On Oct. 6, 2022, Merck and Ridgeback Biotherapeutics issued the following announcement regarding data from two real-world evidence studies evaluating LAGEVRIO™ (molnupiravir), an investigational oral antiviral COVID-19 medicine. The first study, PANORAMIC, was conducted by the University of Oxford in the UK in highly-vaccinated adults mostly less than age 65 during the period when the circulating SARS-CoV-2 variant was predominantly Omicron.

The second study, Clalit, was conducted by investigators in Israel in mostly older adults with underlying chronic health conditions that make them vulnerable to severe COVID-19 disease, also when Omicron was the most dominant strain. The PANORAMIC pre-print was published and the Clalit pre-print was published last week. Additionally, Merck is reporting results from a recent carcinogenicity study in transgenic mice, which demonstrated that LAGEVRIO was not carcinogenic at any dose tested.

The PANORAMIC study, a UK-based clinical trial sponsored by the University of Oxford, included 25,783 participants who were randomized to open label treatment with LAGEVRIO plus usual care (n=12,821) or usual care alone (n=12,962); mean age of participants was 56.6 years. Primary outcome data were available in 25,000 (97%) participants. Nearly all (>98%) participants were vaccinated, with approximately 95% receiving three or more doses of a SARS-CoV-2 vaccine. In the preliminary analysis, the primary endpoint of reduction of hospitalizations and deaths within 28 days of randomization, compared to usual care, was not met; 0.8% of patients in both the LAGEVRIO group (n=103/12,516) and the usual care group (n=96/12,484) were hospitalized or died in the first 28 days.

On secondary objectives, LAGEVRIO was associated with improvement on a range of measures compared to usual care. The observed median time to first self-reported recovery (the main secondary endpoint) was 6 days shorter in the LAGEVRIO group; the median time to first recovery was 9 days on LAGEVRIO (range 5-23 days) vs. 15 days on usual care (range 7 to not reached). Following adjustment for age and baseline comorbidity, there was a substantial estimated improvement of 4 days in time-to-first recovery in the LAGEVRIO group vs. usual care group (10.4 days vs. 14.5 days; treatment benefit ratio 1.36 (95% Bayesian credible interval (BCI) 1.3-1.4). The finding on time-to-first recovery was consistent for LAGEVRIO across key subgroups. Secondary objectives were not adjusted for multiplicity.

In this observational, retrospective cohort study, LAGEVRIO was associated with a lower rate of hospitalizations and mortality due to COVID-19 in patients 65 years and above, but not in younger adults. In patients 65 years of age and above (n=13,569), hospitalizations related to COVID-19, the primary endpoint, occurred in 18 LAGEVRIO-treated patients (74.6 per 100,000 person-days) and in 513 untreated patients (127.6 per 100,000 person-days); adjusted hazard ratio (HR) for hospitalization was 0.55 (95% confidence interval (CI), 0.34 to 0.88). The secondary endpoint of death due to COVID-19 in this same age group occurred in 4 of 845 LAGEVRIO-treated and 137 of 12,724 untreated patients; adjusted HR=0.26 (95% CI, 0.10 to 0.73).

In patients 40 to 64 years of age (n=6,229), hospitalizations related to COVID-19, the primary endpoint, occurred in 8 treated patients (125.8 per 100,000 person-days) and

97 untreated patients (49.1 per 100,000 person-days), and adjusted HR for hospitalization was 1.80 (95% CI, 0.86 to 3.77). The secondary endpoint of death due to COVID-19 in this same age group occurred in 4 of 224 LAGEVRIO-treated and 7 of 6,075 untreated patients; adjusted HR=12.82 (95% CI, 3.41 to 48.17). All four deaths in the LAGEVRIO-treated group occurred in patients 60-64 years of age.