Pharmacodynamic, prognostic, and predictive biomarkers in severe and critical COVID-19 patients treated with sirukumab

Abstract

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Keywords: Biomarkers; COVID-19; IL-4; IL-6; Inflammation.

Fig. 1

Association of biomarkers with clinical outcomes. Prognostic associations of (a, c) baseline and (b, d) change from baseline to Day 5 biomarker values on clinical endpoints assessed in (a, b) All Patients and (c, d) Critical Patients.* CCL, C-C motif chemokine ligand; CRP, C-reactive protein; CXCL, C-X-C motif chemokine ligand; IFNγ, interferon gamma; IL, interleukin; N, no; PCT, procalcitonin; SCI, sustained clinical improvement; TNFα, tumor necrosis factor alpha; Y, yes. *–log₁₀P values. The direction of the bars depicts the sign of the association. For the mortality endpoint, the direction of the bar was inverted to align “favorable clinical outcome” to those of the other 2 endpoints. ^†Represents biomarkers with predictive association of response to sirukumab on all 3 clinical endpoints.

Fig. 2

Biomarkers associated with mortality. (a) Incidence of mortality by Day 28 for the most significant biomarkers with prognostic association. Change from baseline to Day 5 in biomarkers associated with (b) prognosis and (c) prediction of mortality. CCL, C-C motif chemokine ligand; CRP, C-reactive protein; CXCL, C-X-C motif chemokine ligand; IL, interleukin; LLOQ, lower limit of quantification; N, no; T, tertile; Y, yes. P values are shown in Fig. 1. *IL-6 grouped per > vs. ≤ LLOQ (3.16 pg/mL). ^†IL-8 and CCL2 grouped per T (T1: 2.77–4.64 log₂ [pg/mL], T2: 4.64–5.28, T3: 5.28–11.6 and T1: 5.92–7.67 log₂ [pg/mL], T2: 7.67–8.49, T3: 8.49–10.8, respectively).

Fig. 3

Association between detectable postbaseline IL-4 and clinical outcomes. (a) Day 5:Day 1 change in IL-4 levels by mortality at Day 28. (b) Percentage of patients with detectable IL-4 on Day 5 or at any visit postbaseline (any), by baseline disease severity. (c) Median days to SCI, percentage of patients with SCI at Day 28, and percent mortality at Day 28. (d) Kaplan-Meier curve for Critical Patients treated with placebo, or sirukumab with or without detectable IL-4 at any visit postbaseline. Most significant (e) baseline or (f) change from baseline to Day 5 biomarkers between sirukumab-treated patients with or without detectable IL-4 postbaseline. BL, baseline; CCL, C-C motif chemokine ligand; CRP, C-reactive protein; CXCL, C-X-C motif chemokine ligand; IFNγ, interferon gamma; IL, interleukin; N, no; SCI, sustained clinical improvement; Y, yes. Units in (E): log₂ (pg/mL) for cytokines, log₂ (µg/mL) for CRP. Units in (F): log₂ change from baseline.

Fig. 4

Potential predictive biomarkers in patients with COVID-19 without and with detectable IL-4 after administration of sirukumab. Left panel: COVID-19 patients in which an efficacy signal from sirukumab is observed are characterized by (amongst others) a lack of IL-4 upregulation upon treatment, and generally low baseline levels of IL-6. In these patients, inhibition of IL-6 at the effector site (e.g. lung) may contribute to clinical benefit. Right panel: In COVID-19 patients characterized by sirukumab-induced IL-4 upregulation, no efficacy signal was identified. These patients are also characterized by higher baseline levels of systemic IL-6 and other cytokines. Post-treatment, modulation of (inflammatory) molecules is observed, which may be a consequence of systemic IL-6 pathway blockade. CCL, C-C motif chemokine ligand; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CXCL, C-X-C motif chemokine ligand; IFNγ, interferon gamma; IL, interleukin; TNFα, tumor necrosis factor alpha.