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Cells 2023, 12, 2440. https://doi.org/10.3390/cells12202440 www.mdpi.com/journal/cells
Review
Voclosporin: Unique Chemistry, Pharmacology and Toxicity
Profile, and Possible Options for Implementation into the
Management of Lupus Nephritis
Ajinath Kale 1, Vishwadeep Shelke 1, Yutian Lei 2, Anil Bhanudas Gaikwad 1 and Hans-Joachim Anders 3,*
1 Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031,
India; ajinathk3@gmail.com (A.K.); vishwadeepshelke@gmail.com (V.S.);
anil.gaikwad@pilani.bits-pilani.ac.in (A.B.G.)
2 Division of Diabetology, Department of Internal Medicine IV, Hospital of the Ludwig Maximilians
University Munich, 333031 Munich, Germany; yutian.lei@med.uni-muenchen.de
3 Division of Nephrology, Department of Internal Medicine IV, Hospital of the Ludwig Maximilians
University Munich, 80336 Munich, Germany
* Correspondence: hjanders@med.uni-muenchen.de; Tel.: +49-89-4400-32623
Abstract: Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell
function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney`s
filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria.
However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range,
need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic
alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems
to lack these adverse effects, although hypertension and drug–drug interactions still occur. VOC
demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase
2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus
nephritis. However, how to implement VOC into the current and changing treatment landscape of
lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity
profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials,
and discuss the following four possible options to implement VOC into the management of lupus
nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1.
patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL
sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.
Keywords: calcineurin; autoimmunity; inflammation; proteinuria; podocytes; toxicity
1. Introduction
Calcineurin inhibitors (CNI) are a class of immunosuppressive drugs used to
suppress adaptive immunity during solid organ transplantation or in autoimmune
disease [1,2]. CNI are particularly aractive for the treatment of proteinuric kidney
diseases as unlike other immunosuppressants, CNI has specific antiproteinuric effects [3].
Indeed, autoimmune forms of glomerulonephritis can specifically benefit from this dual
mechanism of action but CNI are also used in podocytopathies of unknown causes [4].
However, nephrotoxicity limits the long-term use of CNI [5].
Cyclosporin A (CsA) was the first CNI in use but has a narrow therapeutic range and
a clinically relevant dose-dependent and dose-independent toxicity profile [6]. This
prompted the search for other CNI with beer toxicity profiles. Tacrolimus (TAC) was the
next CNI approved for the treatment of allo- and autoimmunity [7]. Tacrolimus still has a
narrow therapeutic range but comes with a partially different toxicity profile, which
Citation: Kale, A.; Shelke, V.; Lei, Y.;
Gaikwad, A.B.; Anders, H.-J.
Voclosporin: Unique Chemistry,
Pharmacology and Toxicity Profile,
and Possible Options for
Implementation into the
Management of Lupus Nephritis.
Cells 2023, 12, 2440. hps://doi.org/
10.3390/cells12202440
Academic Editor:
Duranton Christophe
Received: 14 September 2023
Revised: 9 October 2023
Accepted: 10 October 2023
Published: 11 October 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Swierland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Aribution (CC BY) license
(hps://creativecommons.org/license
s/by/4.0/).
Cells 2023, 12, 2440 2 of 16
allows diversification of CNI’s use in patients with specific risk factors. However, CsA
and TAC both require monitoring of drug levels and are subject to numerous drug
interferences due to their specific mode of metabolism via cytochrome P450 [8]. VOC, a
more recently developed CNI, no longer requires monitoring of drug levels and has a
different toxicity profile [9]. Currently, VOC has only been tested in the clinical contexts
of kidney transplantation and lupus nephritis. Its potent antiproteinuric effect makes it a
perfect fit for this indication as the trial endpoint heavily relies on the proteinuria
response, which is more difficult to achieve for immunosuppressant agents that do not
directly modulate the glomerular filtration barrier. Here we review the molecular biology
of CN as a target treatment, the pharmacology and toxicity of available CNI, and the
potential use of VOC in the context of its latest approval for the treatment of active lupus
nephritis (LN) [10].
2. Calcineurin as a Molecular Drug Target
CN is a calmodulin/calcium-activated serine-threonine phosphatase that regulates
calcium signaling and immune and inflammatory processes. CN is a heterodimer
composed of two subunits: the catalytic A subunit and the regulatory B subunit [11].
