Abstract / Summary
KM-819, a first-in-class inhibitor of Fas-associated factor 1 (FAF1), was investigated in a Phase 2 clinical trial in Korean patients with multiple system atrophy (MSA). Among 34 KM-819-treated patients, 11 met the case definition for suspected DILI, and 9 of these (26%) were adjudicated by an independent hepatic adjudication committee (HAC) as KM-819-related DILI; no cases occurred among the 34 patients receiving placebo. Blood samples for genetic analysis were available from only 6 of the 9 adjudicated DILI cases; therefore, an exploratory comparative genetic analysis was performed using DNA samples from a total of 16 patients treated with KM-819, including the 6 available DILI cases and 10 patients without DILI. Whole-genome sequencing (WGS) identified the HLA-DPB1*05:01:01:01 allele in all 6 patients with DILI, compared to only 1 of the 10 patients without DILI (p = 0.0009), suggesting a potential association between HLA-DPB1*05:01:01:01 and DILI due to KM-819. In this discovery cohort, HLA-DPB1*05:01:01:01 showed 100% sensitivity, 90.0% specificity, a positive predictive value (PPV) of 85.7%, and a negative predictive value (NPV) of 100% for DILI due to KM-819, albeit with wide confidence intervals reflecting the small sample size. Given the small sample size, exploratory nature of the analysis, and use of the same cohort for both discovery and performance estimation, these findings should be considered hypothesis-generating. Therefore, HLA-DPB1*05:01:01:01 should be regarded as a candidate risk marker specific to this Korean cohort, requiring validation in larger, independent, and ethnically diverse cohorts before its application in clinical risk stratification.