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• W4387301624 abstract "Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of the nine polyQ diseases due to abnormal expansion of the CAG trinucleotide repeat in the gene encoding androgen receptor (AR) and aggregation of the mutant AR protein. The disease is X-linked and affects the lower motor neurons and skeletal muscles characterized by slow progression and late onset of >30-40 years of age. The pathophysiology of SBMA is complex and thought to associate with toxicity mediated by the abnormal polyQ-expanded AR, resulting in dysregulation of AR transcriptional activities, impaired protein quality control, and increased oxidative stress and inflammation. JM17, a novel small molecule, is an effective Nrf2 activator known to induce antioxidant response. Previous study in a SBMA mouse model demonstrated that JM17 improved motor functions and reduced mutant AR aggregates in muscles via activating Nrf2, Nrf1, and Hsf1 pathways. Here, we provided further evidence that JM17 suppressed pro-inflammatory cytokines and exhibited neuroprotective effect through free radical scavenging. Our study suggested JM17 activated Nrf2 by disrupting its interaction with KEAP1, similar to other known Nrf2 activators. In a recently completed Phase 1 study in healthy volunteers (NCT04392830), JM17 was well-tolerated and demonstrated a dose-proportional PK properties over a broad range and no accumulation in systemic exposure after 7-day repeated oral dosing. A current first-in-patient randomized, double-blind, placebo-controlled Phase 1/2a study in SBMA patients is under progress to assess the safety, pharmacokinetic and pharmacodynamic effects of JM17 (NCT05517603). In summary, the overall scientific evidence supports JM17 as an attractive therapeutic approach for SBMA by enhancing degradation of mutant AR aggregates and reducing oxidative stress and inflammation. Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of the nine polyQ diseases due to abnormal expansion of the CAG trinucleotide repeat in the gene encoding androgen receptor (AR) and aggregation of the mutant AR protein. The disease is X-linked and affects the lower motor neurons and skeletal muscles characterized by slow progression and late onset of >30-40 years of age. The pathophysiology of SBMA is complex and thought to associate with toxicity mediated by the abnormal polyQ-expanded AR, resulting in dysregulation of AR transcriptional activities, impaired protein quality control, and increased oxidative stress and inflammation. JM17, a novel small molecule, is an effective Nrf2 activator known to induce antioxidant response. Previous study in a SBMA mouse model demonstrated that JM17 improved motor functions and reduced mutant AR aggregates in muscles via activating Nrf2, Nrf1, and Hsf1 pathways. Here, we provided further evidence that JM17 suppressed pro-inflammatory cytokines and exhibited neuroprotective effect through free radical scavenging. Our study suggested JM17 activated Nrf2 by disrupting its interaction with KEAP1, similar to other known Nrf2 activators. In a recently completed Phase 1 study in healthy volunteers (NCT04392830), JM17 was well-tolerated and demonstrated a dose-proportional PK properties over a broad range and no accumulation in systemic exposure after 7-day repeated oral dosing. A current first-in-patient randomized, double-blind, placebo-controlled Phase 1/2a study in SBMA patients is under progress to assess the safety, pharmacokinetic and pharmacodynamic effects of JM17 (NCT05517603). In summary, the overall scientific evidence supports JM17 as an attractive therapeutic approach for SBMA by enhancing degradation of mutant AR aggregates and reducing oxidative stress and inflammation." @default.
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• W4387301624 date "2023-10-01" @default.
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• W4387301624 title "P446 A novel Nrf2 activator with pleiotropic effects for the treatment of SBMA in a phase 1/2a study" @default.
• W4387301624 doi "https://doi.org/10.1016/j.nmd.2023.07.484" @default.
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