Applying Modeling and Simulations for Rational Dose Selection of Novel Toll-Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need
Lena Klopp-Schulze, Jamie V Shaw, Jennifer Q Dong, Akash Khandelwal, Cristina Vazquez-Mateo, Kosalaram Goteti, Lena Klopp-Schulze, Jamie V Shaw, Jennifer Q Dong, Akash Khandelwal, Cristina Vazquez-Mateo, Kosalaram Goteti
Abstract
Dual toll-like receptor (TLR) 7 and TLR8 inhibitor enpatoran is under investigation as a treatment for lupus and coronavirus disease 2019 (COVID-19) pneumonia. Population pharmacokinetic/pharmacodynamic (PopPK/PD) model-based simulations, using PK and PD (inhibition of ex vivo-stimulated interleukin-6 (IL-6) and interferon-α (IFN-α) secretion) data from a phase I study of enpatoran in healthy participants, were leveraged to inform dose selection for lupus and repurposed for accelerated development in COVID-19. A two-compartment PK model was linked to sigmoidal maximum effect (Emax ) models with proportional decrease from baseline characterizing the PD responses across the investigated single and multiple doses, up to 200 mg daily for 14 days (n = 72). Concentrations that maintain 50/60/90% inhibition (IC50/60/90 ) of cytokine secretion (IL-6/IFN-α) over 24 hours were estimated and stochastic simulations performed to assess target coverage under different dosing regimens. Simulations suggested investigating 25, 50, and 100 mg enpatoran twice daily (b.i.d.) to explore the anticipated therapeutic dose range for lupus. With 25 mg b.i.d., > 50% of subjects are expected to achieve 60% inhibition of IL-6. With 100 mg b.i.d., most subjects are expected to maintain almost complete target coverage for 24 hours (> 80% subjects IC90,IL-6 = 15.5 ng/mL; > 60% subjects IC90,IFN-α = 22.1 ng/mL). For COVID-19, 50 and 100 mg enpatoran b.i.d. were recommended; 50 mg b.i.d. provides shorter IFN-α inhibition (median time above IC90 = 13 hours/day), which may be beneficial to avoid interference with the antiviral immune response. Utilization of PopPK/PD models initially developed for lupus enabled informed dose selection for the accelerated development of enpatoran in COVID-19.
Trial registration: ClinicalTrials.gov NCT04647708 NCT04448756.
Conflict of interest statement
L.K.S. and A.K. are employees of the healthcare business of Merck KGaA, Darmstadt, Germany, and J.V.S., J.Q.D., C.V.M., and K.G. are employees of EMD Serono, Billerica, MA, USA.
© 2022 Merck KGaA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Figures
References
- Vlach, J. et al. Discovery of M5049: a novel selective TLR7/8 inhibitor for treatment of autoimmunity. J. Pharmacol. Exp. Ther. 376, 397‐409 (2020).
- Port, A. et al. Phase 1 study in healthy participants of the safety, pharmacokinetics and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptor 7 and 8. Pharmacol. Res. Perspect. 9, e00842 (2021).
- Dean, G.S. , Tyrrell‐Price, J. , Crawley, E. & Isenberg, D.A. Cytokines and systemic lupus erythematosus. Ann. Rheum. Dis. 59, 243 (2000).
- Braunstein, I. , Klein, R. , Okawa, J. & Werth, V.P. The interferon‐regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br. J. Dermatol. 166, 971–975 (2012).
- Asano, T. et al. X‐linked recessive TLR7 deficiency in ~1% of men under 60 years old with life‐threatening COVID‐19. Sci. Immunol. 6, eabl4348 (2021).
- Jiang, Y. et al. Cytokine storm in COVID‐19: from viral infection to immune responses, diagnosis and therapy. Int. J. Biol. Sci. 18, 459–472 (2022).
- de la Rica, R. , Borges, M. & Gonzalez‐Freire, M. COVID‐19: in the eye of the cytokine storm. Front. Immunol. 11, 558898 (2020).
- Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R‐848. Nat. Immunol. 3, 499 (2002).
- Hemmi, H. et al. Small anti‐viral compounds activate immune cells via the TLR7 MyD88‐dependent signaling pathway. Nat. Immunol. 3, 196–200 (2002).
- Bauer, R.J. NONMEM Tutorial Part I: description of commands and options, with simple examples of population analysis. CPT Pharmacometrics Syst. Pharmacol. 8, 525–537 (2019).
- Bergstrand, M. , Hooker, A.C. , Wallin, J.E. & Karlsson, M.O. Prediction‐corrected visual predictive checks for diagnosing nonlinear mixed‐effects models. AAPS J. 13, 143–151 (2011).
- Mohammad Hosseini, A. , Majidi, J. , Baradaran, B. & Yousefi, M. Toll‐like receptors in the pathogenesis of autoimmune diseases. Adv. Pharm. Bull. 5, 605–614 (2015).
- Farrugia, M. & Baron, B. The role of toll‐like receptors in autoimmune diseases through failure of the self‐recognition mechanism. Int. J. Inflamm. 2017, 8391230 (2017).
- Shrivastav, M. & Niewold, T.B. Nucleic acid sensors and type I interferon production in systemic lupus erythematosus. Front. Immunol. 4, 319 (2013).
- Khanmohammadi, S. & Rezaei, N. Role of toll‐like receptors in the pathogenesis of COVID‐19. J. Med. Virol. 93, 2735–2739 (2021).
- Niewold, T.B. Interferon alpha as a primary pathogenic factor in human lupus. J. Interferon Cytokine Res. 31, 887–892 (2011).
- Tanaka, Y. State‐of‐the‐art treatment of systemic lupus erythematosus. Int. J. Rheum. Dis. 23(4), 465–471 (2020).
- Venkatakrishnan, K. , Yalkinoglu, O. , Dong, J.Q. & Benincosa, L.J. Challenges in drug development posed by the COVID‐19 pandemic: an opportunity for clinical pharmacology. Clin. Pharmacol. Ther. 108, 699–702 (2020).
- Lee, J.S. & Shin, E.‐C. The type I interferon response in COVID‐19: implications for treatment. Nat. Rev. Immunol. 20, 585–586 (2020).
- Lin, F. & Shen, K. Type I interferon: from innate response to treatment for COVID‐19. Pediatr. Investig. 4, 275–280 (2020).
- Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID‐19 patients. Science 369, 718–724 (2020).
Source: PubMed