An Open-Label Study Evaluating Anti-Viral Effects of Voclosporin in SARS-CoV-2 Positive Kidney Transplant Recipients - the VOCOVID Study

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) (Hamawy, 2003). It
is of interest that CNIs, especially CsA, also exert anti-viral effects in
addition to immunosuppressive effects (Ma-Lauer et al, 2017 2016; Ishii et al,
2006; Qing et al, 2009; Braaten et al, 1996; Dang et al, 2017; de Wilde et al,
2011). 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 (Papp et al, 2008; Mayo et al, 2014; Kuglstatter et al, 2011). 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 (Busque et al, 2011). Most recently, VCS as a component of
multitargeted therapy demonstrated superior efficacy compared to standard of
care in lupus nephritis (LN) patients (Rovin et al, 2018; Teng et al, 2020).

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) (de Wilde et al, 2011). Subsequently, VCS
has been shown to have a more potent anti-viral effect on norovirus compared to
CsA (Dang et al, 2017). 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 (Wilde et al., 2018). Different reports stablished
interactions between nsp1 (Pfefferle et al., 2011) or nucleocapsid (Luo et al.,
2004; Chen et al., 2005) 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 (Tseng et al., 2005; Yoshikawa et
al., 2010) 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 (Pruijssers et al.,
2020). 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.

Primary Objective: To investigate the kinetics of the anti-viral effects of
VCS, compared to standard of care with TAC, on SARS-CoV-2 over 56 days, in
stable KTRs.
Secondary Objective: To assess the safety and tolerability of VCS in stable
KTRs infected with SARS-CoV-2.

Open-label, 56 day, single-center, exploratory, proof-of-concept study of VCS
with an extended safety follow-up, up to 1 year.

At study entry, subjects are on standard therapy of dual immunosuppressive
treatment of prednisone and TAC, as per current local guidelines (LUMC
Transplant Center treatment guidelines for COVID-positive transplant patients).
Following randomization, 10 out of 20 subjects will remain on this therapy for
the duration of the study, while the other 10 subjects will switch to VCS
(instead of TAC).

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.