Discussion
liver injury, NASH, headache
INFLAMMATION, EVENT, DRUG INTERACTIONS
At Week 12 in this Phase IIa trial, BI 1467335 strongly inhibited plasma AOC3 activity in a dose-dependent manner, along with showing a reduction in markers of liver injury. There was >80% inhibition of AOC3 activity for the entire 24-hour dosing interval from Week 4 onwards of treatment for doses ≥3 mg indicating adequate target engagement. The magnitude of AOC3 inhibition was similar to that seen in previous studies in healthy volunteers [Mackie et al., manuscript in preparation]. While strong inhibition of plasma AOC3 activity was seen earlier than Week 4 with the 6 mg and 10 mg doses of BI 1467335 in healthy volunteers, this was most likely due to a difference in the timing of sample collection rather than an actual difference in these populations.At Week 12 in this trial, the liver injury biomarkers ALT and CK-18 caspase decreased in response to treatment with 3–10 mg BI 1467335 in a dose-dependent manner, with a similar trend being observed for AST. ALT level is a marker of liver injury and elevated serum ALT indicates hepatic inflammation and liver injury in patients with various liver diseasesThe administration of up to 10 mg BI 1467335 once daily for 12 weeks did not identify any unexpected safety signals and BI 1467335 was well tolerated by the patients with NASH enrolled in this trial. Only one patient in the 6 mg BI 1467335 treatment group discontinued treatment due to a moderate TEAE (headache) and both patients who experienced a liver injury event (TEAESI) recovered and completed the trial. The safety profile of BI 1467335 in the present trial was consistent with that seen in Phase I trials in healthy volunteers (Mackie, et al. manuscript in preparation). Further development of BI 1467335 was stopped due to the risk of drug interactions of the compound with monoamine oxidase (MAO)-B in NASH patients identified in another Phase I trialIn conclusion, BI 1467335 strongly inhibited AOC3, was well tolerated at all tested doses, and showed dose-dependent reductions in serum ALT and CK-18 caspase, resulting in >10% placebo-corrected reduction from baseline for ≥6 mg doses.