An ongoing dialogue on HIV/AIDS, infectious diseases,
March 5th, 2025
What is the Future of Treatments for COVID-19?
Photo by Alexey Komissarov on Unsplash
In this raging flu season, where people with influenza-related illness outnumber those with COVID-19 for the first time since the pandemic hit in 2020, we might be fooled into thinking that we no longer need better treatments for COVID-19. This would be a mistake — this virus still causes much misery, peaking each winter but circulating year-round, destabilizing lives everywhere.
But how will we get these better treatments? How can we do clinical trials with meaningful end points adapted to the current clinical spectrum of the disease? After all, what we have now has some big-time flaws.
These are the questions raised by the SCORPIO-HR study of ensitrelvir, just published in Clinical Infectious Diseases (of which I’m Editor-in-Chief), along with an insightful editorial commentary. Ensitrelvir is a SARS-CoV-2 protease inhibitor similar to nirmatrelvir/ritonavir (Paxlovid), but it’s once-daily and doesn’t need the ritonavir; it’s already approved for use in Japan and Singapore.
In the study, around 2000 non-hospitalized adults with symptomatic COVID-19 were randomized to ensitrelvir once daily for 5 days or to matching placebo. The primary end point was time to sustained reduction of 15 COVID-related symptoms, with secondary end points of time to resolution of a smaller subset of symptoms, as well as viral load reductions.
For the primary end point, the study results were negative — time to resolution of all 15 symptoms was 12.5 days for ensitrelvir, 13.1 days for placebo, a non-significant difference. The treatment did better with secondary end points of time to resolution of 6 symptoms (stuffy nose, runny nose, sore throat, cough, low energy or tiredness, and feeling hot or feverish) and SARS-CoV-2-viral load reduction, both of these statistically significant in favoring ensitrelvir. The treatment was also well tolerated, with no detected safety events of note and rare virologic rebound.
So what should we do with these results? As with Paxlovid in a lower-risk or vaccinated population, ensitrelvir failed to achieve its primary end point. Yet the treatment was active for faster recovery from certain very common symptoms; whether one values this clinically would be a personal preference. One could argue that resolution of all symptoms set the bar too high for an antiviral in our current era of near universal pre-existing immunity.
In the accompanying editorial, Drs. Beatrice Zim and Cameron Wolfe take on the challenge of how to design clinical trials for COVID-19 when the clinical severity of the disease has so dramatically changed. They advise:
The largest unmet opportunity is likely for trial teams and regulatory authorities to be creative in building adaptive design into protocols that cannot only move with the evolution of therapeutics but also with the clinical landscape … Modified regulatory opportunities that are capable of handling modified trial design should be explored in preparation for future pandemics as we reflect on our successes and trial failures of the last few years.
Meanwhile, the venue for making such changes now faces an uncertain pathway. A planned meeting of government regulators, academic clinical trialists, and industry representatives to discuss trial designs for COVID-19 was cancelled unexpectedly earlier this year. Consider this meeting yet another casualty of changes at the top, which have included cancelled meetings on vaccines and reviews of submitted research grants.
Ugh.
But I don’t want to end on this (now familiar) depressing note, and finish instead with some brighter news — ensitrelvir as post-exposure prophylaxis reduced the incidence of COVID-19 in household contacts. It’s the first antiviral to demonstrate this benefit, one not observed with either Paxlovid or molnupiravir in prevention trials. We’ll see more details of this study presented at next week’s Conference on Retroviruses and Opportunistic Infections in San Francisco.
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Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
Biography | Disclosures | Summaries
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Agree we need better treatments for covid, and I think we need better treatments for all respiratory viruses! Our current options are so limited, and not that effective.