Catalytic subunit A shares the major portion and is responsible for calmodulin binding
and associated downstream signaling. However, the regulatory subunit B has four
calcium binding sites sensitive to calcium signaling. The calcium and calmodulin-
mediated activation of calcineurin lead to the dephosphorylation of substrates involved
in several critical cellular processes (Figure 1). Those substrates are not limited to
receptors, channels, and proteins associated with microtubules and mitochondria, and,
more importantly, transcription factors [12]. The most commonly studied transcription
factors are nuclear factors of activated T-cells (NFAT 1-5), nuclear factor kappa-light-
chain-enhancer of activated B cells (NFκB), the forkhead transcription factors, and
transcription factor EB. These factors drive the release of pro-inflammatory cytokines as
interleukins, interferons, CD40 ligand, tumor necrosis factors, and T-cell receptor (TCR)
signaling involved in the activation of T lymphocytes responding to foreign antigens,
autoantigens, or alloantigens [13]. Interleukins/cytokines further activate downstream
signaling via phosphatidyl-inositol-3 kinase, and the mammalian target of rapamycin,
which all regulate the activation, proliferation, and differentiation of T cells (Figure 1) [14].
Moreover, CN is also involved in the glomerular barrier function in kidney podocytes
(Figure 1). Podocytes are epithelial cells in the kidney glomeruli with an essential role in
maintaining integrity and function of the glomerular filtration filter [15]. Specifically, the
interdigitating podocyte foot processes, connected by proteins of the filtration slit in a
zipper-like structure to form a unique intercellular junction called a ’slit diaphragm’ that
is essential for the kidney filter [16]. Any focal or diffuse injury to podocytes and their foot
processes induces serum protein leakage into the urine, i.e., proteinuria [17]. Numerous
proteins are involved in connecting the actin cytoskeleton of podocytes with the proteins
in the slit diaphragm, e.g., synaptopodin [16]. Interestingly, CN can dephosphorylate
podocyte synaptopodin, which destabilizes the actin cytoskeleton, the podocyte
secondary foot processes, and the filtration slit [18]. Thus, CN-mediated
dephosphorylation of synaptopodin contributes to proteinuria, podocyte loss, and
glomerulosclerosis (Figure 1). Vice versa, CNI reverse these processes, and thus have
antiproteinuric and renoprotective effects [18–20]. Together, CN is a molecular target in
allo- and autoimmune and inflammatory diseases including SLE, LN, and other
proteinuric kidney diseases.
Cells 2023, 12, 2440 3 of 16
Figure 1. Roles of calcineurin in T lymphocytes (grey) and podocytes (pink). Phosphatase
calcineurin (CN) is a Ca++ sensitive enzyme in the nuclear factor of activated T cell (NF-AT)
signaling pathways downstream of the T cell receptor activated by foreign, auto-, or alloantigens.
Cyclosporin A (CsA), Tacrolimus (FK506) and Voclosporin (Voc) all block the phosphatase activity
of CN, albeit in different ways. In podocytes, CN dephosphorylates synaptopodin, a protein
involved in the stability of the actin cytoskeleton. CPN = cyclophilin; FK506 = tacrolimus; FKBP =
FK506-binding protein; CsA = cyclosporine A; Voc = voclosporin; IL = interleukin; TNF = tumor
necrosis factor; NF-AT = nuclear factor of activated T cells.
3. Chemistry of the Calcineurin Inhibitors
3.1. Cyclosporin
CsA is a cyclic undecapeptide (C62H111N11O12) with a molecular weight of 1202
Daltons, it is neutral, hydrophobic, and possesses eleven amino acid residues from which
seven amino acids are N-methylated, and the remainder are non-methylated [21,22].
During binding to cyclophilin, one N-methylated amino acid (Mle-3) bond of CsA remains
in the trans-orientation [23]. Due to N-methylated amino acids, there are fewer chances of
intramolecular hydrogen bonds, while the carbon chain of amino acid in position 1 (3-
hydroxy-4-methyl-2-methylamino-6-octanoic acid, abbreviated as MeBmt) is essential for
the bioactivity of CsA. The immunosuppressive effect significantly declines upon removal
of the non-polar part of the side chain [24]. Interestingly, the modifications at amino acid
2 with some alkyl chains, improve the immunosuppressive activity of CsA [23]. All 11
amino acids show an S-configuration of natural L-amino acids except for D-alanine in the
eighth position (R-configuration) and N-methyl-glycine in the third position. The
hydrolysis of CsA yields a cyclic derivative of MeBmt, while an acid treatment of CsA
provides iso-cyclosporine. X-ray crystallography and nuclear magnetic resonance
measurements confirm that CsA in crystal and soluble form mainly differ in their
respective confirmations due to the orientation of the carbon chain of the MeBmt amino
acid [25]. However, several analogs were generated to improve the potency and efficacy
of CsA.
