. News release. March 29, 2021. Accessed February 1, 2023.
6. Ionis' partner to evaluate tominersen for Huntington's disease in new Phase 2 trial. News release. Ionis. January 18, 2022. Accessed February 1, 2023.

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