The effect of canakinumab on clinical outcomes in patients with COVID-19: A meta-analysis.

Dear editor

We read with interest the report in this journal by Zuo et al. regarding the effectiveness of bamlanivimab in patients with COVID-19. On April 16, 2021, the emergency use authorization for bamlanivimab monotherapy was rescinded by the FDA due to the evolution of SARS-CoV-2 variants. Biologic medications have captured attention as powerful therapeutic options that are engineered from human-synthesized proteins and target specific steps along immune system pathways.

Canakinumab is a human monoclonal antibody that was developed for use in auto-inflammatory syndromes and targets IL-1β, an inflammatory cytokine interleukin that is well-known to be elevated in patients with COVID-19 and plays a crucial role in the initiation of cytokine storm. , The cytokine storms mediated by overproduction of proinflammatory cytokines have been observed in patients with COVID‐19, which is associated with the mortality and severity of COVID-19. IL-1β is thus a potential therapeutic target that can be inhibited by canakinumab to control cytokine storms. Through this mechanism, use of canakinumab may have prognostic benefits regarding patient outcomes with COVID-19 infection and serve as an additional treatment modality. Thus, we aim to perform a meta-analysis in the literature to evaluate the relationship between canakinumab administration and patient outcomes following COVID-19 infection.

An electronic search was performed using the electronic platforms (PubMed, Embase, and Cochrane Library databases) from December 1 2019 to February 21th, 2022. No language or publication restrictions were applied. The following subject heading search terms and key words were searched: (“SARS-CoV-2″ or “COVID-19″ or “2019-nCoV” or “novel coronavirus” or “coronavirus disease 2019″) AND (“canakinumab” or “interleukin 1β antibody” or “ACZ885”).

The inclusion criteria for this meta-analysis were as follows: (1) patients with confirmed COVID-19; (2) comparison was reported for clinical outcomes between canakinumab treatment (administered alone) and various control groups (placebo, standard care). Studies were excluded if they were (1) conference abstracts, case reports, editorials, non-clinical studies, and reviews; and (2) duplicated publications. We also extracted baseline information of first author's name, year of publication, study design, country of origin, number of participants, age, gender, dose of canakinumab used, outcomes (mortality, disease severity and change in anti-inflammatory factors).

Meta-analysis was conducted using Review Manager 5.2 (Cochrane Collaboration,

Oxford). We analyzed dichotomous data as a odds ratio (OR) with 95% confidence intervals (CIs) and continuous data as a standardized mean difference (SMD) with 95% CI. Heterogeneity was assessed using Cochran's Q test and the I2 statistic. We performed sensitivity analyses by sequentially omitting one study each time to assess the stability of the results. A p-value below 0.05 is considered to be statistically significant. “PROSPERO (International Prospective Register of Systematic Reviews) database” registration was done with study number as CRD42022314781.

After literature search, a total of 6 studies4, 5, 6, 7, 8, 9 comprising of 1121 adult patients with COVID-19, including 379 in the canakinumab (administered alone) and 742 in the control group arm, were included in this meta-analysis. The study characteristics of the included studies are listed in Table 1 . Four studies were from Italy. Two studies were RCTs, three studies were retrospective cohort and one studies was prospective case-control. All studies included mild to severe COVID-19 hospitalized patients. Canakinumab was intravenously or subcutaneously administered in the included studies. The eligible studies were published between 2020 and 2021 with different sample patient sizes that ranged from 20 to 520 patients with COVID-19.

Table 1

Characteristics of included studies.

