Applying Modeling and Simulations for Rational Dose Selection of Novel Toll-Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need

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

Figure 1

Activation of the TLR7/8 pathway by ssRNA viruses (such as SARS‐CoV‐2), RNA‐containing immune complexes, or the dual TLR7/8 agonist R848 is blocked by enpatoran. Downstream cytokines IL‐6 and IFN‐α were used in PD assessments to indirectly assess TLR7/8 occupancy by enpatoran. CR, complement receptor; DC, dendritic cell; FcR, Fc receptor; IFN, interferon; IRF7, interferon regulatory factor 7; IRAK1/4, interleukin receptor‐associated kinases 1 and 4; IL‐6, interleukin‐6; mDCs, MYD88, myeloid differentiation primary response 88; NETosis, neutrophil extracellular trap death; NF‐κB, nuclear factor‐kappa B; PD, pharmacodynamic; ROS, reactive oxygen species; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus 2; ssRNA, single‐stranded RNA; TLR7/8, toll‐like receptor 7/8; TNFα, tumor necrosis factor alpha. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Visual predictive check for plasma enpatoran PK and PD profiles following multiple dosing. Observed (n = 72) and PopPK/PD model simulated (n = 1,000 subjects per dosing scenario) plasma concentrations of enpatoran and ex vivo‐stimulated IL‐6 and IFN‐α over time on day 14 of multiple oral dose administration (9, 25, and 200 mg q.d., and 25 mg and 50 mg b.i.d.). The b.i.d. dosing cohorts received only the morning dose of 25 or 50 mg on day 14. Solid colored line = simulated median value; shaded colored area = simulated 2.5–97.5th percentiles; circles = observed data; solid black line = observed median value; dotted lines = observed 2.5–97.5th percentiles. b.i.d., twice daily; IFN‐α, interferon alpha; IL‐6, interleukin‐6; PD, pharmacodynamic; PK, pharmacokinetic; PopPK, population pharmacokinetic; PopPK/PD, population pharmacokinetic/pharmacodynamic; q.d., once daily. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Exposure–response relationship between enpatoran plasma concentrations and ex vivo‐stimulated IL‐6 (a) and IFN‐α (b) release from 72 healthy subjects across single and multiple dose cohorts of the phase I study. Solid blue slope = typical profile applying PK/PD models; Rugs on x‐axis = distribution of enpatoran concentrations colored by dosing regimen. b.i.d., twice daily; IC, inhibitory concentration; IFN‐α, interferon alpha; IL‐6, interleukin‐6; PD, pharmacodynamic; PK, pharmacokinetic; q.d., once daily.

Figure 4

Simulated Cmax,ss (a) and Cmin,ss (b) across q.d. and b.i.d. dosing regimens using the PopPK model (n = 1,000 subjects per dosing scenario). For boxplots, boxes represent interquartile ranges, horizontal lines are medians, whiskers extend to the most extreme value, which is no more than 1.5 times the box length, and points are outliers. b.i.d., twice daily; Cmax,ss, maximum concentration at steady‐state; Cmin,ss, minimum concentration at steady‐state; IC50/90, 50/90% inhibitory concentrations; IFN‐α, interferon alpha; IL‐6, interleukin‐6; PopPK, population pharmacokinetic; q.d., once daily. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5

Fraction of simulated subjects achieving IL‐6 (a) and IFN‐α (b) targets throughout the day following continuous enpatoran q.d. and b.i.d. dosing. Enpatoran q.d. and b.i.d. PK profiles over 24 hours at PK steady‐state were simulated (n = 1,000 per dosing scenario) using the PopPK model and the proportion of simulated subjects achieving IL‐6 and IFN‐α inhibition was evaluated across 24 hours. The magnified panels show the fraction of subjects achieving IL‐6 and IFN‐α targets at Cmin,ss at 24 hours. The dark green area represents the proportion of simulated subjects achieving at least 90% inhibition of IL‐6 or IFN‐α release over time. The light green area represents the proportion of simulated subjects achieving between 50 and 90% inhibition of IL‐6 or IFN‐α release, and the orange area represents those achieving < 50% inhibition, over time. b.i.d., twice daily; Cmin,ss, minimum concentration at steady state; IC50/90, 50/90% inhibitory concentrations; IFN‐α, interferon alpha; IL‐6, interleukin‐6; PK, pharmacokinetic; PopPK, population pharmacokinetic; q.d., once daily. [Colour figure can be viewed at wileyonlinelibrary.com]