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: MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody under development to prevent RSV infection in infants. A model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinically relevant endpoints (e.g. incidence rates, IRs) in humans, including lower respiratory tract infection (LRI) in infants, was presented previously [1]. This model accounted for variable exposure to RSV over the course of the season through a force-of-infection (FOI) function modulating the overall risk of RSV infection over time. On each day of the RSV season, overall infection risk is driven by FOI and SNA on that day. Understanding the interplay between FOI and SNA is, therefore, crucial to determine expected RSV infection rates after mAb prophylaxis. Because of this, an efficacy simulation framework was set up to support future MK1654 decision making. The objectives of the work were to: (1) outline how this FOI function can be applied to epidemiological data to account for differences in RSV seasonality; (2) develop a framework to apply this methodology, through efficacy simulation, to evaluate whether variations in regional seasonality would impact the efficacy of different hypothetical compounds; and (3) illustrate the interplay between FOI and efficacies through simulation of varying, extreme SNA profiles.
Methods: An FOI function to describe the degree of RSV exposure as a function of time was created by fitting epidemiological data [2] to a Gaussian function added to a constant baseline value. Epidemiological RSV data from temperate regions in the United States between 2007 and 2012 were used to describe temperate RSV seasonality, while data from Puerto Rico were used to describe tropical RSV seasonality. Clinical trial simulations were conducted using the MBMA model to predict seasonal IR of RSV medically attended LRI (MALRI) and efficacies for the hypothetical compounds with differing potencies in both temperate and tropical regions. Potencies were selected to cover a broad SNA range in the simulations. As a sensitivity analysis, simulations were also performed using non-physiological SNA time courses representing potential extreme scenarios.
Results: Epidemiological data were captured well by the FOI function. Clinical trial simulations indicated that seasonal IRs of RSV were sensitive to differences in the FOI represented by temperate and tropical regions. In contrast, treatment administered at the start of the RSV season is expected to achieve similar efficacy for the prevention of RSV MALRI in late stage clinical trials in both climates, irrespective of the compound simulated. The sensitivity analysis showed that a constant FOI throughout the year results in different predicted efficacy than a FOI representing a tropical climate for SNA time courses representing extreme scenarios, and that timing of maximum SNA (due, in part, due to timing of the trial enrollment) relative to maximum FOI can impact predicted efficacies.
Conclusions: RSV seasonality across different climates was successfully incorporated into clinical trial simulation to account for variations in RSV disease FOI. Simulations indicated that while FOI is a substantial driver of overall RSV incidence rates, efficacy results of late stage clinical trials for temperate and tropical regions may be comparable. These results were incorporated into MK-1654 decision making and will be further substantiated by future efficacy simulations for MK-1654.
References:
[1] Maas BM, Lommerse J, Mueller-Plock N, Caro L, Cheung SYA, Meng J, Qin L, Chen J, Railkar RA, Vora KA, Aliprantis AO, Sachs JR. Closing the Gap: Using MBMA to Make Informed Decisions on Anti-RSV Drug Development. American Conference on Pharmacometrics (ACoP11); Virtual. Nov 2020.
[2] McGuiness, CB, Boron ML, Saunders B, Edelman L, Kumar VR, Rabon-Stith KM. 2014. Respiratory syncytial virus surveillance in the United States, 2007-2012: results from a national surveillance system, Pediatr Infect Dis J, 33: 589-94.
Reference: PAGE 29 (2021) Abstr 9714 [www.page-meeting.org/?abstract=9714]
Poster: Drug/Disease Modelling - Infection