Mendelian randomization to inform a clinical trial of chitotriosidase inhibition for pulmonary sarcoidosis

BackgroundCurrent sarcoidosis treatment is limited to glucocorticoids and immunosuppressants that provide symptomatic relief but carry significant side effects. Chitotriosidase 1 (CHIT1) has been correlated with disease severity and is highly expressed in sarcoidosis granulomas, making it an attractive therapeutic target for disease modification. Research design and methodsWe performed Mendelian Randomization (MR) analysis using published genome-wide association studies to evaluate the causal relationship between CHIT1 levels and sarcoidosis risk. Eight single nucleotide polymorphisms were selected as instrumental variables from multiple sarcoidosis datasets. ResultsMR demonstrated a significant positive causal effect of CHIT1 levels on sarcoidosis risk (p = 0.0355), reproduced across multiple datasets. Building on this genetic evidence, a proof-of-concept study with a CHIT1 inhibitor, OATD-01, was designed (KITE study) that represents an innovative approach highlighting academic-industry partnership to identify therapeutic targets, develop supporting data to de-risk clinical trial development, and implement novel trial endpoints to assess treatment promise. An innovative 18F-FDG-PET/CT-based primary endpoint was proposed for the KITE study to capture anti-granulomatous effects. ConclusionsThese genetic analyses support CHIT1 as a causal factor in sarcoidosis pathogenesis, providing strong rationale for targeting CHIT1 therapeutically. The evidence supports the ongoing development of OATD-01, a first-in-class CHIT1 inhibitor, currently being evaluated in the KITE study using this novel imaging biomarker approach that may provide a template for future sarcoidosis clinical trials. Trial RegistrationThe trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT06205121).