The editorial published in Lancet Infectious Diseases October 14th 2021, reviews this issue.
There has been widespread coverage in the media of Merck and Ridgeback’s interim results of their phase 2 trial of the antiviral molnupiravir. According to a press release from Merck on October 1st, molnupiravir reduced the risk of hospitalisation or death by roughly 50% compared with placebo in non-hospitalised patients with mild to moderate COVID-19 and at least one risk factor for disease progression.
It is worth bearing in mind that molnupiravir can be orally administered, which means that the drug could be taken at home and used widely in settings with inadequate healthcare infrastructure.
Merck had also announced that it plans to implement a tiered pricing approach based on the World Bank income criteria.
It also has agreements with established generic drug manufacturers in more than 100 countries to allow rapid and local production of molnupiravir upon the drug’s approval by licensing authorities.
Owing to the urgent need for treatments for hospitalised, critically ill COVID-19 patients, research on drugs for use in the outpatient setting has understandably lagged behind.
Additionally, the existence of SARS-CoV-2 vaccines that are highly effective against hospital admissions and death might be impacting the sense of urgency for these drugs. Yet, global inequity in access to vaccines means that there is a serious unmet need for pharmaceutical interventions to limit SARS-CoV-2 infections or progression of COVID-19.
Generally, the viral load peaks in the first week, soon after symptom onset, and declines thereafter; antibodies are typically detectable after two weeks.
In certain risk groups including the immunocompromised, viral load remains high for longer owing to delayed or inadequate development of antibodies, resulting in a greater risk of progression to serious illness or death. These people would benefit from a drug that accelerates antiviral clearance.
As well as molnupiravir, another drug that might benefit people with prolonged high viral load is remdesivir; however, disappointing results have been found in hospitalised patients possibly due to the drug being administered too late in the disease to make a difference. Remdesivir has shown promise for use in the outpatient setting.
It was found in the PINETREE study that remdesivir reduced the risk of hospitalisation by 87% and of COVID-19-related medically attended visits or all-cause death by day 28 by 81%, compared with placebo in outpatients at high risk of severe disease.
Despite the promising preliminary results for these two antivirals, there are caveats. Remdesivir is administered intravenously, which might preclude its widespread use in community setting. It is interesting to note that two pharma companies in India have sought permission to end the late-stage trials of molnupiravir in patients with moderate COVID-19 owing to lack of efficacy.
These findings suggest that molnupiravir has efficacy only in the early stages of disease, which limits its usefulness due to delays in testing and healthcare seeking.
Monoclonal antibodies are also being tested in the outpatient setting with some promising results. For example, AstraZeneca has sought emergency use authorisation from the United States regulator for AZD7442, a cocktail of two long-acting monoclonal antibodies after it was shown that they reduce the risk of any COVID-19 symptoms by 77% in a phase 3 trial.
AZD7442 is administered intramuscularly, which might make it more attractive than other monoclonal antibodies under investigation, which typically require intravenous administration. However, the high cost of monoclonal antibodies will be a barrier to their widespread use.
The editorial continues to suggest that as SARS-CoV-2 will become endemic, research should focus on identifying safe, affordable and globally accessible drugs for treatment and prevention of COVID-19 in the community.
The London General Practice, the leading London doctors’ clinic in Harley Street provides full medical services for all aspects of COVID-19. This includes testing, safety net service and referral to appropriate specialists.
Dr Paul Ettlinger
BM, DRCOG, FRCGP, FRIPH, DOccMed