Objective: This study aimed to identify genetic risk factors linked to a drug candidate for MSA (KM-819)-associated drug-induced liver injury (DILI) in patients with multiple system atrophy (MSA).

Background: KM-819, a first-in-class inhibitor of Fas-associated factor 1 (FAF1), was previously presented at the 2025 International Congress of Parkinson’s Disease and Movement Disorders with clinical evidence suggesting potential neuroprotective effects in MSA (C. Lee et al., 2025). However, signs of DILI were observed in 9 out of 34 KM-819-treated patients. To identify potential genetic risk factors associated with KM-819-induced DILI, we conducted a comparative genetic analysis of DNA samples from KM-819-treated MSA patients with and without DILI.

Method: Genomic DNA was obtained from 16 MSA patients treated with KM-819, including 6 who developed DILI and 10 who did not. Whole-genome sequencing (WGS) was performed using short-read next-generation sequencing (NGS) to comprehensively identify genetic variants. We compared variants uniquely present or enriched in the DILI group, with particular attention to those previously associated with drug-induced hepatotoxicity. Based on these initial findings, the HLA region emerged as a strong candidate for further investigation. To achieve higher resolution in this highly polymorphic locus, targeted long-read NGS was subsequently conducted.

Results: WGS identified the HLA-DPB1*05:01:01:01 allele in all 6 patients who developed DILI, compared to only 1 of the 10 patients who did not (p = 0.0009), indicating a strong association between HLA-DPB1*05:01:01:01 and DILI due to KM-819. These findings suggest that HLA-DPB1*05:01:01:01 may increase predisposition to DILI from KM-819 in patients with MSA. As a predictive biomarker, HLA-DPB1*05:01:01:01 demonstrated 100% sensitivity, 90% specificity, a positive predictive value of 85.7%, and a negative predictive value of 100% for DILI due to KM-819, supporting its potential role in clinical risk stratification.

Conclusion: These findings suggest that HLA-DPB1*05:01:01:01 may predispose patients to KM-819-induced liver toxicity. Therefore, excluding patients with the HLA-DPB1*05:01:01:01 allele, who may represent a high-risk group for KM-819, might be considered in future clinical trials to enhance both patient safety and the likelihood of trial success.

References: C. Lee, C. Barlow, E. Kim, D. Kim, D. Doudet, J. Ko, M. Goh. PET and Clinical Evidence for Neuroprotective Effects of KM-819 on MSA [abstract]. Mov Disord. 2025; 40 (suppl 1).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacogenomic-analysis-of-km-819-related-hepatotoxicity-in-patients-with-multiple-system-atrophy/