Casma Therapeutics has nominated CSM-101, a first-in-class TRPML1 agonist, as its lead development candidate for treating neurodegenerative diseases, marking a significant milestone in targeting lysosomal dysfunction through a novel therapeutic approach. The Cambridge-based biotechnology company announced the nomination on June 5, 2025, positioning CSM-101 for initial development in Gaucher's disease patients with Parkinson's disease (GD-PD), with potential expansion into GBA-associated Parkinson's disease (GBA-PD) and broader Parkinson's disease populations.
Novel Mechanism Targets Lysosomal Dysfunction
CSM-101 represents a highly differentiated, orally bioavailable small molecule that restores lysosomal function by activating TRPML1, a critical lysosomal ion channel. TRPML1 regulates essential aspects of lysosomal function, including lysosomal pH and cellular waste clearance. Dysfunction of this channel leads to impaired degradation and accumulation of toxic substrates, contributing to the pathology of neurodegenerative and lysosomal storage diseases.
"Our nomination of CSM-101 marks a major milestone for Casma and the field as we translate our deep expertise in autophagy and lysosomal biology into therapeutic candidates," said Frank Gentile, Ph.D., Chief Executive Officer of Casma Therapeutics. "Our preclinical data demonstrate that activating TRPML1 effectively addresses lysosomal dysfunction, a central driver in both rare and prevalent neurodegenerative diseases."
Promising Preclinical Results Across Disease Models
In preclinical studies, CSM-101 demonstrated high CNS exposure and potent activity across clinically relevant models. The compound showed significant reductions in toxic lipid levels, decreased neuroinflammation, and improved survival in multiple Gaucher's disease models. In GBA-associated Parkinson's disease and idiopathic Parkinson's disease models, CSM-101 reversed pathological phenotypes, lowered toxic alpha-synuclein levels, and preserved dopaminergic neurons, supporting its potential as a disease-modifying therapy.
These results are particularly significant given the genetic connection between Gaucher's disease and Parkinson's disease. Mutations in the GBA1 gene, which cause Gaucher's disease, are the most common genetic risk factor for Parkinson's disease and disrupt lysosomal homeostasis. Restoration of TRPML1 activity has been shown to correct lysosomal defects in preclinical models across this spectrum of diseases.
Strategic Development Approach
Leon Murphy, Ph.D., Chief Scientific Officer of Casma Therapeutics, emphasized the company's targeted strategy: "CSM-101 represents a scientifically validated and targeted approach to restoring lysosomal function through TRPML1 activation, addressing a central driver of disease progression in Gaucher's disease and Parkinson's disease. By focusing first on genetically defined patient populations and leveraging robust biomarkers, we are positioned to deliver rapid clinical proof of concept with the potential for meaningful benefits for patients."
The favorable pharmacokinetic and safety profiles observed in preclinical studies, combined with the mechanistic data, provide strong translational rationale for clinical development. Casma plans to file an Investigational New Drug (IND) application with the US FDA for CSM-101 in the first half of 2026.
Broader Platform Potential
Beyond CSM-101, Casma Therapeutics is advancing targeted therapies that engage lysosomal or autophagy systems to selectively degrade disease targets across neurodegeneration, oncology, inflammation, and metabolic disorders. The company's PHLYT™ degrader platform aims to unlock new therapeutic possibilities through selective autophagy-targeted degradation of large, complex disease targets such as organelles, protein aggregates, and signaling complexes.
The company will present preclinical data supporting CSM-101's progression into IND-enabling studies at the GBA1 Meeting 2025, taking place June 5-7 in Montreal, Canada, providing the scientific community with detailed insights into this novel therapeutic approach.
