To characterize the pharmacokinetics (PK), safety and tolerability following single doses of ABBV-CLS-7262 in healthy Japanese and Han Chinese subjects compared to healthy Western subjects.
ABBV-CLS-7262 is a small molecule activator of eIF2B, the guanine nucleotide exchange factor for eukaryotic translation initiation factor (eIF2). eIF2 is an important node in the Integrated Stress Response (ISR), a pathway implicated in the pathophysiology of several neurological conditions, including Amyotrophic Lateral Sclerosis (ALS) and Vanishing White Matter (VWM) disease. ABBV-CLS-7262 is being studied in ALS (NCT04948645, NCT05740813) and VWM (NCT05757141). To inform future global clinical studies, an Asian PK study was conducted.
A double-blinded, randomized, placebo-controlled single dose study was performed in healthy Western, Japanese and Han Chinese subjects. Three doses were administered in Japanese and Western subjects. The highest dose was administered in the Han Chinese subjects. Serial blood samples were analyzed for drug levels.
PK parameters were obtained by noncompartmental analyses. ANCOVA analyses were performed on log transformed Cmax and AUC, comparing the PK parameters in Japanese and Han Chinese subjects to those in Western subjects.
After single oral doses, Cmax and AUC were comparable between Japanese and Western subjects, with central value estimate (95% CI) of Cmax and AUCinf ratio at 1.152 (0.865 – 1.534) and 0.875 (0.671 – 1.140), respectively. After single oral doses, Cmax and AUC were comparable between Chinese and Western subjects, with central values estimate (95% CI) of Cmax and AUC inf ratio at 1.110 (0.616 – 1.999) and 1.065 (0.691 – 1.641), respectively.
All doses were well tolerated. All adverse events were mild and transient. There were no clinically significant laboratory or ECG findings.
No meaningful differences in exposures after a single oral dose of ABBV-CLS-7262 in Japanese and Han Chinese vs Western subjects were observed. Dose adjustments are not needed for Asian populations.