LB-005 - MOLNUPIRAVIR EXPOSURE-RESPONSE RELATIONSHIPS FOR CLINICAL OUTCOMES, VIROLOGY, AND MECHANISM OF ACTION BIOMARKERS ARE CONSISTENT IN TREATMENT OF COVID-19.

A. Chawla, R. Birger, H. Wan, Y. Cao, J. Strizki, A. Fridman, B. Maas, A. Paschke, C. De Anda, M. Rizk, J. Stone; Merck & Co., Inc., Rahway, NJ, United States.

Background: Exposure-response (E-R) analysis supported molnupiravir Phase 3 dose selection based on viral load (VL) and mechanism of action (MOA) markers from Phase 2. This analysis evaluated how well these biomarkers predict the E-R for hospitalization or death in Phase 3.

Methods: The following E-R models were developed and compared: (1) logistic regression of the primary outcome (hospitalization or death) from Phase 3, (2) VL change from baseline (CFB) from Phase 2 and 3, and (3) low frequency nucleotide substitutions (LNS), a measure of MOA, from Phase 2. Individual estimates of exposure were derived from population PK modeling of sparse samples collected in all patients. All work was performed using R version 3.0 or later.

Results: All E-R relationships were best represented by an Emax model with AUC50 estimates of 19900, 10260, and 4390 nM*hr for hospitalization, Day 5 VL CFB, and LNS mutation rate, respectively. Normalized E-R relationships were overlaid (Figure), illustrating consistency in E-R shape. Plasma NHC AUC0-12 was identified as the PK driver. Patients at 800 mg achieved near maximal response.

Conclusion: E-R results support the dose of 800 mg Q12H for treatment of COVID-19. E-R relationships for MOA and virology biomarkers were consistent with the clinical E-R.

Bernal, A.J. et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 386, 509-520 (2022).

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