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.

Cognitive impairment is a key symptom of many central nervous system disorders. ¹ This extends to neurodegenerative disorders like Alzheimer's disease (AD) and other types of dementia. ¹ Synaptic density is associated with cognitive performance, with lower synaptic density associated with poorer performance on cognitive tests. ² , ³ There are currently limited treatment options for dementia‐related disorders that beneficially impact cognitive impairment.

New mechanisms that could treat impaired cognitive functioning are under investigation. ⁴ , ⁵ One approach is to improve synaptic transmission via modulation of the presynaptic axon terminal. Synaptic vesicle glycoprotein 2 (SV2A) is a vesicle‐specific keratan sulfate integral membrane proteoglycan that is present in all brain regions. ⁶ , ⁷ SV2A plays a role in regulating calcium‐evoked vesicle fusion and neurotransmitter release by interactions with synaptotagmin. ² , ³ , ⁸

ABBV‐552 is a novel, high‐affinity positive modulator of SV2A that has shown pro‐cognitive activity in a range of preclinical animal models of cognitive deficit. ⁴ ABBV‐552 was under investigation as a treatment for AD‐related cognitive decline due to its direct modulation of synaptic function. A first‐in‐human (FIH) randomized controlled trial demonstrated dose‐proportional SV2A occupancy in the brains of healthy male participants. ⁴ Administration of ABBV‐552 as a single oral dose up to 80 mg was tolerated by participants with no serious adverse events (SAEs) or any adverse events that led to discontinuation. ⁴ The most common treatment‐emergent adverse events (TEAEs) observed in the FIH study were mild in severity and included dizziness, hypersomnia, and somnolence. ⁴

ABBV‐552 is primarily eliminated via hepatic metabolism, with less than 1% of parent drug recovered in urine and feces. ⁹ This occurs mainly through oxidative metabolism via cytochrome P450 (CYP) 3A4 and, to a minor extent, CYP2C19. ⁹ Differences in frequencies of polymorphisms related to drug metabolism have been observed across ethnic populations, which can cause variability in pharmacokinetics (PK) and drug response. ¹⁰ In addition to enzymes related to drug metabolism, ethnic differences in the frequency of polymorphisms in genes which encode efflux transporters have also been implicated in differences in drug absorption or CNS penetration. ABBV‐552 is not a substrate of common drug efflux transporters such as P‐gp and BCRP, and therefore no transporter mediated differences between populations would be expected to impact the absorption, systemic exposure, or CNS exposure of ABBV‐552. Additionally, extrinsic factors, such as differences in diet, may play a role in observed variability between populations. ¹¹ , ¹² Investigating potential differences in exposures of new medications across diverse populations is key to ensuring the risk‐to‐benefit balance across different racial and ethnic backgrounds.

This study was a Phase 1, multicenter, open‐label, parallel cohort study to evaluate ABBV‐552 PK, safety, and tolerability in healthy adult Japanese and Han Chinese participants (NCT05686980). PK and safety findings were compared with prior findings in healthy adult Western participants from previous studies.

Methods

Study Design and Population

The Advarra Institutional Review Board (Columbia, MD) approved the study protocol, informed consent forms, and recruitment materials before participant enrollment. The study was conducted in accordance with the International Council for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. All participants provided written informed consent before screening.

This Phase 1, multicenter, open‐label, parallel‐group study consisted of two cohorts to evaluate ABBV‐552 PK, safety, and tolerability following oral administration (NCT05686980). A total of 18 adult Japanese and Han Chinese male and female participants in general good health were selected to participate in the study according to the study eligibility criteria. Cohort 1 consisted of a single‐sequence, three‐period, single‐ascending dose (5, 15, and 40 mg) in Japanese participants with a washout period of 7 days between doses (N = 10). Cohort 2 consisted of a single‐period, single dose in Han Chinese participants (N = 8). Figure 1 illustrates the study design. The study took place between January and March 2023 at two study sites (Anaheim Clinical Trials, LLC, Anaheim, CA; PPD Development, LP, Las Vegas, NV) with plasma and urine concentration measurements performed at a single bioanalytical laboratory (AbbVie Inc., North Chicago, IL). ABBV‐552 was administered as an oral tablet available in 5 and 10 mg strengths. Dosing was administered as follows: 5 mg (1 × 5 mg), 15 mg (3 × 5 mg), 40 mg (4 × 10 mg).

Figure 1.

Study design. *Follow‐up occurred 30 ± 2 days following administration of the last ABBV‐552 dose. Arrows indicate ABBV‐552 dosing. Black filled days indicate required confinement.

Inclusion criteria for participants included willingness to provide informed consent, being 18–55 years of age at the time of screening, and having a body mass index (BMI) ≥18 and ≤32 kg/m². Additional criteria were based on familial heritage. Japanese participants had to be first‐ or second‐generation Japanese based on all four grandparents; Han Chinese participants had to be first‐generation Han Chinese of full Chinese parentage and to have resided outside of China for less than 5 years. Japanese participants were required to maintain a typical Japanese lifestyle, including consuming a typical Japanese diet. Likewise, Han Chinese participants were required to maintain a typical Chinese lifestyle, including consuming a typical Chinese diet.

A screening visit was performed within 4 weeks prior to dosing to confirm eligibility. Participants in Cohort 1 received three ascending oral doses of ABBV‐552 on Day 1 of each 7‐day period (Period 1, Day 1: 5 mg; Period 2, Day 1: 10 mg; Period 3, Day 1: 40 mg; Figure 1). Participants were confined to the study site for approximately 22 days (pre‐dose [Day −1] through Period 3, Day 7). Confinement ended after collection of the Period 3 144‐h blood samples and completion of Period 3, Day 7 scheduled study procedures. Participants in Cohort 2 received a single oral dose of ABBV‐552 on Day 1, Period 1 (40 mg) and were confined to the study site for approximately 8 days (Day −1 through Day 7; Figure 1). Confinement ended after collection of the 144‐h blood samples and completion of scheduled study procedures on Day 7. All ABBV‐552 doses were administered after an overnight fast (minimum of 10 h prior to dosing); fasting continued for 4 h after dosing. Each dose of study drug was taken orally with approximately 240 mL of water. When not fasting, participants consumed a standard Japanese and Chinese diet, respectively.

The dose range for the current study was based on preclinical cognitive models in rodents, in vitro and in vivo data in preclinical species, PK and safety in healthy volunteers in single and multiple ascending dose studies, and anticipated max clinical dose to be administered in Phase 2 and 3 studies. Improvements in preclinical cognition models were observed in rodents between 10% and 80% SV2A receptor occupancy. PET imaging in healthy volunteers indicated that a dose of 15 mg daily would lead to an SV2A receptor occupancy of approximately 80%. Due to the long elimination half‐life, ABBV‐552 was observed to accumulate approximately 3‐ to 4‐fold with daily administration. A single 40 mg dose was chosen as the highest dose for the current study due to it having been previously studied in Western participants during the single‐ascending dose study for ABBV‐552, allowing for a safety comparison between the Han Chinese and Japanese groups to a mainly Caucasian population. In addition, the exposure following a 40‐mg single dose is approximately comparable to that expected for 15‐mg daily dose at steady state. This allowed for the assessment of PK, safety, and tolerability following a single dose of ABBV‐552 with exposures that are approximately similar to those expected in a Phase 2 study with daily administration of 15 mg. Study findings were compared to historical data of healthy adult Western participants (N = 6) who received a single oral 40 mg dose of ABBV‐552 as part of a previous single‐ascending dose study. ⁴ ABBV‐552 was administered using a simple powder in capsule formulation of 40 mg in the single‐ascending dose study. While differing formulations between the current study and the comparator study in Western participants (powder in capsule vs immediate release tablet), ABBV‐552 demonstrates good solubility and permeability in vitro (BCS Class I), minimizing the risk of pharmacokinetic differences due to formulation change.

Pharmacokinetics

Blood samples for ABBV‐552 assay were collected into lithium heparin collection tubes. Samples were collected for plasma PK measurements pre‐dose (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 h after dosing on Day 1 in each period (Cohort 1: Periods 1–3, Cohort 2: Period 1). Urine samples were collected into sterile containers during Period 3 for Cohort 1 and Period 1 for Cohort 2 pre‐dose (12‐h interval prior to dosing), 0–4, 4–8, 8–12, and 12–24 h after dosing on Day 1.

Plasma and urine concentrations of ABBV‐552 were determined using a validated liquid–liquid extraction followed by liquid chromatography‐tandem mass spectrometry method. The LLOQ was established at 0.200 ng/mL. Samples quantified below the lowest standard were reported as zero.

The following PK parameters were estimated for ABBV‐552: maximum observed plasma concentration (C_max), time to C_max (T_max), terminal phase elimination half‐life (t_1/2), area under the plasma concentration–time curve (AUC) from time zero to the last measurable concentration (AUC_t), and AUC from time zero to infinity (AUC_inf). Data from individuals were excluded from summary AUC_inf calculations if extrapolated AUC was greater than 20% of AUC_inf or the terminal elimination rate constant (λ_Z) could not be calculated. Dose proportionality was assessed on dose‐normalized C_max and AUC for Cohort 1.

Safety

Safety assessments included adverse event (AE) reporting and vital signs, orthostatic vital signs, 12‐lead ECG variables, and clinical laboratory value (hematology, chemistry, and urinalysis) monitoring. Participants were also assessed on the Columbia‐Suicide Severity Rating Scale (C‐SSRS) throughout the study to evaluate suicidal ideation and behaviors.

Statistics

For Cohort 1, to evaluate dose proportionality of ABBV‐552 PK, a repeated measures analysis of variance was performed for the natural logarithms of dose‐normalized C_max and AUC_inf. Participants were classified by dose level.

AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 25.1. The number and percentage of participants who experienced a TEAE (any AE that occurred after first study drug dosing) were tabulated by primary System Organ Class and MedDRA preferred term. The tabulation of the number of participants with TEAEs was provided with further breakdowns by severity rating (Vaccine Trials Toxicity Scale Grade 1–4) and relationship to study drug. Laboratory test values, ECG, and vital signs measurements that were potentially clinically significant, were identified. Summary of baseline, post‐dose, and change from baseline to post‐dose values were provided for laboratory variables, vital signs, and ECG measurements. Summary of suicidal ideation or suicidal behaviors from the C‐SSRS assessment was provided by cohort and dose level.

Results

Participant Demographics

A total of 18 participants were enrolled in the study. All participants were included in the safety analysis and 17 participants were included in the PK analysis. A summary of participant characteristics is provided in Table 1. Cohorts had a similar mean age (Cohort 1: 47.0 years, Cohort 2: 43.0 years), mean BMI (23.4, 25.0 kg/m²), and proportion of male participants (70%, 75%). For Cohort 1 (Japanese cohort), 10 participants received three separate single oral doses of ABBV‐552 (5, 15, and 40 mg) on Day 1 of Periods 1–3 (7 days each). For Cohort 2 (Han Chinese cohort), eight participants each received a single oral dose of ABBV‐552 (40 mg) on Day 1 of Period 1. For Cohort 3 (historical data for Western participants) six participants received a single oral dose of ABBV‐552 (40 mg).

Table 1.

Population Characteristics

	Cohort 1: Japanese	Cohort 2: Han Chinese	Overall Total
Variable	N = 10	N = 8	N = 18
Sex, n (%)
Male	7 (70)	6 (75)	13 (72)
Female	3 (30)	2 (25)	5 (28)
Age (years), mean (SD)	47.0 (7.47)	43.0 (9.29)	45.2 (8.32)
Weight (kg), mean (SD)	69.4 (12.6)	70.7 (7.33)	70.0 (10.3)
Height (cm), mean (SD)	172 (8.52)	169 (7.09)	170 (7.84)
BMI (kg/m2), mean (SD)	23.4 (2.71)	25.0 (2.67)	24.1 (2.72)

BMI, body mass index; SD, standard deviation.

Pharmacokinetics

Mean plasma concentration–time profiles for ABBV‐552 in Cohorts 1 (Japanese) and 2 (Han Chinese) are presented in Figure 2 on both linear and log‐linear scales. In Cohort 1 (Japanese), the C_max and AUC_inf were dose proportional over a dose range of 5 to 40 mg (Table 2). Over this range, the harmonic mean plasma t_1/2 was similar across doses, ranging from 35.4 to 38.9 h. Median T_max ranged from 1.5 to 1.8 h (Table 3). For Cohort 1, the mean percentage of the ABBV‐552 recovered as intact drug in urine was 0.8% with a mean renal clearance of 0.058 L/h. For Cohort 2 (Han Chinese), following a single 40 mg dose of ABBV‐552, median T_max was 2.0 h and the harmonic mean plasma t_1/2 was 57.7 h (Table 3). For Cohort 2, the mean percentage of the ABBV‐552 recovered as intact drug in urine was 0.6% with a mean renal clearance of 0.041 L/h. One participant in Cohort 2 was observed to not have any measurable ABBV‐552 concentrations at any of the measured timepoints and was excluded from the PK analysis.

Figure 2.

Mean ABBV‐552 plasma concentration versus time profiles for Cohort 1 (Japanese) and Cohort 2 (Han Chinese) following administration of a single dose. Both linear (A) and log‐linear (B) scales are shown.

Table 2.

Linear Trend and Dose Proportionality Assessment of ABBV‐552 Pharmacokinetics Following a Single Dose of ABBV‐552 in Cohort 1 (Japanese Participants)

	Pharmacokinetic Parameter	Estimate	95% Confidence Interval
Linear trend	Cmax/Dose	−0.02	−0.10 to 0.05
	AUCinf/Dose	−0.01	−0.08 to 0.06
Dose proportionality	Cmax/Dose	−0.01 a	−0.12 to 0.09
	AUCinf/Dose	0.01 a	−0.09 to 0.11

AUC_inf, area under the concentration–time curve from time zero to infinity; C_max, maximum plasma concentration.

^a 40 versus 5 mg.

Table 3.

Mean (%CV) Plasma Pharmacokinetic Parameters of ABBV‐552

	Cohort 1 Japanese			Cohort 2 Han Chinese	Comparator a Western
PK Parameter	ABBV‐552 5 mg (N = 10)	ABBV‐552 15 mg (N = 10)	ABBV‐552 40 mg (N = 10)	ABBV‐552 40 mg (N = 7)	ABBV‐552 40 mg (N = 6)
Tmax (h) b	1.5 (0.5–2.0)	1.5 (1.0–2.0)	1.8 (1.0–3.0)	2.00 (2.0–4.0)	1.50 (1.0–4.0)
Cmax (ng/mL)	57 (15)	183 (18)	446 (17)	449 (12)	371 (31)
Cmax/Dose (ng/mL/mg)	11.1 (14)	12.2 (20)	10.9 (16)	11.3 (9)	9.3 (31)
AUCt (ng h/mL)	1720 (17)	5560 (16)	13900 (21)	17000 (22)	12600 (23)
AUCinf (ng h/mL)	1840 (20) c	5960 (20) c	14800 (27) c	17300 (25) d	13600 (25)
AUCinf/Dose	367 (21)	397 (20)	370 (28)	432 (24)	351 (27)
t1/2 (h) e	38.9 (15.0)	37.5 (14.7)	35.4 (16.3)	57.7 (19.8)	41.2 (9.4)
Renal CL (L/h)	NC	NC	0.06 (42)	0.04 (22)	NC

AUC_t, area under the plasma‐concentration–time curve from time zero to the last measurable concentration; AUC_inf, area under the plasma‐concentration–time curve from time zero to infinite time; C_max, maximum observed plasma concentration; NC, not calculated; t_1/2, terminal phase elimination half‐life; T_max, time to maximum plasma concentration.

Data displayed as geometric mean (% coefficient of variation).

^a Historical data.

^b Median (range).

^c n = 9.

^d n = 4.

^e Harmonic mean (pseudo‐standard deviation).

Healthy adult Japanese and Han Chinese participants had comparable T_max and C_max values (Table 3). The mean AUC value for Han Chinese participants was approximately 20% higher than that for Japanese participants for the 40 mg dose. Dose‐normalized values for C_max and AUC_inf were comparable between the Han Chinese, Japanese, and Western groups. Harmonic mean values for half‐life were observed to be 63% higher in the Han Chinese group compared with the Japanese group; however, small sample size and high interindividual variability within the Han Chinese group are potential contributors to these observations (Table 3). The range (minimum and maximum observed plasma concentrations, per timepoint) of individual plasma concentrations and the mean concentration–time profiles over 24 h following administration of a 40 mg ABBV‐552 dose were similar between Cohorts 1 and 2 and to historical data from healthy adult Western participants (Figure 3).

Figure 3.

