Novartis Suspends Phase 2 Study of Huntington Disease Agent Branaplam


Branaplam, an mRNA splicing modifier, was being evaluated in a cohort of 75 participants with early manifest Huntington disease, using change in mutant huntingtin protein as the primary outcome measure.

According to a community update, Novartis has temporarily suspended dosing of the phase 2 VIBRANT-HD study (NCT05111249) evaluating its experimental Huntington disease (HD) drug branaplam, citing issues with nerve damage that was reported in treated participants.1

Following a regularly planned data review, an Independent Data Monitoring Committee made the recommendation to stop dosing, which was endorsed by the VIBRANT-HD steering committee, a group made up of medical professionals and community members. In a statement expressing its gratitude for those involved in the program, Novartis noted that it plans on providing updates when more information becomes available in the coming months.

Branaplam, also called LMI070, was developed originally to treat spinal muscular atrophy. In the summer of 2021, Novartis made the decision to stop developing the drug for children with SMA, to focus its efforts on adults with HD. The decision was supported by data in HD animal models, and early safety trials of branaplam in healthy adults.

VIBRANT-HD, a double-blind, placebo-controlled study, began 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 were using reduction percentage of mutant huntingtin (HTT) protein levels at the end of the 17-week treatment period as the primary end point.2

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There are currently no disease-modifying therapies approved for HD that delay onset or slow progression of the disease. In December 2021, the FDA granted fast track designation for the agent, thus expediting the process of review. An investigational oral DMT, branaplam 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.3

In the update, Novartis wrote, "We wish to highlight how grateful we are to the people participating, and their families, and how important it is for those in the study to continue to be assessed. With this participation, the community will add to the body of knowledge about HD, help continue progress toward new treatments, and assist us in making the best decisions regarding the future development of branaplam. The level of engagement of everyone in the HD community is incredible and this provides us all with hope."1

The challenge of developing therapeutics for HD has been on display in recent years. In March 2021, another company, Wave Life Sciences, announced the discontinuation of 2 HD agents—WVE-120102 and WVE-120101—based on early results from a phase 1b/2a study, which showed no dose-response across all dose levels tested.4

Around the same time, another promising agent, tominersen, from Roche, the first to successfully target and reduce levels of mutant HTT protein, was also discontinued. Almost a year after the news, Roche announced it was designing a new phase 2 trial for the drug, stating that a post-hoc analysis showed a possible benefit for a subgroup of patients who are younger with less disease burden.5

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