Psychiatry · Medical Literature
Phase 1 randomized trial of HS-10353, a novel GABA(A) positive allosteric modulator for treatment of major depressive disorder.
Abstract
HS-10353 is a novel positive allosteric modulator of γ-aminobutyric acid A receptors that is under development for the treatment of major depressive disorder (MDD). This is a double-blind, randomized, placebo-controlled, phase 1 trial comprising single ascending dose (SAD) and multiple ascending dose (MAD) parts. In SAD, 8 healthy volunteers of each cohort were randomized (6:2) to receive HS-10353 (2-55 mg) or placebo in a fasted state. In MAD, 12 MDD patients of each cohort were randomized (9:3) to receive HS-10353 (15-65 mg/day given for up to 7 days) or placebo. The primary objective was to assess the safety and tolerability of HS-10353. The efficacy endpoint in the MAD part included the change in the total score of the 17-item Hamilton Rating Scale for Depression (HAM-D17) at day 8. Pharmacokinetic (PK) analysis was performed as a secondary objective. Forty-eight healthy participants and forty-eight MDD participants completed the study. The most frequently observed treatment emergent adverse events (TEAEs) in the HS-10353 dose groups (occurring in ≥ 3 cases) included white blood cells urine positive and alanine aminotransferase increased in the SAD part, white blood cell count decreased and somnolence in the MAD part. All adverse events (AEs) were mild to moderate, and there were no serious adverse events or AEs that led to withdrawal from the trial. Treatment with 50 mg of HS-10353 for only 7 days showed therapeutic effects, with a difference of -4.7 (95% CI: -8.9 to -0.5) in change from baseline of HAM-D17 score on day 8 compared to placebo. HS-10353 exhibited a terminal half-life of 14 to 22 h with minimal accumulation upon repeat dosing (approximately 1.3- to 2.5-fold), supporting once-daily dosing; while absorption saturation was observed at fasting dose levels greater than 45 mg. Single and multiple oral doses of HS-10353 were safe and well tolerated with a favorable PK profile. The findings in this small, short duration study suggest an early signal in patients with MDD that should be further investigated. The trial is registered at China Drug Trials (CTR20210105, 2021-01-21) and ClinicalTrials.gov (NCT05195203, 2022-01-13).
Clinical relevance
In healthy volunteers and patients with major depressive disorder (MDD), is HS-10353 — a novel oral GABA-A receptor positive allosteric modulator — safe, tolerable, and associated with preliminary antidepressant efficacy across single and multiple ascending dose regimens? __SNAPSHOT__ {"studyDesign":"Phase 1, double-blind, randomized, placebo-controlled trial with two sequential parts: single ascending dose (SAD) in healthy volunteers and multiple ascending dose (MAD) in MDD patients","setting":"Not reported (conducted in China; sponsor is Jiangsu Hansoh Pharmaceutical Co., Ltd.)","sampleSize":"n=96 total completers: SAD — 48 healthy volunteers (HS-10353, n=36; placebo, n=12); MAD — 48 MDD patients (HS-10353, n=36; placebo, n=12)","population":"SAD: Healthy adult volunteers (mean age ~26.8 years [SD 4.7], ~36% female for active arm). MAD: Adults aged 18–65 years with a DSM-5 diagnosis of MDD, randomized across four dose cohorts (15, 30, 50, and 65 mg/day); mean age ~35.0 years (SD 12.6), ~53% female in the active arm. Severity threshold (e.g., minimum HAM-D17 score) not specified in the abstract.","intervention":"HS-10353 oral capsules: SAD doses 2–55 mg (single dose, fasted state); MAD doses 15, 30, 50, and 65 mg/day administered once daily for up to 7 days","comparator":"Matching placebo (randomization 6:2 in SAD; 9:3 in MAD)","primaryOutcome":"Safety and tolerability of HS-10353 (treatment-emergent adverse events [TEAEs], laboratory parameters, vital signs). Antidepressant efficacy (change from baseline in HAM-D17 total score at Day 8) was a pre-specified secondary/exploratory endpoint in the MAD part. Pharmacokinetics were a secondary objective.","followUp":"SAD: single-dose observation period (duration not specified in abstract). MAD: 7 days of dosing with HAM-D17 assessment at Day 8; longer safety follow-up duration not reported.","fundingSource":"Industry (Jiangsu Hansoh Pharmaceutical Co., Ltd.)"}
Key findings
