John McKinnon1, Joel Santiaguel2, Claudia Murta De Oliveira3, Dongzi Yu4, Mukhy Khursheed5, Flavie Moreau6, Lena Klopp-Schulze7, Jamie Shaw8, Sanjeev Roy9 and Amy Kao10, 1Department of Medicine, Henry Ford Hospital, Detroit, MI, 2Internal Medicine, Quirino Memorial Medical Center, Quezon City, Philippines, 3Ambulatório de Pesquisa Clínica, Santa Casa de Misericórdia, Belo Horizonte, Brazil, 4Global Clinical Development, EMD Serono, Billerica, MA, 5Global Patient Safety, Merck Serono Ltd., an affiliate of Merck KGaA, Darmstadt, Germany, 6Global Biostatistics, EMD Serono, Billerica, MA, 7Translational Medicine, the healthcare business of Merck KGaA, Darmstadt, Germany, 8Translational Medicine, EMD Serono, Billerica, MA, 9Global Clinical Development, Ares Trading SA, an affiliate of Merck KGaA, Darmstadt, Germany, 10EMD Serono, Billerica, MA
Background/Purpose: Enpatoran 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). As TLR7/8 mediate immune responses to single-stranded RNA viruses, we postulated that enpatoran may prevent hyperinflammation and cytokine storm in COVID-19. In response to the COVID-19 pandemic, we conducted an exploratory trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. Pharmacokinetics (PK) and pharmacodynamics (PD) of enpatoran were also evaluated.
Methods: ANEMONE was a randomized, double-blind, placebo (PBO)-controlled study (NCT04448756). Pts aged 18–75 years, hospitalized with COVID-19 pneumonia 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) over time.
Results: In total, 149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID. Median age was 50 years (77% < 60 years old), 66% were male, and 50% had ≥ 1 comorbidity. Treatment-emergent adverse events (TEAEs) were reported by 59% pts, with lower proportions of serious TEAEs reported in the enpatoran groups (50 mg BID 9%; 100 mg BID 2%) vs PBO (18%). Treatment-related TEAEs were reported by 11% pts. There were 3 non-treatment related deaths. 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, 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.
Conclusion: The ANEMONE trial was the first to evaluate the safety and efficacy of a TLR7/8 inhibitor for cytokine storm prevention in an infectious disease. Enpatoran was well tolerated by pts acutely ill with COVID-19 pneumonia. Time to recovery was not improved by enpatoran, possibly because the patients were younger, with fewer comorbidities, than 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.
Disclosures: J. McKinnon, EMD Serono, Billerica, MA, USA, ViiV Healthcare, Theratechnologies; J. Santiaguel, the healthcare business of Merck KGaA, Darmstadt, Germany; C. Murta De Oliveira, Pfizer/Wyeth (vaccines); D. Yu, EMD Serono, Billerica, MA, USA; M. Khursheed, Merck Serono Ltd (an affiliate of Merck KGaA); F. Moreau, EMD Serono, Billerica, MA, USA; L. Klopp-Schulze, the healthcare business of Merck KGaA, Darmstadt, Germany; J. Shaw, EMD Serono, Billerica, MA, USA; S. Roy, Ares Trading SA (an affiliate of Merck KGaA); A. Kao, EMD Serono, Billerica, MA, USA.
