Anti-Viral Effects of Voclosporin in COVID-19 Positive Kidney Transplant Recipients

Calcineurin inhibitors (CNIs) are general immunosuppressive agents commonly used in the setting of transplantation to prevent solid organ rejection. CNIs form the cornerstone of immunosuppressive treatment in kidney transplant recipients (KTRs) including the 1st generation CNI Cyclosporin-A (CsA) and the most commonly employed 2nd generation CNI tacrolimus (TAC). It is of interest that CNIs, especially CsA, also exert anti-viral effects in addition to immunosuppressive effects. Common side effects of CNIs are hypertension, new-onset diabetes, renal insufficiency and neurotoxicity. Therefore, in the recent decennium, efforts have been directed at developing a novel CNI, voclosporin (VCS), that has improved pharmacodynamic (PD) and pharmacokinetic (PK) attributes with respect to calcineurin inhibition as well as an improved safety profile to common side effects. VCS has been extensively studied in KTRs demonstrating equivalent efficacy to TAC with respect to prevention of rejection while showing a reduction in CNI-related toxicity. Most recently, VCS as a component of multitargeted therapy demonstrated superior efficacy compared to standard of care in lupus nephritis (LN) patients. In 2011, a pivotal study from Leiden University Medical Center (LUMC) demonstrated in vitro anti-viral effect of CsA on Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1). Subsequently, VCS has been shown to have a more potent anti-viral effect on norovirus compared to CsA. The anti-viral effects of CNIs have a different mechanism of inhibition in each virus but mainly through inhibiting cyclophilins, an essential protein for viral replication. The SARS-CoV-1 interacts with human cyclophilins, however the role of these proteins in infection remains elusive. Different reports stablished interactions between nsp1 or nucleocapsid proteins with Cyps and hypothesize its influence in viral replication and viral entry. Unlike VCS and CsA, TAC binds to FK binding proteins rather than cyclophilin A (CypA). Given the current COVID-19 pandemic, the LUMC has very recently demonstrated anti-viral effects of CNIs on SARS-CoV-2 infected cells in vitro: a 2-log reduction of SARS-CoV-2 viral titers in Calu-3 2B4 bronchial cell cultures was observed when incubated with \~3 μM VCS compared to 25μM CsA and 25μM TAC. In each experiment Remdesivir was taken as positive control as it inhibits viral replication by \>4log at 10 μM concentration. As such, VCS becomes an attractive and potentially feasible CNI to use or switch to in COVID-19 infected KTRs who are already using CNIs as part of their chronic immunosuppressive therapy. Because subjects will be randomized to either VCS or TAC as immunosuppressive agent during COVID-19 infection, the burden of the study is two-fold: first, subjects will need to switch to a novel CNI which intrinsically will harbour an uncertainty. However, from a clinical point-of-view VCS is proven equivalent to TAC with respect to organ rejection and safety monitoring of adequate drug levels is incorporated in the study. Secondly, subjects will need to agree to self-assessments including monitoring of vital signs and collection of saliva samples and a throat swab in the first 56 days. We believe that it is actually in the interest of subjects to undergo this intensive monitoring because current standard practice is for KTRs with mild symptoms to not be hospitalized and stay at home until recovery without further monitoring. In addition, blood sampling (10 x 38.5 mL), urine sampling and additional hospital visits will take place which are outside of normal clinical practice. The potential advantage of the study to KTRs is that VCS may lead to a quicker reduction of SARS-CoV-2 viral load and quicker relief of symptoms. Altogether, we believe the burden of the study is minimal and outweighed by the potential benefit of the treatment on COVID-19 infection.