Tocilizumab: A role for biomarker directed therapy?

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has resulted in an urgent need to develop efficacious therapies. As a result, an unprecedented number of clinical trials have been initiated, primarily evaluating repurposed therapeutics with existing U.S. Food and Drug Administration (FDA) approvals. One such agent is tocilizumab, a humanized monoclonal antibody that competitively inhibits binding of interleukin-6 (IL-6) to its receptor. Tocilizumab is FDA approved for multiple rheumatologic conditions including systemic juvenile idiopathic arthritis, polyarticular juvenile arthritis, rheumatoid arthritis, giant cell arteritis, and systemic sclerosis-associated interstitial lung disease as well as for treatment of severe or life-threatening cytokine release syndrome associated with chimeric antigen receptor (CAR) T-cell therapy. Interest in tocilizumab as an adjunct therapy for severe Coronavirus Disease 2019 (COVID-19) stems from early observations that IL-6 levels are elevated in hospitalized patients with COVID-19, although dramatically less so than among patients with CAR T-cell induced cytokine release syndrome, sepsis, and non-COVID-19 related acute respiratory distress syndrome[1].

Numerous clinical trials have now been completed evaluating the efficacy of tocilizumab for treatment of hospitalized patients with COVID-19, with mixed results. The COVACTA trial was an international, randomized, double-blinded, placebo-controlled trial that assessed safety and efficacy of tocilizumab in hospitalized patients with severe COVID-19 pneumonia[2]. This trial did not meet its primary endpoint of improved clinical status at day 28. Further, no difference in mortality was observed across treatment groups. In contrast, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial met its primary composite endpoint of respiratory and cardiovascular organ support free days and death [3]. The open-label Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial evaluated the efficacy of tocilizumab in hospitalized patients with systemic inflammation, defined by C-reactive protein (CRP) >75 mg/L. In this large trial 4,116 adults were enrolled and the primary endpoint of reduced 28-day mortality was met (31% vs 35%, rate ratio 0.85; 95%CI 0.76–0.94, p=0.0028)[4]. However, only with inclusion of the RECOVERY trial did a meta-analysis of the nine randomized control trials (RCT) of tocilizumab to date demonstrate improved 28-day mortality [mortality rate ratio, 0.86 (0.78–0.94), p=0.0017][4]. Conflicting findings across trials might be attributable to differences in trial enrollment criteria, degree of systemic inflammation among enrolled populations, variable use of systemic glucocorticoids within or across trials, or other factors[5].

The lack of clear and consistent findings in RCTs evaluating efficacy of tocilizumab as an adjunct therapy for severe COVID-19 leaves the clinician wondering in which of my COVID-19 patients should I prescribe tocilizumab. Based upon currently available evidence, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines recommend using tocilizumab in combination with dexamethasone in two specific patient populations who exhibit rapid clinical decompensation; 1) patients hospitalized within three days and admitted to the intensive care unit (ICU) within the prior 24 hours who require invasive mechanical ventilation or high flow nasal canula, and 2) patients hospitalized within three days not admitted to the ICU but with rapidly increasing oxygen needs requiring noninvasive ventilation or high flow nasal oxygen and evidence of significant systemic inflammation as defined by CRP >75 mg/L.

In this issue of Critical Care Medicine, Tom et al. performed a retrospective exploratory analysis of samples collected during the COVACTA trial seeking to identify biomarkers that are prognostic of clinical outcome and predictive of a therapeutic response to tocilizumab[6]. Predetermined biomarkers including IL-6, CRP, lactate dehydrogenase (LDH), ferritin, lymphocytes, neutrophils, monocytes, d-dimer, and platelets were measured in 295 and 142 patients randomized to tocilizumab and placebo, respectively. Each of these biomarkers, except LDH, d-dimer, and neutrophil-lymphocyte ratio, correlated with 28-day outcomes including illness severity, [measured on a seven-category ordinal scale (1, discharge; 7, death)], mechanical ventilation, time to hospital discharge, and mortality. Further analysis identified ferritin as predictive of tocilizumab’s effect on 28-day need for mechanical ventilation and mortality, but not time to hospital discharge. This finding was corroborated using data from patients with severe disease in the tocilizumab 8mg/kg arm of the MARIPOSA trial (A Study to Investigate Intravenous Tocilizumab in Participants with Moderate to Severe COVID-19 Pneumonia).