Observed plasma ABBV‐552 concentration following oral administration of a single 40 mg dose of ABBV‐552 in healthy Japanese (N = 10), Han Chinese (N = 7), and Western (N = 6) adults. Inset shows the range (minimum and maximum observed plasma concentrations, per timepoint) of individual plasma concentrations and the mean concentration–time profiles over 24 h following administration of a 40 mg ABBV‐552 dose.

Safety

No new ABBV‐552‐related safety issues were identified in these Asian study populations. The proportions of participants that reported at least one TEAE were similar between Han Chinese participants (75%) and Japanese participants (70%), TEAEs are described in detail in Table 4. There were no deaths, no serious TEAEs (SAEs), and no adverse events leading to treatment discontinuation. The most common TEAEs reported across the study by at least two participants were dizziness (38.9%), somnolence (11.1%), and fatigue (11.1%). No unique safety signals were observed compared with Western participants. Most TEAEs were transient and resolved without specific treatment within the study period. Most TEAEs were Grade 1 in severity but two events had a severity of Grade 2 (somnolence in a Japanese participant and alanine aminotransferase increase in a Han Chinese participant) following administration of a 40 mg dose of ABBV‐552. Both Grade 2 TEAEs were deemed possibly related to study drug and resolved with no intervention. Both participants completed the study through the final safety follow‐up with no additional TEAEs. No clinically meaningful changes were observed in vital signs, orthostatic vital signs, or ECG measurements during the study and no positive C‐SSRS responses were reported. There was no clear dose‐related pattern to the TEAEs reported.

Table 4.

Treatment‐Emergent Adverse Events by Preferred Term in Healthy Participants Receiving Single Doses of ABBV‐552

	Japanese			Han Chinese
Preferred term	5 mg, N = 10 n (%)	15 mg, N = 10 n (%)	40 mg, N = 10 n (%)	40 mg, N = 8 n (%)
Any adverse event	5 (50.0)	3 (30.0)	3 (30.0)	6 (75.0)
Nausea	0	0	0	1 (12.5)
Fatigue	1 (10.0)	1 (10.0)	1 (10.0)	0
Alanine aminotransferase increased	0	0	0	1 (12.5)
Aspartate aminotransferase increased	0	0	0	1 (12.5)
Musculoskeletal stiffness	1 (10.0)	0	0	0
Myalgia	0	1 (10.0)	0	0
Dizziness	0	1 (10.0)	0	6 (75.0)
Headache	0	0	0	1 (12.5)
Somnolence	2 (20.0)	0	1 (10.0)	0
Confusional arousal	1 (10.0)	0	0	0
Micturition urgency	0	0	0	1 (12.5)
Dermatitis contact	0	1 (10.0)	0	0
Papule	0	1 (10.0)	0	0
Urticaria	0	0	1 (10.0)	0

Note: Participants are counted once in each row, regardless of the number of events they may have had.

Discussion

Many factors can potentially contribute to interindividual variability in PK including genetic polymorphisms, diet, weight, and environmental factors. ¹⁰ , ¹¹ As such, it is important to study potential differences in drug exposure between ethnic populations during drug development to ensure optimal dosing regimens. Studies are often required as a prerequisite to patient studies within certain regions or countries in late‐stage clinical development, as well as for the international approval of new drugs. ABBV‐552 is an orally administered drug which is primarily metabolized by CYP3A4 and to a minor extent CYP2C19. ⁹ Ethnic differences have been observed across populations regarding the frequency of polymorphisms for a number of CYP enzymes commonly identified in drug metabolism, including higher proportions of poor metabolizer polymorphisms of CYP2C19 in East Asian populations as compared with Caucasian and European populations. ¹³ Due to the potential impact of genetic and other extrinsic factors such as diet or lifestyle may have on the exposure of ABBV‐552, this Phase 1 study was conducted to evaluate potential differences in safety and PK between healthy adult Japanese and Han Chinese participants, as compared with previous data obtained in healthy adult Western participants. ⁴

