Novartis Repurposes SMA Drug Branaplam to Significantly Reduce Mutant Huntingtin Protein in Huntington’s Disease

Compiled by Draven

In Novartis' research and development process for Spinal Muscular Atrophy (SMA), in addition to Zolgensma, there is also Branaplam (LMI070). Branaplam is a small molecule RNA splicing modulator, originally designed to enhance the splicing of the SMN2 gene for the treatment of Spinal Muscular Atrophy. After the trial failure, Novartis shifted its research to test the drug for the treatment of Huntington's Disease (HD).

Recently, Novartis researchers found that after administering Branaplam to HD patients and examining their fibroblasts (skin cells), both the Huntington mRNA and mutant Huntingtin protein levels were significantly reduced.

Novartis is currently conducting a Phase IIb trial evaluation in early manifest HD patients to determine if Branaplam is safe and tolerable for adults and to test whether Branaplam can reduce mutant huntingtin protein in the cerebrospinal fluid of patients to a level that slows the disease.

Huntington's disease is a devastating neurodegenerative disorder caused by CAG repeats in the first exon of the huntingtin gene, which leads to the production of a defective mutant huntingtin protein. The aggregation of this protein causes brain cell death, resulting in cognitive, psychiatric, and motor impairments, leading to involuntary twitching or writhing movements, also known as chorea. HD is a hereditary condition and ultimately fatal, with current treatments only aimed at controlling symptoms.

RNA Alternative Splicing is a Key Mechanism for Regulating Gene Expression and Generating Proteomic Diversity. Branaplam modulates the splicing of the Huntington gene by incorporating an exon marked for RNA degradation, thereby reducing the expression of the Huntington gene and mutant protein. Wild-type Huntington protein plays a role in neuroprotection, and its loss may render patients more susceptible to the toxic effects of mutant Huntington protein; thus, precise RNA splicing targeting is crucial.

As an oral small molecule, Branaplam can be widely distributed in critical brain regions of patients, thereby achieving better efficacy and offering greater dose flexibility, allowing for dose reduction when there is excessive lowering of huntingtin protein. Additionally, for a slowly progressing neurodegenerative disease like Huntington's disease, the mutant huntingtin protein is expressed years before clinical symptoms appear.

To this end, Novartis made the decision not to continue the development of Branaplam for the SMA indication. However, it remains to be determined whether solely reducing huntingtin protein is sufficient to be effective against the disease, and clinical validation is still required.

Compared with Novartis' HD research progress, in March 2021, Roche and Ionis Pharmaceuticals terminated the Phase III study of the HD treatment drug tominersen due to its failure to show higher efficacy than a placebo and worse outcomes when administered more frequently. Additionally, WAVE Life Sciences shelved its two antisense oligonucleotide (ASO) candidate drugs for failing to reach the target and produce therapeutic effects.

Reference Source: Novartis’ Fortuitous Discovery Could Deliver Breakthrough in Huntington’s Disease