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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-ii-trial-of-enpatoran-in-patients-hospitalized-with-covid-19-pneumonia/