Study	Country	Study design	Sample size	Canakinumab	Control	Usage of canakinumab	Patients included
				Agea	Male (%)	Agea	Male (%)
Caricchio4 2021	Europe and America	RCT	454	59 (49–69)	135 (59%)	57 (50–68)	132 (58%)	Canakinumab 450 mg for body weight of 40-<60 kg, 600 mg for 60–80 kg, and 750 mg for>80 kg, intravenous	Patients hospitalized with severe COVID-19 without invasive mechanical ventilation
Cremer5 2021	America	RCT	45	NR	20 (68.96%)	68.2 (56.1, 83.3)	13 (81.3%)	Canakinumab 300 mg (n = 14), Canakinumab 600 mg (n = 15), intravenous	Hospitalized patients
Generali6 2021	Italy	Prospective case-control study	48	70 (29–89)	25 (76%)	69 (44–85)	13 (87%)	canakinumab (150 mg) was administered by subcutaneous injection on day 1 and on day 7	Hospitalized patients
Katia7 2021	Italy	Retrospective cohort	34	53 (48, 62)	15 (88.2%)	59 (50, 72)	13 (76.5%)	A subcutaneous single dose of canakinumab 300 mg	Hospitalized mild or
severe non ICU patients
Mastroianni8 2021	Italy	Retrospective cohort	20	56 (46–82)	4 (50%)	NR	NR	150 mg BID for a body weight of 60–80 kg (or 2 mg/kg for participants weighing ≤40 kg), subcutaneous	Hospitalized patients
Potalivo9 2020	Italy	Retrospective cohort	520	NR	NR	NR	NR	NR	Hospitalized patients

Age data presented as median (IQR) or mean (SD); ICU: intensive care units; RCT: randomized controlled trial; NR: not reported.

The meta-analysis showed the overall mortality was lower in the canakinumab group compared to control group (OR=0.56, 95%CI: 0.35, 0.90, P = 0.02; I2=0%) (Fig 1 A). Moreover, canakinumab treatment were not associated with developing severe COVID-19 disease (OR=1.58, 95%CI: 0.73 to 3.41, P = 0.24; I2=66%) (Fig.1B). Compared with control group, CRP levels were significantly decreased in the canakinumab group (SMD=−1.51, 95%CI: −2.33 to −0.96, P = 0.0003; I2=64%) (Fig.1C). In addition, sensitivity analyses by excluding each study at a time did not materially change the overall results, indicating that our results were statistically stable.

Fig. 1

. A Association between canakinumab treatment and mortality, Fig. 1B. Association between canakinumab treatment and developing severe COVID-19, Fig. 1C Association between canakinumab treatment and CRP levels.

In this study, we find that treatment with canakinumab is associated with improvements in overall mortality as well as decreased serum CRP levels, suggesting lower levels of acute inflammation.

The association between treatment with canakinumab and decreased mortality and serum CRP concentration is likely mediated through the mechanism of action of the monoclonal antibody. By inhibiting IL-1β, a key inflammatory response mediator in the cytokine storm triggered by infection by COVID-19, there is a decreased likelihood of systemic hyperinflammation, a well-known predictor of all-cause mortality. , C-reactive protein (CRP) is an inflammatory biomarker that serves many functions during episodes of acute inflammation, including promoting the secretion of pro-inflammatory cytokines, enhancing leukocyte function and activating the complement cascade. Higher serum concentrations of acute phase reactants indicate more severe inflammatory episodes, allowing for CRP to be used as a marker of inflammation in COVID-19 infection and extrapolated to determine potency and response to canakinumab. Furthermore, by limiting the level of acute inflammation and propensity for the activation of a cytokine storm, canakinumab is thus potentially able to mitigate and even prevent immune-mediated tissue damage and organ dysfunction, both factors which improve overall mortality. , These restrictions of inflammatory activity are supported by the negative association of canakinumab and serum CRP levels in COVID-19 patients, an outcome that is well documented for other indications of canakinumab as well. , Altogether, canakinumab serves as a powerful anti-inflammatory therapeutic option that is able to specifically target and limit inflammatory mechanisms.

There are several limitations that should be noted with our study. There was a relatively small sample size for use in the meta-analysis with 6 included articles. There were other inflammatory factors investigated in the included studies, however, the sample size was too small for a meta-analysis to be conducted. However, despite these limitations, our study is the first meta-analysis to explore the association between treatment with canakinumab and patient outcomes following COVID-19 infection.

Additional research is needed to further probe this association and provide a more diverse and sufficiently large sample size to provide a better understanding of what circumstances provide optimal clinical utility.

In conclusion, treatment with canakinumab in patients with COVID-19 infection is associated with a mortality benefit and lower levels of acute inflammation. Additional studies are required to confirm these findings.

Declaration of Competing Interest

The authors declare that they have no competing interest