Cells 2023, 12, 2440 4 of 16
3.2. Tacrolimus
TAC (also refered to as Fujimycin, tsukubaenolide, or FK506) is a member of the L-
pipecolic acid-derived macrolides class and has at least one deoxy sugar connected to a
large macrocyclic 14-16-membered ring as part of its 23-membered lactone ring [26]. The
molecular formula of TAC is C44H69NO12 with a molecular weight of 803.5 Daltons and is
generally found in a white to slightly off-white crystalline form. TAC is poorly soluble in
water and has a LogP value of 3.3. However, in aqueous solutions, TAC undergoes cis-
trans-isomerization and exists in three different forms, mainly due to changes at the C-12
position [27]. The limited and restricted rotation of the two amide bonds creates two
conformational rotamers of TAC. Importantly, tautomeric structural modifications can be
produced due to three adjacent carbonyl groups in the TAC ring, resulting in different
TAC analogs [28]. The pipecolic acid moiety, free hydroxy groups, and tricarbonyl groups
are essential for functional activity. The 2-propynyl group presented at the C-8 position is
important for the interaction with the FK-binding protein (FK-BP) and calcineurin
inhibition. Any modification at the C-8 position would result in instability in the FK-BP-
TAC complex [29]. Moreover, the 2-propynyl group at C-8 replaced with -CH2-CH3 or -
CH2-CH2=CH3 yields ascomycin and TAC 8-propyl analog, which further complicates
the purification of TAC [27].
3.3. Voclosporin or ISA247
VOC (C63H111N11O12) is a cyclic undecapeptide like CsA but with a molecular weight
of 1214.6 Daltons. It forms a heterodimeric complex with cyclophilin A that binds to CN
[30]. To create VOC, a single carbon extension was placed at the amino acid 1 position of
CsA. VOC is available in cis- and trans-isomers, from which the trans-isomer is considered
more potent. These two isomers differ in the orientation of one functional group [31,32].
Similar to CsA, modification at the amino acid 1 position with single carbon results in a
more prominent binding of the cyclophilin-VOC complex to the ‘latch-region’ of CN thus
increasing the potency of VOC [30]. More importantly, the amino acid 1 position is
essential for VOC metabolism. Therefore, any modifications at this position result in
shifting the metabolism site from the amino acid 1 to the amino acid 9 position, producing
less potent metabolite [33]. On the other hand, CsA undergoes a tremendous metabolism
and yields highly nephrotoxic metabolites, which limit the use of CsA in kidney disease
patients [34,35]. Therefore, the structural modifications at amino acid 1 renders VOC more
safe and more potent compared to CsA [35].
4. Pharmacology of the Calcineurin Inhibitors
4.1. Cyclosporine A (Sandimmune®, Neoral®)
Since 1980, CsA has been widely used in autoimmune and inflammatory disorders
and organ transplant recipients [36]. However, it has a narrow therapeutic range and can
cause serious side effects which limit its chronic use or its use as a first-line therapy in
many seings (Table 1) [36].
Table 1. The dosage, clinical indications, and adverse effects of calcineurin inhibitors.
Drugs Clinical Use Contraindications/
Adverse Effects
Cyclosporine
Solid organ transplantation (liver, kidney,
and heart), rheumatoid arthritis, psoriasis,
amyotrophic lateral sclerosis, nephrotic
syndrome, graft vs. host disease (GVHD),
refractory posterior uveitis, and Behcet
disease.
Contraindications: Amphotericin B, neomycin,
atorvastatin, cidofovir, elbasvir/grazoprevir,
flibanserin, lomitapide, mifepristone, tacrolimus,
life vaccines, etc.
Adverse effects: Dyslipidemia, hyperkalemia,
gynecomastia, hypertension, arrhythmia, decrease
Cells 2023, 12, 2440 5 of 16
Off-label: Allergic conjunctivitis, autoimmun
e
hepatitis, keratoconjunctivitis, Langerhans
cells histiocytosis, Duchenne muscular
dystrophy, ocular graft vs. host disease,
ulcerative colitis, pure red cell aplasia,
Henoch Schönlein purpura nephritis,
proteinuric forms of glomerulonephritis and
podocytopathies.
in eGFR and creatinine clearance, convulsions,
bleeding gums, GIT upset, infectious
complications.
Tacrolimus
Solid organ transplantation (liver, kidney,
and heart.
Off-label: Crohn’s disease, Graft-versus-host
disease (GVHD), Myasthenia gravis, and
Rheumatoid arthritis, Ulcerative colitis,
proteinuric forms of glomerulonephritis and
podocytopathies.
Contraindications: some antifungal agents,
polyoxyl 60 hydrogenated castor oil (HCO-
60), and
derivatives.
Adverse effects: Nephrotoxicity, neurotoxicity,
post-transplant diabetes mellitus, hypertension,
dyslipidemia, angina pectoris, cardiac arrhythmias,
urinary tract infections, cosmetic and electrolyte
disturbances, infectious complications.
Voclosporin
Active lupus nephritis.
Off-label: Plaque psoriasis, prevention of
organ rejection after transplantation, uveitis,
arthritis, and Crohn’s disease.
Contraindications: Phenylalanine, flunisolide,
bortezomib, cladribine, and in patients with renal
and hepatic impairments.
Adverse effects: Reduced eGFR, increased blood
pressure, diarrhea, headache, anemia, cough, UTI,
upper abdominal pain, dyspepsia, alopecia, renal
dysfunction, abdominal pain, mouth ulceration,
nausea, tremor, acute kidney injury and decreased
appetite, infectious complications.
Pharmacokinetic: CsA is available in liquid (oral or intravenous solution) and solid
dosage forms (capsules). Close therapeutic drug monitoring of CsA is recommended [37].
CsA is a lipophilic peptide and shows a variable pharmacokinetic profile. Oral absorption
of CsA is low which further decrease with the presence of food. Upon oral administration,
it can achieve bioavailability in a wide range [38]. CsA is extensively distributed in
peripheral tissues, blood erythrocytes, and plasma. It binds with albumin and lipoproteins
in the plasma [38]. The volume of the distribution of CsA lies between 3–5 L/kg and the
reported half-life varies from 5–27 h. The liver and intestines are the major sites wherein
CYP3A1,2,4,5,9, and CYP3C are the common enzymes responsible for CsA metabolism
[39]. AM1, AM1c, AM9, AM1c9, and AM4N are the CsA metabolites in which AM19 is the
major contributor to CsA-associated nephrotoxicity [6]. The underlying mechanisms of
CsA-induced nephrotoxicity are not entirely clear; however, the p38, JNK, ERK, and
MAPK subfamilies signaling are involved in CsA nephrotoxicity [40]. CsA is mainly
eliminated via biliary excretion and feces (~70%), and only 6–15% via the urine [41].
Contraindications: CsA shows significant interactions with certain medications such
as amphotericin B, neomycin, atorvastatin, cidofovir, elbasvir/grazoprevir, flibanserin,
lomitapide, mifepristone, tacrolimus, etc. The CYP3A4 inhibitors like macrolides,
verapamil, amiodarone, colchicine, oral contraceptives, and azole antifungals are known
to increase the plasma concentrations of CsA, TAC, and VOC when used concomitantly.
Moreover, CNI should not be given alongside CYP3A4 inducers which can decrease the
plasma concentrations of these drugs to subtherapeutic levels, e.g., carbamazepine,
orlistat, phenytoin, etc. Thus, close monitoring and/or dose adjustments are often required
when calcineurin inhibitors are used in combination with these drugs.
Adverse effects: Arterial hypertension, dyslipidemia, hirsutism, hyperuricemia,
hyperkalemia, and nephrotoxicity are more pronounced with CsA compared to TAC and
VOC (Table 2). CsA increases the low-density lipid, triglycerides, apolipoprotein B, and
Cells 2023, 12, 2440 6 of 16
lipoprotein (a) levels, and thus decreases the transportation of cholesterol to the intestines.
CsA also reduces the process of lipolysis and levels of high-density lipids. Other common
adverse effects include gynecomastia, arrhythmia, diabetes, a decrease in eGFR and
creatinine clearance, convulsions, bleeding gums, gingical hyperplasia, hypertrichosis,
and gastrointestinal upset.
Table 2. Comparison of major adverse effects of cyclosporine and tacrolimus with voclosporin.
