Neurology · Medical Literature
Comparison of ABBV-552 Safety and Pharmacokinetics in Healthy Asian and Western Adults.
Abstract
ABBV-552, a positive modulator of synaptic vesicle glycoprotein 2A (SV2A), was under investigation as a treatment for cognitive impairment related to Alzheimer's disease. This Phase 1, multicenter, open-label, parallel cohort study (NCT05686980) was conducted to examine the pharmacokinetics (PK), safety, and tolerability of ABBV-552 in healthy adult Japanese and Han Chinese participants and to compare PK and safety findings with healthy adult Western participants from previous studies. Japanese participants in Cohort 1 (N = 10) received three ascending single oral doses (5, 15, and 40 mg) of ABBV-552 with a washout of 7 days between doses. Han Chinese participants in Cohort 2 (N = 7) received a single oral dose of 40 mg ABBV-552. After a single oral dose of 40 mg ABBV-552, PK was comparable between both cohorts. Additionally, the range of individual ABBV-552 concentrations and mean 24-h profiles were comparable with historical data in healthy adult Western participants. In this small study population, single doses of ABBV-552 were well tolerated at all tested doses. Common adverse events reported were dizziness (39%), somnolence (11%), and fatigue (11%). No unique safety signals following single dose ABBV-552 administration were observed in the Japanese or Han Chinese populations examined compared with the previously examined Western population.
Clinical relevance
Are the pharmacokinetics, safety, and tolerability of single oral doses of ABBV-552 (a positive SV2A modulator) in healthy adult Japanese and Han Chinese participants comparable to those previously observed in healthy adult Western participants? __SNAPSHOT__ {"studyDesign":"Phase 1, multicenter, open-label, parallel cohort, single- and ascending-dose study (NCT05686980)","setting":"Multicenter; country or institution type not reported in abstract","sampleSize":"n=17 total (Cohort 1 [Japanese]: n=10; Cohort 2 [Han Chinese]: n=7); Western historical comparators from prior separate studies","population":"Healthy adult Japanese (Cohort 1) and Han Chinese (Cohort 2) participants; prior Western adult healthy volunteers from historical studies. Patients with Alzheimer's disease or cognitive impairment were not enrolled.","intervention":"ABBV-552 oral capsules: Cohort 1 received three ascending single doses (5 mg, 15 mg, and 40 mg) with 7-day washout periods between doses; Cohort 2 received a single oral dose of 40 mg","comparator":"No concurrent control arm; pharmacokinetic and safety data were compared with historical data from healthy adult Western participants enrolled in prior Phase 1 studies","primaryOutcome":"Pharmacokinetics (Cmax, AUC, Tmax, and 24-hour concentration-time profiles) of ABBV-552; safety and tolerability (adverse events, vital signs, 12-lead ECG, clinical laboratory values)","followUp":"Plasma PK sampling up to 144 hours post-dose; overall study duration not reported in abstract","fundingSource":"Industry (AbbVie, Inc.; all authors are AbbVie employees)"}
Key findings
All 17 participants completed the study and were included in safety analyses. Among Japanese participants (Cohort 1), Cmax and AUC increased dose-proportionally across the 5, 15, and 40 mg doses. At the 40 mg dose, Tmax and Cmax were comparable between Japanese and Han Chinese cohorts; however, mean AUC for Han Chinese participants was approximately 20% higher than for Japanese participants. Individual concentration-time profiles at 40 mg were similar between both Asian cohorts and consistent with historical data from healthy adult Western participants. Formal statistical comparisons with confidence intervals or p-values were not reported. No NNT or NNH is calculable from available data. Regarding safety: dizziness was the most common adverse event (39%), followed by somnolence, fatigue, and papule (11% each). All adverse events were Grade 1 (61%) or Grade 2 (11%), and all resolved. There were no serious adverse events. No unique safety signals were identified relative to Western historical data, and no clinically significant laboratory or ECG findings were reported. Transient liver enzyme elevations were noted but were not clinically significant and normalized at follow-up.
Practice implications
This study established that single oral doses of ABBV-552 up to 40 mg are well-tolerated in healthy adult Japanese and Han Chinese participants, with a CNS-related adverse event profile (dizziness, somnolence, fatigue) consistent with prior Western experience. The PK data support broad ethnic comparability, though the ~20% higher AUC observed in Han Chinese versus Japanese participants warrants attention and may warrant further exploration in larger samples. The study did NOT establish efficacy, did not enroll patients with Alzheimer's disease or cognitive impairment, and was not powered to detect clinically meaningful ethnic PK differences. The Western comparison was historical and cross-study, not a concurrent randomized control, introducing potential confounding. Importantly, a separate Phase IIb randomized controlled trial of ABBV-552 in mild Alzheimer's disease (Lynch et al., Alzheimer's & Dementia, 2025) failed to demonstrate efficacy over placebo on the primary cognitive endpoint (ADAS-Cog 14 at 12 weeks), and the developer has indicated that further development of ABBV-552 for AD is not currently warranted. These Phase 1 ethnic PK data therefore address a regulatory bridging question but do not change the overall clinical development trajectory. Only the abstract was available for direct review; full PK parameter tables and statistical analyses were not fully accessible, limiting detailed interpretation. __LIMITATIONS__ Extremely small sample size (n=10 Japanese, n=7 Han Chinese) severely limits statistical power and generalizability; the study was likely designed for descriptive regulatory bridging purposes, not hypothesis testing.,Open-label design with no concurrent control; Western comparison is cross-study historical, introducing potential for selection bias and cohort-level confounding.,Healthy adult volunteers only — findings cannot be extrapolated to older patients with Alzheimer's disease, who differ markedly in body composition, comorbidities, polypharmacy, and drug metabolism.,The approximately 20% higher AUC in Han Chinese versus Japanese participants is noted descriptively; no formal equivalence testing, confidence intervals, or p-values are reported, precluding conclusions about the clinical significance of this difference.,Follow-up duration covers only single-dose PK (up to 144 hours); multiple-dose steady-state PK differences between ethnic groups are not assessed.,All authors are AbbVie employees and the study is industry-funded, creating significant risk of publication bias and selective reporting.,The truncated abstract suggests incomplete adverse event data (text appears cut off at 'No unique sa...'), limiting full safety characterization.,Safety outcomes are graded descriptively; formal statistical testing of adverse event rates between cohorts or versus historical Western data is not reported.,The broader clinical context is critical: the Phase IIb trial of ABBV-552 in mild AD failed to show efficacy over placebo, substantially limiting the relevance of further PK bridging work. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ In this small Phase 1 bridging study (n=17), single oral doses of ABBV-552 demonstrated broadly comparable pharmacokinetics and a consistent CNS-related adverse event profile (primarily Grade 1–2 dizziness and somnolence) across healthy Japanese, Han Chinese, and historical Western adults, supporting ethnic PK similarity for regulatory purposes. Clinicians should be aware that a Phase IIb trial of ABBV-552 in mild Alzheimer's disease failed to show cognitive benefit over placebo, and the compound's development for AD is not currently being pursued further. These PK findings, while methodologically sound for their limited bridging purpose, have no direct implications for clinical practice at this time.