Alumis Reports Positive Phase 1 Data for CNS Penetrant TYK2 Inhibitor A-005

Alumis Inc., a biopharmaceutical company focused on developing oral therapies for immune-mediated diseases, has announced promising results from a Phase 1 clinical trial of its drug candidate A-005. A-005 is a potent and selective inhibitor of tyrosine kinase 2 (TYK2) with the unique ability to cross the blood-brain barrier, making it a potential game-changer for treating neurological conditions. The trial assessed the safety, tolerability, and pharmacokinetics of A-005 in healthy participants, and the findings suggest that it could become a valuable treatment for multiple sclerosis (MS) and other related disorders.

A-005 stands out as the first allosteric TYK2 inhibitor capable of penetrating the central nervous system (CNS) to combat inflammation. The trial results have set the stage for a Phase 2 clinical trial in MS, which Alumis aims to initiate in the latter half of 2025. According to Dr. Jörn Drappa, Alumis' Chief Medical Officer, the Phase 2 trial will focus on confirming that the selective targeting of A-005 within the CNS can deliver tangible clinical benefits for patients suffering from MS and potentially pave the way for treating other neuroinflammatory and neurodegenerative disorders.

The Phase 1 trial involved a comprehensive evaluation of A-005 across several dosing cohorts. This included a single-ascending dose (SAD) portion with ten dose levels and a 14-day multiple-ascending dose (MAD) portion comprising five dose cohorts. The study monitored pharmacodynamic markers, notably phosphorylated STAT proteins, to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship. Findings showed that A-005 was well tolerated, with no serious adverse events reported, and demonstrated significant and sustained exposure in the cerebral spinal fluid (CSF). The drug reached peak concentrations rapidly and maintained half-lives up to 12 hours. Notably, A-005's exposure levels in the CSF were comparable to plasma levels, surpassing the necessary inhibition levels seen in cell-based assays.

Alumis plans to present these findings at the upcoming ACTRIMS Forum in February 2025. The trial involved 135 participants and included a specific cohort where a lumbar puncture was performed to measure A-005 concentrations in the CSF, further validating the drug's CNS penetration capabilities.

A-005, poised to become a first-in-class treatment, is being developed for neurological conditions like multiple sclerosis and potentially Parkinson's Disease. It aims to achieve maximal TYK2 inhibition both within the CNS and the peripheral system, thereby addressing a variety of conditions mediated by TYK2 genetics. TYK2 is a crucial protein in the signaling pathways of several proinflammatory cytokines, which have been implicated in various autoimmune and CNS diseases.

Alumis is leveraging its precision data analytics platform to build a robust pipeline of molecules targeting immune-mediated diseases. Their approach involves using these analytics to identify potential treatments that can function as standalone therapies or in combination with others. Alumis' flagship product, ESK-001, is a selective TYK2 inhibitor currently being tested for psoriasis and systemic lupus erythematosus. The company's focus on precision in drug development aims to bring forward the next generation of treatments to effectively manage and potentially cure immune dysfunctions.

With its innovative approach to drug development and a focus on maximizing TYK2 inhibition, Alumis is positioning itself as a leader in the treatment of immune-mediated and neurodegenerative diseases. The advancement of A-005 into further clinical trials marks a significant step in the ongoing battle against these challenging conditions.