Pos1268 phase ii trial of enpatoran in patients hospitalized with covid-19 pneumonia

BackgroundEnpatoran is a selective and potent dual toll-like receptor (TLR) 7/8 inhibitor in development for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE). Enpatoran inhibits TLR7/8 activation in vitro and suppresses disease activity in lupus mouse models.1 Enpatoran was well tolerated and had linear pharmacokinetic (PK) parameters in healthy volunteers.2 As TLR7/8 mediate immune responses to single-stranded RNA viruses, including SARS-CoV-2, it was postulated that enpatoran may prevent hyperinflammation and cytokine storm in COVID-19.ObjectivesIn response to the COVID-19 pandemic, we conducted an exploratory Phase II trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. PK and pharmacodynamics (PD) of enpatoran were also evaluated.MethodsANEMONE was a randomized, double-blind, placebo (PBO)-controlled study conducted in Brazil, the Philippines, and the USA (NCT04448756). Pts aged 18–75 years, hospitalized with COVID-19 pneumonia (WHO 9-point scale score =4) but not mechanically ventilated, with SpO2 <94% and PaO2/FiO2 ≥150 (FiO2 maximum 0.4) were eligible. Those with a history of uncontrolled illness, active/unstable cardiovascular disease and SARS-CoV-2 vaccination were excluded. Pts received PBO or enpatoran (50 or 100 mg twice daily [BID]) for 14 days, with monitoring to Day 28 and safety follow-up to Day 60. Primary outcomes were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (time to clinical status >4, WHO 9-point scale) was a secondary outcome. Exploratory endpoints were enpatoran and biomarker concentrations (cytokines, C-reactive protein [CRP], D-dimer and interferon gene signature [IFN-GS] scores) assessed over time.Results149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID; 88% completed treatment and 86% received concomitant steroids. Median age was 50 years (77% <60 years old), 66% were male, and 50% had ≥1 comorbidity (40% hypertension, 24% diabetes). Overall, 59% pts reported a treatment-emergent adverse event (TEAE) with three non-treatment-related deaths; 11% reported a treatment-related TEAE. The proportion of pts in the enpatoran group reporting serious TEAEs was low (50 mg BID 9%; 100 mg BID 2%) vs PBO (18%). Gastrointestinal disorders were most common (PBO 8%; 50 mg BID 28%; 100 mg BID 9%). The primary outcome of time to recovery with enpatoran vs PBO was not met; medians were 3.4–3.9 days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed; hazard ratios [95% CI] for enpatoran vs PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Mean enpatoran exposure was dose-proportional, and PK properties were within expectations. The median (quartile [Q]1– Q3) interleukin 6 (IL-6), CRP and D-dimer baseline concentration across the groups were 5.7 (4.0–13.5) pg/mL, 30.04 (11.40–98.02) and 0.62 (0.39–1.01) mg/L, respectively. Baseline IFN-GS scores were similar across groups.ConclusionThe ANEMONE trial was the first to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpatoran up to 100 mg BID for 14 days was well tolerated by patients acutely ill with COVID-19 pneumonia. Time to recovery was not improved with enpatoran, perhaps due to the younger age of patients who had fewer comorbidities compared to those in similar COVID-19 trials. However, there was less likelihood for clinical deterioration with enpatoran than placebo. This trial provides important safety, tolerability, PK and PD data supporting continued development of enpatoran in SLE and CLE (NCT04647708, NCT05162586).References[1]Vlach, et al. J Pharmacol Exp Ther 2021;376:397–409;[2]Port, et al. Pharmacol Res Perspect 2021;9:e00842.AcknowledgementsWe would like to thank those who took part in the the ANEMONE trial. This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsJohn E. McKinnon Consultant of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Joel Santiaguel Speakers bureau: Merck Healthcare KGaA, Claudia Murta Speakers bureau: Pfizer/Wyeth, Dongzi Yu Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Mukhy Khursheed Employee of: Merck Serono Ltd (an affiliate of Merck KGaA), Flavie Moreau Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Lena Klopp-Schulze Employee of: Merck Healthcare KGaA, Jamie Shaw Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Sanjeev Roy Employee of: Ares Trading SA (an affiliate of Merck KGaA), Amy Kao Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA)