ENPATORAN SAFETY and EFFICACY in COVID-19 PNEUMONIA: ANEMONE TRIAL

ABSTRACT

Background: Enpatoran, a selective and potent toll-like receptor 7 and 8 (TLR7/8) inhibitor, is in development for treating autoimmune diseases. Enpatoran may prevent hyperinflammation and cytokine storm in COVID-19 by targeting pro-inflammatory pathways induced by SARS-CoV-2. Methods: The ANEMONE study, a phase II, randomized, double-blind, placebo-controlled trial conducted in the US, the Philippines, and Brazil, assessed the safety and efficacy of enpatoran in COVID-19 pneumonia (NCT04448756). Eligible hospitalized patients were aged 18-75 years, with a WHO 9-point scale score of 4, confirmed COVID-19 pneumonia, SpO2 <94%, PaO2/FiO2 ≥150 (FiO2 max 0.4) and not on mechanical ventilation. Key exclusion criteria were active/unstable cardiovascular disease, history of uncontrolled illness and SARS-CoV-2 vaccination. Randomized patients (N=149) received placebo (PBO;n=49), enpatoran 50 mg twice daily (BID;n=54) or 100 mg BID (n=46) for 14 days, with monitoring up 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. Results: 88% of patients completed treatment (66% male, median age 50 years);50% had ≥1 comorbidity (including 40% hypertension, 24% diabetes). Treatment-emergent adverse events (TEAEs) were reported by 59% of patients;11% reported treatment-related TEAEs (Table). Serious TEAEs were higher with PBO (18%) than enpatoran (6%). Three non-treatment-related deaths occurred. Gastrointestinal disorders were most common (PBO 8%;50 mg BID 28%;100 mg BID 9%). Infections and infestations were reported by 18% (PBO), 17% (50 mg BID) and 4% (100 mg BID);COVID-19 worsening (PBO 8%;50 mg BID 9%) and bacterial sepsis (PBO 4%) were most common. Headache and dizziness were only reported with enpatoran (<3% across groups). Psychiatric disorders were higher with PBO (14%) than enpatoran (50 mg BID 7%;100 mg BID 4%). There was no dose effect on TEAEs. Median [95% CI] time to recovery from Day 1 through Day 28 was 3.4 [2.7, 4.9] (PBO), 3.7 [2.6, 4.0] (50 mg BID) and 3.9 [2.0, 4.8] (100 mg BID) days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed;hazard ratios [95% CI] for enpatoran versus PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Conclusion: Enpatoran was considered safe and well tolerated in hospitalized patients with acute COVID-19 pneumonia.