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Background <p>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).</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Trial registration <p>The trial is registered at China Drug Trials (CTR20210105, 2021-01-21) and ClinicalTrials.gov (NCT05195203, 2022-01-13).</p>

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Phase 1 randomized trial of HS-10353, a novel GABA(A) positive allosteric modulator for treatment of major depressive disorder

  • 期刊论文

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  • 发表日期：

    2026年5月21日

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  • Zhenlei Wang,
  • Mingli Li,
  • Xiaojin Xu,
  • Ruiling Zhang,
  • Huali Lin,
  • Fude Yang,
  • Jie Qi,
  • Huifeng Zhang,
  • Yuying Tao,
  • Qi Shen

摘要

Background

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).

Methods

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.

Results

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.

Conclusions

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.

Trial registration

The trial is registered at China Drug Trials (CTR20210105, 2021-01-21) and ClinicalTrials.gov (NCT05195203, 2022-01-13).