Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trialResearch in context

• Published in: EClinicalMedicine 2024-05, Vol.71, p.102582
• Main Authors: Hongzhou Lu, George Zhang, John Mao, Xiaochun Chen, Yangqing Zhan, Ling Lin, Tianxiang Zhang, Yanan Tang, Feng Lin, Feiyue Zhu, Yuanlong Lin, Yiming Zeng, Kaiyu Zhang, Wenfang Yuan, Zhenyu Liang, Ruilin Sun, Liya Huo, Peng Hu, Yihua Lin, Xibin Zhuang, Zhaohui Wei, Xia Chen, Wenhao Yan, Xiuping Yan, Lisa Mu, Zhuhua Lin, Xinyu Tu, Hongshan Tan, Fuhu Huang, Zhiqiang Hu, Hongming Li, Guoping Li, Haijun Fu, Zifeng Yang, Xinwen Chen, Fu-Sheng Wang, Nanshan Zhong
• Format: Article
• Language: English
• Subjects: 3CL protease; Anti SARS-CoV-2 drug; COVID-19; RCT; XBB variants
• ISSN: 2589-5370

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0–15.0] vs. 15.0 days [14.0–15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated with