Virus World

The antiviral ensitrelvir, which is not approved in the United States, shortens symptoms in people with mild COVID and might reduce risk of long COVID — but more data are needed. COVID-19 can inflict days of misery, even on people who do not develop serious illness. Now, trial data show that an antiviral called ensitrelvir shortens symptoms of mild to moderate COVID-19 by about a day — and is the first drug to make a statistically significant cut in the number of days people test positive for SARS-CoV-2. The drug’s manufacturer, Shionogi in Osaka, Japan, says the data also show that ensitrelvir has the potential to prevent long COVID. But scientists are sceptical about that claim and critical of the design of the clinical trial. The research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, on 21 February, and has not yet been peer reviewed. Two oral antivirals are already widely used to treat COVID-19: Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. Both target people who are at high risk of severe disease. But ensitrelvir was tested on people irrespective of their risk, which could have implications for its use in individuals at low risk. No drug has been conclusively shown to reduce the risk of long COVID, although preliminary evidence hints that Paxlovid might have this effect.

A pill for COVID cough

Organizers of the ensitrelvir trial investigated roughly 1,200 people, with the main goal of determining whether the drug could accelerate recovery. The results showed that participants who took 125-milligram ensitrelvir pills recovered from five specific symptoms — stuffy or runny nose, sore throat, cough, feeling hot or feverish and low energy or tiredness — about 24 hours earlier than did those in the control group. Participants who took the 125-milligram dose also tested negative for SARS-CoV-2 about 29 hours earlier than did those who took a placebo. According to Shionogi, the study was the first to show a statistically significant reduction in the time to a negative test result. A subset of participants were asked about their COVID-19 symptoms three and six months after trial enrolment as well as during their acute infection period. Those who reported two or more of the same symptoms at least twice in a row over this period were defined as having developed long COVID. Participants who had a relatively high number of symptoms during the illness's early stages had a 14% risk of developing long COVID if they took the antiviral, compared with a 26% risk for similar participants in the placebo group. This led Shionogi to conclude that participants who received ensitrelvir had a reduced risk of developing long COVID.

Doubts about design

But scientists who were not involved with the study point out that the trial was not specifically intended to investigate the risk of long COVID. That means that the pre-trial research plan didn’t describe any methods for analysing long COVID data. This means, for example, that it’s unclear whether Shionogi’s definition of long COVID was determined before the trial began, notes physician Eric Topol, director of the Scripps Research Translational Institute in San Diego, California. Because this was an exploratory phase of the study, it’s not possible to make any strong conclusions, he adds. Simon Portsmouth, head of clinical development at Shionogi in Florham Park, New Jersey, says that the company could not specify the plan for analysing long COVID data ahead of time because long COVID was less clearly defined in the past than now. He says that these results, although not definitive, will shape an ongoing trial evaluating ensitrelvir’s effect on COVID-19 symptoms. Scientists say it’s plausible that antivirals could prevent long COVID. One recent analysis found that people who took Paxlovid had a reduced risk of developing long COVID compared with those who took no antiviral drugs1. The study, published as a preprint, has not yet been peer reviewed. Study co-author Ziyad Al-Aly, chief of research and development at the VA St Louis Health Care System, in Missouri, says the ensitrelvir data make him more optimistic that attacking the virus early during an infection “seems to hold the key to reducing the risk of long COVID.” Topol agrees that the data that Shionogi have made public support the idea that antivirals protect against long COVID, at least when residual virus is involved in causing prolonged symptoms.

Published in Nature March 3, 2023:

https://doi.org/10.1038/d41586-023-00548-6 

OSAKA, Japan, April 24, 2022 – Shionogi & Co., Ltd. (hereafter “Shionogi”) today announced new results from two late-breaking presentations of S-217622 at the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon, 23 – 26 April. S-217622 is an investigational 3CL protease inhibitor that was studied for once-daily oral administration in mainly vaccinated patients (~85%), with no risk factors for severe complications, within five days of COVID-19 symptom onset. At the meeting, Shionogi presented new late-breaking Phase 2b results from the Phase 2/3 clinical trial of S-217622, completed in Asia (presenter: Norio Ohmagari, Disease Control and Prevention Center, National Center for Global Health), which followed previously reported topline results from the Phase 2b study. These new data showed:

Antiviral effect:      

・S-217622 demonstrated rapid clearance of the infectious SARS-CoV-2 virus.

・On day four of treatment (following the third dose), the proportion of patients with positive viral titer decreased by approximately 90% versus placebo.

・S-217622 shortened infectious virus shedding by 1-2 days versus placebo.

・S-217622 showed a significant reduction in viral RNA on days 2, 4, 6 and 9 versus placebo (difference versus placebo in the Least Squares mean change from baseline in viral RNA; under -1.0 logx copies/mL on day four at each dose). 

Clinical symptom improvement:

・There was no significant difference in total score of 12 COVID-19 symptoms between treatment arms, however, S-217622 showed improvement in composite score of five “respiratory and feverish” symptoms (post-hoc analysis).

Safety:

Both the Phase 1 and 2a/b parts of the Phase 2/3 clinical trials showed that S-217622 was well-tolerated, with few discontinuations due to drug, and no reports of serious adverse events or death. Treatment-emergent adverse events in these trials were generally mild to moderate, and resolved without treatment. The Phase 2b study was conducted with 428 patients in Japan and South Korea. Its main purpose was to confirm the antiviral effect and clinical symptom improvement of S-217622 when orally administered once daily for five days, versus placebo. A second late-breaking presentation by Shionogi reported results from both the Phase 1 clinical trial and the Phase 2a part of the Phase 2/3 clinical trial of S-217622 completed in Japan (presenter: Hiroshi Yotsuyanagi, The Institute of Medical Science, The University of Tokyo), which demonstrated it was generally well-tolerated, and rapidly cleared SARS-CoV-2. The full abstracts and oral presentations are available on the ECCMID website.

“These results demonstrate that S-217622 rapidly eliminates SARS-CoV-2 in patients versus placebo, marking its potential, if approved, as an effective treatment option for COVID-19. As infections continue to rise in areas worldwide, it is important we have access to a range of easily administered treatment options to ease the pressures on our healthcare systems,” said Isao Teshirogi, Ph.D., President and CEO at Shionogi & Co., Ltd. “We look forward to continued study of this antiviral in Phase 3 trials.” A separate global Phase 3 study of S-217622 is underway aiming to recruit participants globally to support regulatory filings this year.