PI-068 - EXPOSURE-RESPONSE ANALYSIS OF MK-5475 IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION

D. Li¹, Z. Hu¹, T. Peyret², S. Mouksassi^3,4, S. Ayalasomayajula⁵, M. Rizk⁶, M. Johnson⁷, I. Younis⁷; ¹Merck, MRL, Merck & Co., Inc., Rahway, NJ, USA, ²Certara, Radnor, PA, USA, ³Certara, PA, USA, ⁴Applied Pharmacometrics Training - Africa Program, c/o Pharmacometrics Africa NPC, Cape Town, South Africa, ⁵MRL-TMED-QP2, Rahway, NJ, USA, ⁶Merck, Rahway, USA, ⁷Merck, Rahway, NJ, USA.

Background: MK-5475 is a sGC stimulator being developed for the treatment of PAH following inhalation administration. The objective of this study was to develop a population exposure-response model to characterize the relationships between MK-5475 exposures with efficacy endpoints including pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD).

Methods: Data from an ongoing Phase 2 study wherein the efficacy data from 168 PAH patients receiving inhalation treatment once daily for 12 wks are available and included in this analysis. The treatments include placebo (N=41), 32 µg (N=42), 100 µg (N=44) or 380 µg (N=41) of MK-5475. A previously developed popPK model was used to estimate exposure in PAH patients in the study. Efficacy data including PVR and 6MWD at baseline and week 12 were utilized for development of the exposure-efficacy model.

Results: A significant dose/exposure-response relationship was observed for PVR endpoint. An Emax model based on steady state AUCo-24hr was fitted to describe the exposure-PVR relationship. The typical placebo-adjusted Emax for MK-5475 on PVR decrease from baseline was predicted to be ~16.7% (100 Dyn.s/m-5). No covariate was found to significantly impact the exposure-PVR relationship. The plateau of PVR response was achieved at 380 µg dose. The observed maximum 6MWD change from baseline was 26.3m. However, based on exploratory analysis, no dose/exposure-response relationship was identified for 6MWD endpoint.

Conclusion: Exposure-response relationship of MK-5475 exposure and PVR endpoint can be well described by an Emax model, with no significant covariates identified. No exposure-response relationship was identified for the 6MWD endpoint.