PANORAMIC: important insights into molnupiravir use in COVID-19

Oral antivirals have been an important addition to efforts to minimise adverse COVID-19 outcomes in individuals at high risk. Although no head-to-head comparisons of the widely available treatments molnupiravir and nirmatrelvir–ritonavir have been published, early trial findings (done largely in unvaccinated populations during pre-omicron SARS-CoV-2 waves) suggested less benefit from molnupiravir.

The first trial¹ of nirmatrelvir–ritonavir in COVID-19 suggested that participants were 89% less likely to be hospitalised or die (compared with placebo), whereas the first trial² of molnupiravir showed only a 30% reduction with molnupiravir compared with placebo. Subsequent observational studies in Hong Kong,³ Israel,⁴ and Australia⁵ have suggested an association between molnupiravir and a reduced risk of death among high-risk people, especially those aged 65 years or older.

PANORAMIC is a UK-based national, multicentre, open-label, multigroup trial of COVID-19 treatments in primary care. In The Lancet, Christopher Butler and colleagues⁶ report the results of the PANORAMIC arm in which molnupiravir plus usual care was compared with usual care alone as an early treatment for community-based adults with COVID-19 at higher risk of adverse outcomes. These findings provide important further contributions to knowledge about community use of oral COVID-19 antiviral treatments, including insights into how molnupiravir might be used to maximise benefits to individual patients and the wider community.

The primary outcome in PANORAMIC was all-cause hospitalisation or death within 28 days of randomisation. Although the large sample size in PANORAMIC (n=25 708 in the primary analysis population) was reflective of much of the general UK population, and was powered for the primary outcome, the population studied was young (mean age 56·6 years). Only 1638 (6%) of participants were aged 75 years or older. 13 090 (51%) were aged 18–65 years (included because they were in an at-risk group), and 5796 (23%) were aged 50–65 years and not in an at-risk group. 24 198 (94%) participants were white. The study population is thus not representative of the population most at risk of hospitalisation and death from COVID-19 infection in the UK, including care home residents and people with dementia and Parkinson's disease.⁷

Data for the primary outcome were available for 25 054 (97%) participants. 105 (1%) of 12 529 people in the molnupiravir plus usual care group and 98 (1%) of 12 525 in the usual care group were hospitalised or died (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; posterior probability of superiority 0·33).⁶ The study provides strong evidence that molnupiravir does not reduce the already low frequency of hospitalisation and death among high-risk—but not necessarily the highest risk—highly vaccinated adults in the community infected mainly with the omicron variant of COVID-19.

In view of the study population, and the fact that 24 290 (94%) participants had received at least three doses of a COVID-19 vaccine, the study findings are not surprising—particularly the low rate of hospitalisation or death in both groups. It will be interesting to see if the results of the nirmatrelvir–ritonavir arm of the study will be similar.

Butler and colleagues acknowledge that their findings might be “less applicable” in people with COVID-19 who are extremely clinically vulnerable.⁶ We would go a step further and urge caution in seeking to apply the findings of this study to those at highest risk from COVID-19 complications.

In Australia, nirmatrelvir–ritonavir and molnupiravir are provisionally approved for the treatment of COVID-19 and subsidised under the national Pharmaceutical Benefits Scheme. Both treatments can be prescribed by general practitioners (and dispensed through community pharmacies) to people at high risk of severe illness who test positive for COVID-19, including all people aged 70 years or older. A large proportion of people enrolled in PANORAMIC would not be eligible for subsidised treatment in Australia.⁸

The advice in Australia is that molnupiravir should be considered for use only if nirmatrelvir–ritonavir is contraindicated or unsuitable.⁹ However, the many potential drug interactions with nirmatrelvir–ritonavir mean that molnupiravir is the dominant antiviral being used to treat people aged 70 years or older (especially in care homes). Analysis of Australian data⁵ suggests that early treatment provides the greatest benefit, with a reduced risk of hospitalisation not apparent in older people treated 2 or more days after diagnosis (the median time from symptom onset to starting medication in PANORAMIC was 3 days). Prompt commencement of oral treatments after diagnosis might be essential to maximise benefits.

Although PANORAMIC was not powered for secondary outcomes, there are important policy implications in the study's secondary endpoints. The trial showed that the addition of molnupiravir to usual care resulted in faster time to recovery and reduced viral detection and load (in a small virology substudy).⁶ The shortened and sustained symptom reduction, together with the effects on viral clearance, could be an important consideration in high-risk settings, such as care homes, in terms of potentially minimising the spread of infection among high-risk people. Molnupiravir might also provide benefits to health-care systems, especially during community surges, by potentially allowing health workers to return safely to work sooner.

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