This study demonstrated that ABBV‐552 was safe and well tolerated in these small populations of healthy Japanese and Han Chinese participants following single dose administration. Consistent with a ABBV‐552 PK study in healthy Western adults (0.3–80 mg ABBV‐552 doses), ⁴ ABBV‐552 exposure was dose proportional over the studied dose range (5–40 mg). ⁴ Overall, PK profiles and parameters were comparable between healthy adult Japanese and Han Chinese participants. In the Han Chinese cohort, the observed AUC_inf was approximately 20% higher than in the Japanese cohort at the 40 mg dose level. Further, the Han Chinese population had a longer observed harmonic mean half‐life (57.7 vs 35.4 h; Figure 2, Table 3). This small difference between Japanese and Han Chinese exposures and half‐life values may be explained by the small sample size, which is typical of clinical pharmacology descriptive studies, as well as moderate variability observed in the PK parameters, which is consistent with the interindividual variability of 15% to 30% observed in previous phase 1 studies. ⁴ In addition, comparison of dose‐normalized C_max and AUC_inf shows comparable results, with geometric mean values overlapping within the geometric mean %CV for all three populations at the 40 mg dose level. This small difference in exposure is not considered clinically relevant as the relative differences in exposure are within the observed PK variability. Additionally, 24‐h plasma concentration profiles were similar for both cohorts and historical data for ABBV‐552, further supporting the similarity in PK between these populations for a drug which is intended to be administered daily.

Historical data of healthy adult Western participants from a previous Phase 1 single‐ascending dose study was compared with data of the current study in healthy Japanese and Han Chinese cohorts. Mean plasma concentrations and PK parameter values were comparable across all three populations following administration of a single 40 mg ABBV‐552 dose. Though slightly higher mean AUC_t and AUC_inf values were observed in Asian versus Western populations, particularly in the Han Chinese cohort, the majority of individual participant PK profiles in the different groups overlapped. This suggests that inter‐participant variability and small sample size, along with inter‐study comparison, largely contributed to the observed differences (Figure 3). Of note, one Han Chinese participant in the current study had no detectable ABBV‐552 concentration at any timepoint examined and was excluded from PK analysis. The lack of ABBV‐552 exposure may have been caused by participant non‐compliance. Further investigation did not produce any new evidence or indicate any protocol deviations. These investigations included re‐analysis of the samples which confirmed that all samples were below the limit of quantitation, as well as confirmation that hand and mouth check were performed by the site. The lack of quantifiable ABBV‐552 at any timepoint was not observed for any other participant. Overall, given the PK properties of ABBV‐552, these results suggest that there are no ethnic differences in ABBV‐552 PK across these tested populations.

ABBV‐552 had an acceptable safety profile in this small population of healthy Japanese and Han Chinese adults at all tested doses following single dose administration. There were no deaths, no SAEs, and no TEAEs leading to treatment discontinuation. All but two of the AEs were Grade 1, and the most common AEs reported across the study were dizziness, somnolence, and fatigue. All AEs resolved by the end of the study. In the Han Chinese group, the most common AE was dizziness, which was reported by 6/8 participants (75%). All the dizziness events were Grade 1, resolved within hours of study drug administration without any specific therapy. While dizziness was minimally reported in the Japanese cohort within this study, dizziness has been one of the commonly observed AEs in previous studies, occurring in 50% of healthy volunteers at the 40 mg dose level during the single‐ascending dose study. There was no clear dose‐related pattern to the TEAEs reported, and no unique safety signals were observed in the studied Asian populations compared to a previously studied Western population.

This study had limitations. Similar to most early phase clinical trials, this study tested ABBV‐552 in a small number of healthy participants for a short period of time. Despite administration in the fasted state for this study, prior research suggests that there is no significant food effect on ABBV‐552 PK. ⁴ This study was conducted in the United States, and therefore the impact of global differences in gut microbiota on PK is unknown. ¹⁴ Although investigated for, dosing, and bioanalytical errors, the reasons for lack of exposure in one Han Chinese participant were not clear.

In conclusion, ABBV‐552 was well tolerated in this small population of healthy adult Japanese and Han Chinese participants at the tested doses (5–40 mg single dose). There were no TEAEs leading to study discontinuation and no clear dose‐related patterns in TEAE incidence or severity were observed. No new safety signals were identified in the studied Asian versus Western populations and no meaningful differences in ABBV‐552 PK were observed.

Conflicts of Interest

Nick Miles, Brian McNamee, Cindy Zadikoff, Joey Boiser, Mohamad Shebley, and Ramesh Boinpally are employees of AbbVie Inc. and may hold stock or stock options in the company.

Funding

AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.

Data Availability Statement

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