Voclosporin and the Antiviral Effect Against SARS-CoV-2 in Immunocompromised Kidney Patients

Abstract

Introduction: Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients.

Methods: First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic.

Results: The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8-28) and tacrolimus-treated KTRs (median 12 days, IQR 4-16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4-10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; P = 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97-2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90-2.54]).

Conclusion: This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.

Keywords: COVID-19; SARS-CoV-2; calcineurin inhibitors; kidney transplantation; lupus erythematosus; lupus nephritis.

Graphical abstract

Figure 1

Individual courses of SARS-CoV-2 viral clearance, according to the prespecified definition of time in days to first negative PCR test, in 10 kidney transplant recipients (KTRs) randomized to voclosporin treatment versus continuation of tacrolimus treatment. Prerandomization COVID19-related symptom duration is depicted in gray; categories of PCR Ct-values are depicted in red (high viral load with Ct-value <30), orange (low viral load with Ct-value from 30–37) and green (no viral load with Ct-value >37). Symbol # corresponds to 1 vaccination dose.

Figure 2

Summary by Whisker boxplots and Kaplan-Meier plots on SARS-CoV-2 viral clearance (a–d) and COVID19-related clinical courses (e–h). (a) Time to first negative PCR test with a cut-off Ct-value > 37. (b) Time to 2 consecutive negative PCR tests with a cut-off Ct-value >37. (c) Time to 2 consecutive negative PCR tests with a cut-off Ct-value > 24. (d) Time to a quantitative log-reduction in viral RNA load. (e) Time to clinical recovery defined as free of symptoms for at least 5 days. (f) Time to clinical symptom relief defined as free of symptoms for at least 1 day. (g) Time to hospital discharge for KTRs requiring hospital admission (N = 3). (h) Time to treatment failure within 56 days after randomization (N = 2).

Figure 3

Pharmacokinetics (upper panels) of voclosporin (VCS-red) and tacrolimus (TAC-blue) in relation to SARS-CoV-2 viral clearance (lower panels) in KTRs. Each red/blue dot represents 1 patient; dotted lines illustrate the target trough concentrations for voclosporin 30–60 ng/ml (red) and tacrolimus 3–7 ng/ml. Upper panels shows trough levels of KTRs on voclosporin (red) and tacrolimus (blue) and in the lower panels the corresponding viral clearance (ΔCt) between (a) day 0 and day 4; (b) day 4 and day 8 and (c) day 8 and day 12 after study inclusion.