Update on new clinical and non-clinical studies of Lagevrio

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.

Preliminary results from the PANORAMIC study: 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 greater than 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.

Results from the Clalit study 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 Lavevrio-treated group occurred in patients 60-64 years of age.

“The totality of the data from both PANORAMIC and Clalit give us critical insights into the ways certain patients may benefit from treatment with Lagevrio. These data also emphasize the critical need and value for Lagevrio in the treatment of mild to moderate COVID-19 for appropriate high-risk patients. Most significantly, the Clalit study reinforces what the Phase III MOVe-OUT study demonstrated - a reduction in hospitalizations and mortality in an older population at high risk for progression to severe disease, where a clinically meaningful benefit was observed,” said Dr. Dean Y. Li, president, Merck Research Laboratories. “These findings, particularly with regard to symptomatic improvement seen in a secondary objective in PANORAMIC and the reduction in hospitalization and death rates seen in the older part of the patient population in Clalit, further support the urgent need for global access to Lagevrio for the treatment of COVID-19 in appropriate high-risk patients.”

“With the continuing uncertainty about potential severity of emerging variants, we are pleased that the real-world data from Israel showed that, in an older part of the study population that experienced more hospitalizations, rates of hospitalization and death were reduced in patients taking Lagevrio. Also notable is the substantial reduction in time to symptom resolution observed on a secondary endpoint in PANORAMIC even when background hospitalization rates were low. The observed six-day improvement symptom resolution in the PANORAMIC study is an important finding as we look for ways to further reduce the burden of this virus" said Wendy Holman, chief executive officer, Ridgeback Biotherapeutics.

Additional results - PANORAMIC secondary and virology endpoints: On additional secondary objectives in the PANORAMIC study, compared to usual care,Lagevrio-treated participants reported: i. Reduced time to sustained recovery (21 days vs. 24 days);ii. Reduced time to sustained alleviation of all symptoms (9 days vs. 12 days); iii.Reduced time to reduction of symptom severity (8 days vs. 12 days); iv. Higher self-rating of wellness on Days 7, 14, and 28; v. Fewer moderate or severe symptoms at Day 7, 14, and 28 for cough, shortness of breath, loss of taste/smell, and fatigue; vi. 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: i. Early sustained recovery, defined as recovered by Day 14 and remained recovered until Day 28 (32% receiving Lagevrio. 23% receiving usual care); ii. Sustained recovery, defined as date participant first reported recovery and subsequently remained well until 28 days (69% vs. 60%); iii. 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%).

In a substudy in which a cohort of participants was sampled for virology outcomes: i. On Day 7, SARS-CoV-2 virus was below detection in 21% receiving Lagevrio vs. 3% receiving usual care; ii. The mean viral load on Day 7 was lower on Lagevrio (3.82 log10 viral load) as compared to usual care (4.93 log10 viral load). iii.Lagevrio was generally well tolerated, with serious adverse events reported at a rate of 0.4% in both study groups and a low treatment withdrawal rate (1.1%).

About the PANORAMIC study: 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.The study was designed as an open-label, prospective, individually-randomized, controlled clinical trial evaluating the efficacy and safety for Lagevrio added to usual care compared to usual care alone in participants who have confirmed COVID-19 infection, in adults who were either greater than 50 years of age or greater than 18 years of age with comorbidities/known underlying chronic health conditions making them clinically vulnerable to COVID-19 infection. Usual care was predominantly focused on managing symptoms with antipyretics; however, participants at highest risk (very impaired immunity or extremely clinically vulnerable) were eligible for additional therapies, including monoclonal antibodies (sotrovimab) and intravenous remdesivir.

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.

Update on results from recent carcinogenicity study: Results from a recent study (Tg RasH2) evaluating carcinogenicity in transgenic mice that received molnupiravir orally for six months at doses of 30, 100 or 300 mg/kg/day demonstrated that Lagevrio was not carcinogenic. These results further support the safety profile of Lagevrio.

See- "Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): preliminary analysis from the United Kingdom randomised, controlled open-label, platform adaptive trial".Christopher Butler, Richard Hobbs, Oghenekome Gbinigie,Najib M. Rahman,et al. October 4, 2022.https://papers.ssrn.com/sol3/papers.cfm.abstract_id=4237902.

See- "Molnupiravir Use and Severe Covid-19 Outcomes During the Omicron Surge":Ronen Arbel, Yael Wolff Sagy, Erez Battat, Gil Lavie, Ruslan Sergienko, and 6 more. This is a preprint; it has not been peer reviewed by a journal. https://doi.org/10.21203/rs.3.rs-2115769/v1.(Research Square).