Adverse Effects Cyclosporin Tacrolimus
Voclosporin
Hypertension ++ + +
Nephrotoxicity ++ ++ +
Decrease in eGFR + + +
Arrhythmia/cardiovascular risk + + −
Anemia + + +
Neurotoxicity/convulsions + ++ +
Gastrointestinal upset + ++ +
Gum hyperplasia ++ − +
Dyslipidemia ++ + −
Gynecomastia + − −
Alopecia − ++ +
Post-transplant diabetes mellitus + ++ −
Urinary tract infection + +
Hyperkalemia ++ + +
Cosmetic and electrolyte disturbances ++ + −
Hyperuricemia ++ + −
Hirsutism/hypertrichosis ++ − −
++: more pronounced side effects, +: less pronounced side effects, −: no side effects.
4.2. Tacrolimus (Astagraf XL, Envarsus XR, Prograf, and Protopic)
TAC is a macrolide, one of the commonly prescribed immunosuppressants in
combination with other drugs to prevent solid organ transplant rejection (heart, liver,
lung, and kidney) [42]. Indeed, it is now used as a standard first-line therapy in kidney
transplant recipients. TAC is also approved to treat skin disorders such as atopic
dermatitis/eczema [43]. However, TAC has a narrow therapeutic window, its metabolism
is disturbed by various factors, and hence requires therapeutic drug monitoring [8,44]. It
also shows complex pharmacokinetics, pharmacodynamics, and pharmacogenetics
among organ transplant recipients which limits its clinical applications [45,46].
Pharmacokinetics: TAC is formulated in oral, intravenous, and topical dosage forms
(Table 1). The oral dosage form is designed in different release paerns: immediate, slow,
and extended release [47]. It combines with one or more therapies such as monoclonal
antibody-basiliximab, or drugs, such as sirolimus, azathioprine, mycophenolate mofetil,
and steroids [48–50]. TAC is metabolized by CYP3A4, CYP3A5, and P-glycoprotein
(PGP)/ABCB1 into the different metabolites, among which the main and major metabolite
is 13-O-dimethyl-tacrolimus [45]. The half-life ranges from 4 to 41 h, and the approximate
volume of distribution is 30 L/kg [45]. It is mainly excreted by the biliary route (~95%) and
2–3% is unchanged in the urine.
Contraindications: Antifungal agents and multiple other drugs metabolized by
CYP450 enzymes, including polyoxyl 60 hydrogenated castor oil (HCO-60), and their
derivatives require close drug level monitoring and/or dose adjustment to avoid TAC
toxicity [51].
Adverse effects: Post-transplant diabetes mellitus, neurotoxicity, GIT upset, and
alopecia are more pronounced with TAC when compared to CsA and/or VOC (Table 2).
It causes diabetes by stimulating glucolipotoxicity in β cells and thus leads to decreasing
Cells 2023, 12, 2440 7 of 16
insulin secretion. Nephrotoxicity, hypertension, dyslipidemia, angina pectoris, cardiac
arrhythmias, hyperkalemia, urinary tract infections, cosmetic, and electrolyte
disturbances are other common adverse events associated with TAC [52].
4.3. Voclosporin (Lupkynis™)
Voclosporin is a potent cyclosporine derivative, safer, more efficacious, and tolerable
than other calcineurin inhibitors [53]. VOC received clinical approval from the USFDA to
be used in combination with MMF and corticosteroids for treating LN [10]. However,
against psoriasis, it is inferior to CsA in terms of efficacy.
Pharmacokinetics: VOC is available only in oral solid dosage form. For treating LN,
the starting dose of VOC is 23.7 mg twice a day, with 8 or 12 h intervals (Table 1) [10].
VOC is recommended to be consumed on an empty stomach for its maximum absorption
and optimum bioavailability. The Tmax lies between 1 and 4 h and Cmax is estimated at
955.5 ng/mL
(hps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213716s000lbl.pdf,
Accessed on 10 January 2023). Moreover, 2154 L/kg is the apparent volume of distribution
of VOC. Orally administered VOC is extensively metabolized by CYP 450 (3A4/5) in the
liver, hence drugs with CYP450 induction or inhibition properties are not recommended
to be administered concomitantly
(hps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213716s000lbl.pdf,
Accessed on 10 January 2023). The half-life of VOC ranges from 25 to 36 h, the mean
apparent steady-state clearance is 63.6 L/h, and it is excreted in feces (~88%) and urine
(~2%) [10,31]. It is advised to be used in patients with a baseline eGFR of >45 mL/min/1.73
m2 wherein continuous eGFR monitoring is required. Moreover, it should be avoided in
patients with eGFR of ≤45 mL/min/1.73 m2 or a baseline blood pressure of >165/105 mmHg
and mild-to-moderate hepatic impairment.
