Objective: To assess the effect of KM-819 on the progression of multiple system atrophy (MSA).

Background: Parkinson’s brain is associated with increased expression of the FAF1 protein, which promotes dopamine cell death. KM-819, an inhibitor of FAF1, has shown neuroprotective effects in animal models of MSA. We conducted a phase 2 trial of KM-819 for MSA patients, which was put on hold due to the unexpected occurrence of drug-induced liver injury (DILI). We analyzed the data collected before trial termination.

Method: The KM-819 trial was a randomized, double-blind, placebo-controlled study conducted over 9 months. The effects of KM-819 were assessed through clinical tests every 3 months and PET scans using [18F]FP-CIT, a ligand for the dopamine transporter (DAT), before and after treatment. At the time of drug withdrawal, 6 patients had completed post-treatment PET scans (3 KM-819, 3 placebo). Additionally, 15 patients completed the UPDRS III assessment over the 6-month period before and after drug withdrawal (7 KM-819, 8 placebo). The mechanism underlying KM-819-associated DILI in MSA patients were also investigated.

Striatal DAT binding ratios were compared between the KM-819 and placebo groups, as well as with age-matched healthy controls (n=17). Serial UPDRS III data collected 6 months before and after drug withdrawal were analyzed between the two groups. Statistical analysis employed both parametric and non-parametric methods with the significant level set at p ≤ 0.10.

Results: Results: Striatal FP-CIT binding ratios at 9 months showed a significant decline from baseline in the placebo group(p<0.001) but not in the KM-819 group. Compared to healthy controls, striatal FP-CIT binding ratios significantly decreased in the placebo group (p=0.003) but not in the KM-819 group (Fig 1). Changes in UPDRS III scores over 6 months showed significant differences before and after withdrawal of KM-819 (p=0.07). In contrast, no significant difference was observed in UPDRS III scores before and after placebo withdrawal (Fig 2).

Conclusion: Our PET imaging data suggest limited degeneration of the DA system in the KM-819 group, aligning with UPDRS III observations. These findings support the conclusion that KM-819 treatment slowed MSA progression. Regarding DILI, we conclude that KM-819-associated DILI is most consistent with drug-induced autoimmune-like hepatitis of acute onset (see the supplement for details).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pet-and-clinical-evidence-for-neuroprotective-effects-of-km-819-on-msa/