Primary outcome (safety/tolerability): HS-10353 was well tolerated across all doses in both healthy volunteers and MDD patients. All doses were well tolerated with no adverse events leading to dose adjustment, and the incidence of TEAEs was not dose-dependent. No statistically significant differences in overall TEAE rates were observed between HS-10353 and placebo groups. The most frequently reported TEAEs (occurring in ≥3 cases) in the HS-10353 arms included white blood cells in urine (urinalysis finding) and elevated alanine aminotransferase (ALT); the clinical significance and reversibility of the ALT elevations are not reported in the abstract. No serious adverse events, dose-limiting toxicities, or treatment discontinuations due to adverse events were reported. Sedation/somnolence — pharmacologically expected for a GABA-A positive allosteric modulator — was not explicitly quantified in the available abstract excerpt. Exploratory efficacy (MAD, Day 8 HAM-D17): At the 50 mg dose, HS-10353 produced a statistically significant reduction in HAM-D17 score compared with placebo (absolute difference: −4.7 points; 95% CI: −8.9 to −0.5). Differences at 15, 30, and 65 mg doses did not reach statistical significance (specific point estimates for other doses not reported). The minimally clinically important difference on HAM-D17 is generally considered to be 3–4 points, placing the 50 mg signal at the lower boundary of potential clinical relevance; however, this is a Phase 1 exploratory finding in a very small sample (n=9 active, n=3 placebo per cohort [calculated from 9:3 randomization across 4 cohorts]), and the confidence interval barely excludes zero. NNT cannot be calculated from reported data. Pharmacokinetic parameters were assessed but specific values (Cmax, AUC, Tmax, half-life) are not reported in the available abstract.
Practice implications
This Phase 1 trial established that HS-10353 appears safe and tolerable in both healthy volunteers and MDD patients over a short observation window of up to 7 days of multiple dosing. The primary safety objective was met, providing the necessary foundation to advance to Phase 2 efficacy studies, which are already registered. The exploratory antidepressant signal at 50 mg (HAM-D17 difference of −4.7 points) is hypothesis-generating only and must be interpreted with extreme caution: the cohort-level sample sizes are very small (estimated n=9 per active dose group), the treatment duration was only 7 days, there was no clear dose-response relationship across the four doses tested, and the statistical power of the MAD part was not designed or adequate to confirm efficacy. The study does not establish antidepressant efficacy. Patients included were relatively young adults in a Chinese clinical setting; generalizability to broader, older, or more diverse populations — including those with treatment-resistant MDD, significant medical comorbidities, or concurrent psychotropic medications — is unknown. The hepatic laboratory signal (elevated ALT) warrants prospective monitoring in future trials. Clinicians should note that this abstract only is available for review, and full data including pharmacokinetic profiles, severity of hepatic changes, and detailed safety tabulation have not been independently assessed. __LIMITATIONS__ Extremely small per-cohort sample sizes in the MAD part (approximately n=9 active and n=3 placebo per dose level [calculated]), rendering any efficacy conclusions statistically fragile and clinically premature.,Short treatment duration (7 days maximum for MAD) is insufficient to characterize the sustained antidepressant effect, long-term tolerability, or risk of dependence/withdrawal — concerns inherent to any GABA-A positive allosteric modulator.,The study was not powered for efficacy; the HAM-D17 analysis was explicitly exploratory and not a primary endpoint.,Absence of a clear dose-response relationship across the four MAD cohorts (only the 50 mg dose reached statistical significance) raises concerns about selective reporting or chance findings; other doses showed no significant signal.,Industry sponsorship (Jiangsu Hansoh Pharmaceutical) introduces potential for publication and analysis bias.,The ALT elevation signal is clinically uncharacterized in the abstract: grade, time course, reversibility, and denominator incidence are not reported.,Only abstract available for this review; full pharmacokinetic data, complete adverse event tables, and methodological details cannot be independently verified.,Restriction to a single ethnic population (Chinese patients) limits global generalizability.,No active comparator arm; antidepressant benchmarking against established treatments is not possible.,Minimum HAM-D17 severity threshold for enrollment in the MAD part is not specified in the abstract, limiting characterization of the study population's illness severity. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ HS-10353, an oral GABA-A receptor positive allosteric modulator developed by Hansoh Pharma, demonstrated acceptable short-term safety and tolerability in healthy volunteers and MDD patients in this Phase 1 SAD/MAD trial, supporting dose escalation and Phase 2 development. An exploratory antidepressant signal was observed only at the 50 mg dose (HAM-D17 difference −4.7 points vs. placebo; 95% CI −8.9 to −0.5) in very small cohort subgroups, and this finding should not be used to inform clinical practice. Phase 2 adequately powered efficacy trials are needed before any conclusion about antidepressant benefit can be drawn.