Compared to other CNI, VOC has linear and predictable pharmacokinetic profiles
[54]. Unlike CsA and TAC, it does not require therapeutic drug monitoring and thus a
fixed dose can be prescribed. In addition, when CsA and MMF are combined, the
enterohepatic circulation of MMF is inhibited, and plasma concentrations of
mycophenolic acid (MPA) will be lower. Voclosporin does not affect the enterohepatic
circulation of MMF, leading to higher MPA exposure and potentially beer efficacy
compared to an equivalent MMF dose combined with CsA [55]. In kidney transplant
recipients and plaque psoriasis patients, VOC showed a strong correlation between dose,
its systemic concentration, CN inhibition, efficacy, and the threat of adverse events [56,57].
Contraindications: CYP3A4 induces or inhibits P-gp and OATP1B1 substrates
(statins), phenylalanine, flunisolide, bortezomib, and cladribine in patients with renal and
hepatic impairments. Close monitoring as well as dosage adjustment are recommended
when VOC is used along with such drugs.
Adverse effects: Overall, the safety profile of VOC is good when compared to CsA
and TAC (Table 2). VOC has not been reported to produce the other CNI related serious
adverse effects such as diabetes, gum hyperplasia, dyslipidemia, arrhythmia, and
disturbance in electrolyte balance and metabolic profile. Other common but non-serious
adverse effects, including increased blood pressure, diarrhea, headaches, anemia, coughs,
UTIs, upper abdominal pain, dyspepsia, alopecia, abdominal pain, mouth ulceration,
nausea, tremors, and decreased appetite, were occasionally observed. The most common
adverse effect from VOC was a transient drop in eGFR.
5. Experience with Calcineurin Inhibitors in Autoimmune Glomerulonephritis
and Podocytopathies
The current KDIGO guidelines recommend the use of CNI as a second line treatment
in a number of autoimmune glomerular diseases, namely for beer control of proteinuria
[58]. Especially in podocytopathies presenting as steroid-dependent nephrotic syndrome,
CNI are used as steroid-sparing agents [17,58]. In cases of steroid-resistant nephrotic
Cells 2023, 12, 2440 8 of 16
syndrome, CNI are in use while awaiting the results of genetic testing [4]. In membranous
nephropathy, a glomerulonephritis with an autoimmune podocyte injury [59,60], the
results of the MENTOR trial have reduced the enthusiasm for the use of CsA because B
cell depletion with rituximab was equally effective but, unlike CsA, did not show
nephrotoxicity [61]. TAC in combination with rituximab was beer tolerated but was
inferior to cyclophosphamide in this context [62]. In contrast, studies from China
convincingly demonstrate the superiority of a combination of MMF and TAC to reach
traditional trial endpoints in LN that heavily depend on the proteinuria response [63,64].
Confirmation from other world regions remained pending due to the lack of sponsor
interest to invest into trials with “old” drugs. This changed with the introduction of VOC.
5.1. Preclinical Data of Voclosporin and the Rationale to Develop Voclosporin for
Lupus Nephritis
VOC can aenuate the severity of disease in rodent models of autoimmune uveitis
and corneal inflammation [65,66]. However, experimental data on animal models of
autoimmune glomerulonephritis, LN, or other proteinuric kidney diseases, have not been
reported in the public domain. There may be reasons for this lack of preclinical data. The
mechanism of action of CNI is well established. Mouse models of SLE respond to the
traditional CNI, especially in terms of proteinuria control [67,68]. In addition, mice are not
a sensitive tool for a subtle drug safety analysis. In the clinical seing, most LN trials
testing modulators of adaptive immunity failed to reach the primary endpoint that
heavily relies on proteinuria control [69]. Indeed, an anti-proteinuric drug may be more
likely to reach standard endpoints in LN trials, with or without a capacity to suppress
autoimmunity, than a potent immune modulator because the processes underlying
proteinuria only indirectly relate to the immune system [70]. Hence, immunotherapies
acting outside of the kidney can control proteinuria only with some delay, while
antiproteinuric drugs, including CNI, show a more rapid response [59]. Finally, the
market potential of LN may exceed that of other autoimmune and proteinuric kidney
diseases [3].
