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. On additional secondary objectives in the PANORAMIC study, compared to usual care, LAGEVRIO-treated participants reported: Reduced time to sustained recovery (21 days vs.

24 days); Reduced time to sustained alleviation of all symptoms (9 days vs. 12 days); Reduced time to reduction of symptom severity (8 days vs. 12 days); Higher self-rating of wellness on Days 7, 14, and 28; Fewer moderate or severe symptoms at Day 7, 14, and 28 for cough, shortness of breath, loss of taste/smell, and fatigue; Less health care seeking in primary care, including less contacts with a general practitioner or the UK National Health Service (NHS).

Additionally, a greater proportion of LAGEVRIO patients reported: Early sustained recovery, defined as recovered by Day 14 and remained recovered until Day 28 (32% receiving LAGEVRIO vs. 23% receiving usual care); Sustained recovery, defined as date participant first reported recovery and subsequently remained well until 28 days (69% vs. 60%); Sustained alleviation of all symptoms, defined as date symptoms first reported as minor or none and subsequently remained minor or none until 28 days (84% vs.

79%). The PANORAMIC trial (Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In the Community), led by the University of Oxford and funded by UK Research and Innovation (UKRI) and National Institute for Health Research (NIHR), studied treatments approved by the UK Medicines and Health Care Products Regulatory Agency (MHRA), including LAGEVRIO, in patients with confirmed COVID-19 and ongoing symptoms. The study is a pragmatic-design trial intended to inform policy and public on treatments for COVID-19. The study began recruitment in December 2021 and completed enrollment in April 2022, all during the era of the Omicron variant.

Overall, 25,783 participants were randomized in the trial to LAGEVRIO (added to usual care) or usual care alone; the participant demographics, baseline characteristics, and other COVID-related characteristics at baseline were similar in the 2 groups. The trial sample size was intentionally expanded during the course of the trial from the initial goal of 10,600, due to a very low observed event rate for the primary endpoint of hospitalizations/deaths through Day 28 (observed <1% vs. initial estimate of 3%).

Approximately 20% of participants were aged 50 to 65 years without additional risk factors. Treatment with LAGEVRIO (standard dose 800 mg twice daily for 5 days; added to usual care) or usual care alone was initiated within 5 days of COVID-19 symptom onset in participants confirmed to have a positive PCR or rapid antigen test for SARS-CoV-2 in the past 7 days prior to treatment onset. The median duration of COVID-19 symptoms prior to treatment onset was 3 days.

Overall, 87% of participants received treatment within 5 days of symptom onset. More than 95% of the participants reported taking LAGEVRIO for the full 5-day treatment course.