A combination regimen comprising the novel agent GST-HG171 (also known as atilotrelvir) and ritonavir improves clinical symptom recovery and viral clearance in low-risk vaccinated adults with mild-to-moderate COVID-19, findings from a pivotal phase II/III study have shown.
“[This effect was observed] regardless of whether the infection is caused by newly emerging SARS-CoV-2 XBB or non-XBB variants. There were also no apparent safety concerns associated with the treatment,” said the researchers.
The administration of GST-HG171 plus ritonavir within 72 hours after COVID-19 symptom onset cut the median time to sustained recovery of clinical symptoms by 2 days vs placebo (13 vs 15 days; hazard ratio [HR], 1.15; p=0.031). A little over 80 percent of GST-HG171–ritonavir recipients achieved this endpoint; in the placebo arm, the corresponding percentage was 78 percent. [EClinicalMedicine 2024;doi:10.1016/j.eclinm.2024.102582]
There was a consistent pattern favouring the combination regimen over placebo on post hoc analysis, specifically in participants infected by XBB variants (median time to sustained recovery of clinical symptoms, 11 vs 13 days; HR, 1.20).
Secondary outcomes
Fever and respiratory symptoms also got better faster with the GST-HG171–ritonavir combo than with placebo (estimated median time to sustained recovery, 13 vs 14 days; HR, 1.13; p=0.0021).
Viral load dropped with time in both treatment arms, but the change from baseline was markedly greater with the combo regimen vs placebo through day 14, more so on days 3, 4, and 5, by an additional least-squares mean (LSM) of -1.14, -1.10, and -1.75 log10 copies/mL, respectively (p<0.0001 for all).
The difference in LSM change in viral load from baseline to day 4 was also seen in the XBB and non-XBB subgroups (-0.83 and -1.38 log10 copies/mL, respectively; p<0.0001 for both).
GST-HG171–ritonavir also cut the estimated median time to negative conversion of SARS-CoV-2 nucleic acid vs placebo in the overall cohort (11 vs 14 days; p<0.0001) and XBB (13 vs 14 days; p=0.031) and non-XBB subgroups (10 vs 14 days; p<0.0001).
Safety profile
The incidences of any adverse event (AE) were similar between the combination and placebo arms (52 percent vs 49 percent). Most AEs were nonserious and grade 1/2 in severity, with the most common being hypertriglyceridaemia (10 percent vs 15 percent). There were fewer AEs leading to any drug withdrawal (0.6 percent vs 1.1 percent) or interruption (0 percent vs 0.2 percent) with the combo regimen vs placebo.
Over a third (36 percent) of GST-HG171–ritonavir recipients reported drug-related AEs (29.8 percent with placebo). Nonetheless, all were nonserious, mostly grade 1/2 in severity, and over half of the cases resolved by end of study, the researchers noted.
Targets the latest SARS-CoV-2 XBB variants
According to the investigators, the positive results for GST-HG171 particularly in patients infected with the latest SARS-CoV-2 XBB variants is “an outstanding contribution of this study.”
“GST-HG171 is a novel, potent, broad-spectrum, orally administered small-molecule inhibitor targeting SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) … To our knowledge, this is the first demonstration of the clinical benefits of an oral 3CLpro inhibitor in a randomized, double-blind, placebo-controlled clinical study with XBB variant-infected patients,” they said.
The study was conducted during the Omicron prevalence in China (from late 2022 to mid-2023, with rapid circulation of XBB and its sublineages beginning around April 2023). A total of 1,246 participants (median age at randomization 34 years, 56 percent women) were randomized 1:1 to either GST-HG171 plus ritonavir or placebo. All patients included in the efficacy analysis were infected by the Omicron strain (45.7 percent XBB; 54.3 percent non-XBB).
The findings thus reflect the clinical benefits of the combo regimen against different Omicron variants, including XBB and non-XBB, the researchers said.
Edge over approved COVID-19 agents
Despite various effective COVID-19 antivirals, GST-HG171 has notable strengths. For one, its oral administration offers the convenience that the intravenously administered remdesivir lacks; remdesivir is currently used for severe COVID-19 treatment. [N Engl J Med 2022;386:305-315]
Moreover, molnupiravir and nirmatrelvir-ritonavir, though approved for nonhospitalized COVID-19 patients, are indicated for those at high-risk for progression to severe disease. [N Engl J Med 2022;386:509-520; N Engl J Med 2022;386:1397-1408] Among standard-risk COVID-19 patients with mild-to-moderate disease, there was no significant effect on symptom resolution with nirmatrelvir-ritonavir. [https://www.pfizer.com/news/press-release/press-release-detail/pfizer-reports-additional-data-paxlovidtm-supporting] “GST-HG171 is able to target a wider patient population regardless of their risk levels for overall symptom recovery,” said the researchers.
Ensitrelvir (only approved in Japan) was studied in a cohort of patients mirroring the current analysis’ population; however, the efficacy of GST-HG171 on recovery of 11 COVID-19 symptoms was not seen with ensitrelvir. [JAMA Netw Open 2024;7:e2354991] The difference in the change of subtotal of five fever and respiratory symptoms achieved with ensitrelvir was also seen with GST-HG171 in the current analysis, they noted.
In another study evaluating VV116 and placebo, the 2-day between-group difference in median time to sustained clinical symptom resolution for 2 consecutive days strongly correlates with the current findings. However, the investigators underscored that the dominant subvariants in this study were Omicron BA.5.2.48 and BF.7.14. [Lancet Infect Dis 2023;24:129-139]
Advantage over other 3CLs
Two 3CLpro inhibitors that recently gained approval in China – simnotrelvir and leritrelvir – were evaluated in studies with the same primary outcomes as the current study. Both trials showed faster resolution of 11 COVID-19 symptoms with simnotrelvir-ritonavir and leritrelvir vs placebo. [N Engl J Med 2024;390:230-241; EClinicalMedicine 2023;67:102359]
However, both studies were conducted before the Omicron XBB wave in China in 2023. Also, the XBB variant was only detected in one patient (out of 140 assessed for viral strains) in the simnotrelvir trial; in the leritrelvir study, viral strains were not reported, the researchers noted.
“Consequently, GST-HG171 stands out as the only [3CLpro inhibitor] showing benefits in patients infected with XBB variants,” said the researchers.
Furthermore, the viral load reductions seen with GST-HG171–ritonavir vs placebo was greater when compared against leritrelvir (day 4; -1.10 vs -0.82 log10 copies/mL) and simnotrelvir-ritonavir (day 5; -1.75 vs -1.51 log10 copies/mL).
“Considering that the viral load of SARS-CoV-2 is associated with disease severity, potential mortality, and risk of transmission, GST-HG171 may bring more clinical benefits than currently approved drugs targeting 3CL,” the researchers explained.
They added that the recommended GST-HG171 dose of 150 mg BID is the lowest among the approved 3CLpro inhibitors, which could encourage better medication compliance.
Real-world studies warranted
Taken together, the findings demonstrate the efficacy and safety of oral administration of GST-HG171 150 mg with ritonavir 100 mg BID for 5 days, the researchers said.
“As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies,” they concluded.