Significantly reduces expression of pathogenic protein Novartis SMA treatment effective in Huntington's disease

In Novartis' research and development process for spinal muscular atrophy (SMA), in addition to Zolgensma, there is also Branapam (LMI070)
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Branaplam is a small molecule RNA splicing regulator originally designed to enhance splicing of the SMN2 gene to treat spinal muscular atrophy
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After the trial failed, Novartis shifted its research to testing the drug as a treatment for Huntington's disease (HD)
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Novartis researchers found that after administration of Branaplam to HD patients, the patient's fibroblasts (skin cells), huntingtin mRNA and mutant huntingtin protein levels were significantly reduced
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Novartis is currently evaluating a Phase IIb trial in patients with early-stage overt HD, both to determine that Branaplam is safe and tolerable in adults, and to test whether Branaplam can reduce the mutant huntingtin protein in the patients' cerebrospinal fluid to levels that slow the disease
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Huntington's disease is a devastating neurodegenerative disease caused by CAG repeats in the first exon of the huntingtin gene, a mutation that produces defective mutant huntingtin proteins that aggregate and cause brain cell death, which in turn causes cognitive, A mental and movement disorder that causes the patient to twitch or writhe involuntarily, also known as chorea
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HD is a genetic disorder that is ultimately fatal, and the only current treatment is to manage symptoms
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RNA alternative splicing is an important mechanism for regulating gene expression and generating proteomic diversity.
The regulation of huntingtin gene splicing by Branaplam drug reduces the expression of huntingtin gene and mutant proteins by splicing an exon that marks RNA degradation
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Wild-type huntingtin is neuroprotective, and loss of it may leave patients vulnerable to the toxicity of mutant huntingtin, so accurate RNA splicing localization is critical
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Branaplam, an oral small molecule, can be widely distributed in key brain regions of patients, resulting in better efficacy and greater dosing flexibility, allowing lower drug doses when huntingtin is lowered too much
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In addition, in Huntington's disease, a slow-course neurodegenerative disease, mutant huntingtin proteins are expressed years before clinical symptoms appear
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To this end, Novartis has made a decision not to continue to develop Branaplam for SMA indications, but whether lowering huntingtin protein alone is enough to be effective in the disease remains to be determined and still needs to be clinically confirmed
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In March 2021, Roche and Ionis Pharmaceuticals discontinued III of HD treatment drug tominersen after failing to show greater efficacy than placebo and resulting in worse outcomes when administered more frequently compared to Novartis' HD study progress period research
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In addition, WAVE Life Sciences also shelved two of its antisense oligonucleotide (ASO) drug candidates because they did not reach their targets to produce therapeutic effects
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