5.2. Clinical Efficacy Data of Voclosporin in Lupus Nephritis
Clinical efficacy of VOC in LN was tested in the phase 2 AURA-LV and the phase 3
AURORA-1 studies in 265 patients requiring treatment for a first diagnosis or relapse of
biopsy-proven LN [53,71]. The AURA-LV study tested two oral doses of 23.7 mg VOC or
39.5 mg VOC or a placebo as an add-on to 2g/d mycophenolate mofetil (2 g/d), and rapidly
tapered oral corticosteroids [71]. A total of 32.6% of the low-dose VOC group achieved a
complete renal response at week 24, 27.3% of the high-dose VOC group, and 19.3% of the
placebo group. The significantly greater CRR rate in the low-dose VOC group persisted
for up to 48 weeks [71].
The AURORA-1 trial included SLE patients who had a kidney biopsy within 2 years
showing proliferative LN class III or IV, membranous LN class V, or combinations of these
[53]. Patients received either oral 23.7 mg VOC twice daily or a placebo as add-on to a
background of mycophenolate mofetil (2 g/d) and rapidly tapered oral corticosteroids.
The primary endpoint of a complete renal response at 52 weeks was defined as a
composite of proteinuria of 0.5 or less, stable estimated glomerular filtration rate (eGFR)
≥60 mL/min/1.73 m2, or no GFR decline from baseline of >20%, no rescue medication, and
no more than 10 mg prednisone equivalent per day [53]. The 357 patients were
randomized in a 1:1 ratio. A total of 41% of VOC-treated patients reached a complete renal
response at week 52 compared to 23% of the placebo group with an odds ratio of 2.65; 95%
CI 1.64–4.27; p < 0.0001). The majority of patients reached proteinuria treatment targets as
defined by the current EULAR/ERA recommendations [69,72]. These are similar to what
has been proposed for lupus nephritis by the global KDIGO guidelines [73]. It is of note
that a difference in proteinuria control between the two groups was evident as early as
two weeks after the start of VOC, which is unique among the non-CNI drugs used in the
Cells 2023, 12, 2440 9 of 16
LN sphere. Meanwhile 2 year follow-up analyses have been reported that document a
persistent benefit of VOC-treated patients in terms of this endpoint [74]. It is of note that
the parameters of systemic autoimmunity and extrarenal manifestations of SLE were
hardly assessed in this trial [53]. Complement and anti-dsDNA levels were not much
different between the groups further supporting the predominant antiproteinuric effect of
VOC [53]. Thus, the two trials confirmed that the antiproteinuric effect of CNI in
combination with MMF is potent enough to meet traditional trial endpoints in LN in
patients from various world regions, validating earlier Chinese studies. Thus, VOC shares
the immunosuppressive and antiproteinuric effects with the traditional CNI.
5.3. Clinical Safety Data of Voclosporin in Lupus Nephritis
Even novel immune modulators are still associated with adverse events, namely
infectious complications [75]. The safety analysis of the AURA-LV trial revealed more
serious adverse events in both VOC groups, and more deaths in the low-dose group
compared to the placebo and high-dose VOC groups (11.2%, 1.1%, and 2.3%, respectively)
[71]. Although these results raised some concerns, the safety analysis of the AURORA-1
trial displayed different results. Pneumonia occurred in 4% of VOC and 4% of placebo-
treated patients [53]. Six patients died during the study and follow-up period, of which
only one was treated with VOC. None of the fatal events were considered related to the
study treatments. Similarly, in the AURORA 2 follow-up study, a total of 216 patients
continued from the AURORA 1 trial, among which 116 were VOC treated while the rest
were in the control group; the investigators found that the treatment with VOC did not
increase chronic injury and helped in minimizing the renal histological changes [76].
These two follow-up data from different studies suggest that VOC is safer, and other side
effects matched the known safety profile of CNI, such as occasional hypertension or a
transient drop in GFR [53]. However, as judged by the estimated GFR, nephrotoxicity was
not observed during the reported two years of follow up. GFR remained stable in both
treatment groups [74]. Other adverse effects known from CsA or TAC such as gingival
hyperplasia, diabetes or hyperlipidemia were not observed [53]. Thus, VOC seems to have
a beer safety profile than other CNI, especially regarding metabolic disturbances and
long-term nephrotoxicity.