While predictive modeling using the COVACTA data identified ferritin as a potentially useful biomarker, the same was not true for baseline IL-6 levels and CRP >75mg/L, which were not found to be predictive of tocilizumab effect in sensitivity analyses. As mentioned previously, CRP >75mg/L was part of the inclusion criteria for the tocilizumab RECOVERY trial. Given the positive effect observed in RECOVERY, and despite limitations inherent to its open label design, CRP >75mg/L has since been integrated into the NIH guidelines recommending tocilizumab in a subset of hospitalized patients with COVID-19. The fact that CRP>75mg/L was not predictive of tocilizumab benefit in exploratory analyses of the COVACTA data, brings into question whether CRP, or ferritin for that matter, should guide clinical decision making for use of tocilizumab among hospitalized patients with COVID-19. The uncertainty in the value of CRP >75mg/L to guide tocilizumab use is in part reflected by the moderate rating (BIIa) assigned to its evidence in the NIH guidelines. Evidence supporting utility of ferritin presented by Tom et al., based on their retrospective analysis of the COVACTA data, is equally limited. Thus, the value of CRP >75mg/L or ferritin to guide clinical decisions in the care of hospitalized patients with COVID-19 remains an open question.

Importantly, in the authors’ attempt to identify a subgroup of COVACTA patients that might benefit from tocilizumab therapy, they uncovered a group of patients where tocilizumab use was potentially associated with harm. Specifically, in hospitalized patients with low baseline ferritin levels, tocilizumab use was associated with increased mortality. This signal for potential harm cannot be ignored and the dichotomy between a subgroup of patients with improved outcomes (high ferritin) and worse outcomes (low ferritin) might in part explain the often-contradictory findings across tocilizumab clinical trials.

Phenotyping patients with severe infection including sepsis using biomarkers, among other factors, to identify groups most likely to respond to therapies is common in clinical practice [7, 8]. Extending these efforts to COVID-19 is rationale and of potential value. Qualities of a clinically useful, well-validated, and robust (generalizable) biomarker include that it be readily available near the point-of-care, along the mechanistic pathway by which the therapy is thought to mitigate disease, and predictive of multiple clinically relevant outcomes within and across well-designed prospective clinical studies. When these stringent criteria are applied to IL-6, CRP, and ferritin, these biomarkers fall short of having meaningful utility to guide use of Tocilizumab among hospitalized patients with severe COVID-19.

While CRP and ferritin levels, although not IL-6 levels, are readily available to the bedside clinician, the role of IL-6, CRP, and ferritin along causal pathways contributing to COVID-19 pathogenesis is not well defined. When stimulated by pathogen-associated molecular patterns, macrophages produce IL-6, a pleotropic proinflammatory cytokine, which among its many roles stimulates hepatocytes to release acute phase reactants including CRP and ferritin. CRP binds phosphocoline on damaged tissue and pathogenic organisms facilitating complement driven opsonization and phagocytosis of pathogens and cellular debris[9]. Ferritin is an acute phase reactant that plays a key role in regulation of iron stores and is known to be elevated following macrophage activation[10]. While these and other biological activities of IL-6, CRP, and ferritin may play a role in severe COVID-19 pathogenesis, it remains unclear if their relationship with severe disease is limited to associations or are truly along causal pathogenic pathways, which may or may not be mitigated by IL-6 blockade. Furthermore, there is a lack of definitive data that CRP or Ferritin are robust predictors of response to tocilizumab across multiple outcomes and trials.

A constructive path forward, is that biomarkers of interest be identified prospectively during RCT design and that uniform sample collection and storage, both at study baseline and during relevant intervals along study implementation, be prioritized in addition to the collection of clinical data. The development of biorepositories with uniformly handled biospecimens, alongside matched clinical data, will inform risk stratification, predictive tool development, and allow valuable ex vivo mechanistic studies to clarify disease pathogenesis and in vivo therapeutic mechanisms across diverse study populations.

The decision as to whether ferritin should be included as a biomarker for clinicians at the bedside when deciding to prescribe tocilizumab in hospitalized patients with severe COVID-19 remains an open question. Moving forward it will be important to further explore CRP and ferritin as biomarkers in an attempt to find populations where clinical benefit might be achieved with tocilizumab. However, it is the impression of these authors that we remain in an exploratory and not implementation phase when it comes use of these biomarkers to guide utilization of tocilizumab in patients hospitalized with COVID-19. Furthermore, the finding of potential harm in patients with low ferritin requires additional emphasis. The opportunity to further inform this question, through additional retrospective analyses of RECOVERY data, where baseline ferritin levels were routinely collected, should be pursued [4]. These additional data may advance efforts at providing the medical community an evidence-based approach to prescribing a therapy that has had conflicting results across numerous trials but may have a role in a specific population.