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1.
Annals of the Rheumatic Diseases ; 81:971-972, 2022.
Article in English | EMBASE | ID: covidwho-2009130

ABSTRACT

Background: 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). 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 hyperinfammation and cytokine storm in COVID-19. Objectives: In 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. Methods: ANEMONE was a randomized, double-blind, placebo (PBO)-con-trolled 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. Results: 149 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. Conclusion: The ANEMONE trial was the frst to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpa-toran 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).

2.
Topics in Antiviral Medicine ; 30(1 SUPPL):179, 2022.
Article in English | EMBASE | ID: covidwho-1880576

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.

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