Nele Plock (1), Jos Lommerse (1), Brian M. Maas (2), Jingxian Chen (2), Francesco Bellanti (1), Li Qin (1), Han Witjes (1), Philippe Pierrillas (1), Radha A. Railkar (2), Antonios O. Aliprantis (2), Kalpit Vora (2), Wei Gao (2), Luzelena Caro (2), S. Y. Amy Cheung (1), Jeffrey R. Sachs (2)
(1) Certara, Princeton, NJ, USA (2) Merck & Co., Inc., Kenilworth, NJ, USA
Objectives:
There is a high unmet medical need for respiratory syncytial virus (RSV) prophylaxis in infants with convenient once-per-season dosing. MK-1654 is an RSV neutralizing monoclonal antibody with an extended half-life under development for this population. A model-based meta-analysis (MBMA) approach describing the relationship between RSV serum neutralizing activity and clinically relevant endpoints in humans has been used to predict the efficacy of MK-1654 in an ongoing Phase 3 trial in infants [1]. Precautions taken in response to the COVID-19 pandemic, such as masking and social distancing, have reduced seasonal transmission of respiratory viruses, including RSV [2]. Removal of these precautionary measures may result in more severe and atypical outbreaks of RSV [2]. The objective of this work was to conduct clinical trial simulations using the MBMA model, which accounts for variable exposure to RSV over the course of the season through a force-of-infection function, and to evaluate whether a protracted, delayed, and more intense RSV season could impact the predicted efficacy of MK-1654 in the ongoing trial.
Methods: A force-of-infection function to describe the time-dependent strength of RSV exposure was created by fitting epidemiological data [3] from temperate regions in the United States to a Gaussian function. Clinical trial simulations were conducted to predict seasonal incidence rates of RSV medically attended lower-respiratory tract infection and efficacies. Simulations were performed (1) for a typical force-of-infection profile from a temperate climate, and (2) a force-of-infection profile modified to represent COVID-19 pandemic impact, assuming higher intensity, 1-month peak delay, and a prolonged season of 7 months.
Results: Clinical trial simulations revealed that for a typical RSV season not impacted by the pandemic, MK-1654 is predicted to maintain high efficacy (> 75%) for the prevention of RSV medically attended lower-respiratory tract infection with doses of 75 mg or greater, through 150 days. Results from simulations for an RSV season impacted by the COVID-19 pandemic (longer, more intense season delayed by 1 month) indicate increases in overall RSV incidence rates. However, despite somewhat lower efficacy estimates, MK-1654 would still yield efficacy of at least 65% at a dose of 75 mg for up to 7 months. A dose of 90 mg is predicted to yield efficacy of at least 70% through 7 months for the same scenario.
Conclusions: Predictions from the MBMA/Clinical trial simulation/force-of-infection framework show that MK-1654 maintains high efficacy through a typical 5-month RSV season. Atypical RSV seasonality – caused by prior pandemic precautions – may result in an underestimation of true MK-1654 efficacy in the ongoing trial, relative to a trial conducted during standard RSV seasons. Regardless, simulation results suggest that MK-1654 is likely to demonstrate high efficacy against RSV medically attended lower-respiratory tract infection through 150 days, even in the face of pandemic-driven changes to RSV seasonality.
References:
[1] Maas BM. Closing the Gap: Using MBMA to Make Informed Decisions on Anti-RSV Drug Development. ACoP11; Virtual. Nov 2020.
[2] Baker RE, et. al. Proc Natl Acad Sci USA. 2020 Dec 1;117(48):30547-30553.
[3] McGuiness, CB, et.al. Pediatr Infect Dis J. 2014 Jun;33(6):589-94.
Reference: PAGE 30 (2022) Abstr 9996 [www.page-meeting.org/?abstract=9996]
Poster: Drug/Disease Modelling - Infection