Enpatoran in COVID-19 pneumonia: Safety and efficacy results from a phase II randomized trial

Abstract

Enpatoran is a selective inhibitor of toll-like receptors 7 and 8 (TLR7/8) that potentially targets pro-inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID-19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9-point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (WHO 9-point scale ≥ 5) was a key secondary objective. Treatment-emergent adverse events (TEAEs) were comparable across groups (56.5%-63.0%). Treatment-related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4-3.9 days across groups, with placebo-treated patients recovering on average faster than anticipated. Clinical deterioration event-free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID-19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.

FIGURE 1

Patient disposition. Efficacy and safety analyses were according to the actual treatment received: enpatoran 50 mg b.i.d. n = 54, enpatoran 100 mg b.i.d. n = 46, and placebo n = 49 (safety analysis set). b.i.d., twice daily. ^a151 patients were eligible to be randomized; however, 2 patients received intervention but were not randomized (enpatoran 50 mg n = 1; placebo n = 1).

FIGURE 2

Cumulative distribution function of (a) time to recovery and (b) time to clinical deterioration. Time to recovery (the time from Day 1 to first occurrence of WHO 9‐point ordinal scale of ≤3) was not improved despite a numerical trend towards higher recovery rates in both enpatoran groups. Recovery rates from Day 1 through Day 28 were 75.5% (n = 37/49) with placebo compared with 88.9% (n = 48/54) with 50 mg b.i.d. and 91.3% (n = 42/46) with 100 mg b.i.d. (p = 0.054 and 0.107 vs. placebo, respectively). The event‐free rates for clinical deterioration (the time from Day 1 to first occurrence of WHO 9‐point ordinal scale of ≥5) were higher in the enpatoran groups compared with placebo. Clinical deterioration rates Day 1 through Day 28 were 20.4% (n = 10/49) with placebo compared with 9.3% (n = 5/54) with 50 mg b.i.d. and 6.5% (n = 3/46) with 100 mg b.i.d. (p = 0.0390 and 0.0249 vs. placebo, respectively). Kaplan–Meier curves are shown. Safety analysis set, N = 149. Two patients in the placebo group had SpO₂ ≥94% at the first timepoint and were therefore not counted as at risk in the time to recovery analysis. b.i.d., twice daily.

FIGURE 3

Proportion of patients in each ordinal scale category from Day 1 to Day 60 in the (a) placebo, (b) enpatoran 50 mg b.i.d., and (c) enpatoran 100 mg b.i.d. groups. Clinical score was recorded daily during hospitalization, at the time of hospital discharge, and on study visits following discharge up to Day 60, using the WHO 9‐point ordinal scale. Fewer disease progression events were observed with enpatoran compared to placebo. Safety analysis set, N = 149. Data presented as collected with no imputation of missing data. b.i.d., twice daily. Key: 0 = Uninfected; 1 = Ambulatory: no limitation of activities; 2 = Ambulatory: limitation of activities; 3 = Hospitalized, mild disease: no oxygen therapy; 4 = Hospitalized, mild disease: oxygen by mask or nasal prongs; 5 = Hospitalized, severe disease: noninvasive ventilation or high‐flow oxygen; 6 = Hospitalized, severe disease: intubation and mechanical ventilation; 7 = Hospitalized, severe disease: ventilation plus additional organ support; 8 = Death.

FIGURE 4

Cumulative distribution function of time to recovery for patients with (a) high and (b) low interferon‐gene signature (IFN‐GS) scores at baseline. IFN‐GS scores were evaluated at baseline using DxTerity's IFN‐I Test. The cut‐off for high and low IFN‐GS was predefined based on expression profiles in previous studies (data on file). Time to recovery was defined as the time from Day 1 to first occurrence of WHO 9‐point ordinal scale of ≤3. In the subgroup with high IFN‐GS, the cumulative recovery rates were higher for patients who received enpatoran compared to those who received placebo. From Day 1 through Day 28, recovery rates in the high IFN‐GS group were 73.3% (n = 11/15; p = 0.031) and 88.2% (n = 15/17; p = 0.031) with enpatoran 50 mg b.i.d. and enpatoran 100 mg b.i.d., respectively, and 53.3% (n = 8/15) with placebo. In the subgroup with low IFN‐GS, there was a lack of differentiation between placebo and enpatoran. From Day 1 through Day 28, recovery rates in the low IFN‐GS group were 100% (n = 28/28; p = 0.236) and 91.3% (n = 21/23; p = 0.458) with enpatoran 50 mg b.i.d. and enpatoran 100 mg b.i.d., respectively, and 86.2% (n = 25/29) with placebo. Kaplan–Meier curves are shown. High IFN‐GS score subgroup, N = 47; low IFN‐GS score subgroup, N = 80. b.i.d., twice daily.