5.4. How to Integrate Voclosporin into the Treatment Landscape of Lupus Nephritis
Based on the results of the AURORA-1 trial, numerous countries approved VOC for
the initial treatment of active LN [10]. This approval is very welcome in the community
but raises numerous questions about how to implement VOC into the current treatment
landscape. Meanwhile, Belimumab (BEL) had also been approved for the same indication
based on the results of the BLISS-LN trial [77]. In contrast to VOC, BEL is well known to
rheumatologists as BEL has been in use for the treatment on non-renal SLE since 2011 and
has demonstrated good long-term efficacy on SLE activity and non-renal SLE
manifestations at a comfortable safety profile [78]. As such data are lacking for VOC, the
predominant advantage of VOC over BEL seems to be its capacity to control proteinuria
much faster than BEL [53,77]. Rapid control of proteinuria might help to avoid irreversible
kidney injury early in the disease course [79], but data supporting this concept are still
pending. Indeed, the AURORA-1 trial included a subset of patients that underwent repeat
biopsy, which would allow us to see if VOC-treated patients develop less chronic lesions.
However, for the moment, a specific renoprotective effect of early proteinuria control
remains speculative. Various concepts of how to implement VOC in the management of
LN are possible (Figure 2).
5.4.1. Option 1—Patient Selection
Rovin et al. started out with a pragmatic proposal to consider BEL and VOC as
second line drug options only for those patients not adequately responding to standard-
Cells 2023, 12, 2440 10 of 16
of-care within the first 3 months of treatment [80]. They proposed a threshold of 25%
reduction in proteinuria as a marker of non-response [80] but without specifying whether
this includes low-salt diet, a maximal tolerated dose of renin-angiotensin-system (RAS)
inhibitors, and an inhibitor of sodium-glucose transporter-2 (SGLT2) or not, which all
have substantial impact on proteinuria levels independent from the immunological SLE
activity [70]. The choice for either BEL or VOC would consider an individual cost–benefit
assessment as performed elsewhere [81]. Rovin et al. proposed a preference of BEL over
VOC in patients on MMF with a residual proteinuria of <3 g/d [80]. This option
acknowledges that a significant number of patients can reach a treatment response
without any of the new drugs and that limited resource seings may not be able to afford
the new drugs in all patients. However, as a limitation, a partial proteinuria response as a
guidance factor is subject to numerous confounders of proteinuria as a criterion for
treatment decisions in LN. For example, being overweight, having a salty diet, non-use of
RAS inhibition, and the use of dihydropyridin therapy to control hypertension may
explain an insufficient drop in proteinuria not necessarily requiring BEL or VOC add-on
therapy but other interventions.
5.4.2. Option 2—Combination Therapy
BEL and VOC both improve responder rates, but still a significant number of patients
do not reach a complete renal response [53,77]. Thus, combining the B cell deactivator BEL
and the T cell suppressor and podocyte protector VOC may have synergistic effects in
controlling all aspects of LN. As of now, this concept has not been tested in a controlled
study and not even case reports or series have been reported. Therefore, caution is
warranted regarding possible drug interferences and toxicity profiles. However, as
belimumab is not metabolized in the liver, the risk for interferences may be limited to a
possible additive effect on host defense and infectious complications. Given the different
sponsors of BEL and VOC, such a trial is unlikely to be conducted. As another limitation,
costs for such a treatment regime would hardly be affordable in most regions of the world.
Cells 2023, 12, 2440 11 of 16
Figure 2. Four different options for the implementation of voclosporin into the treatment landscape
of lupus nephritis. The different colors of grey indicate relative dosage. MMF = mycophenolate
mofetil, MPA = mycophenolic acid, VOC = voclosporin, BEL = belimumab, RASi = renin-angiotensin
system inhibitor, SGLT2i = sodium-glucose transporter-2 inhibitor.
5.4.3. Option 3—Sequential Therapy
The strength of VOC is rapid proteinuria control [53], which qualifies VOC for
immediate use in the management of LN in cases where rapid proteinuria control would
be associated with long-term benefits, e.g., by avoiding irreversible injury in this phase.
By contrast, the mechanism of action of BEL is rather long-term by controlling the
autoreactive lymphocytes clones that drive SLE activity and trigger flares of LN [82]. In
this regard, one could imagine the sequential use of VOC and BEL or starting LN therapy
with both of them and stopping VOC after 6 months when the effect of BEL kicks in.
Cells 2023, 12, 2440 12 of 16
However, such a regimen would be costly and data to support a sequential therapy
regimen are lacking so far.
5.4.4. Option 4—Other Antiproteinuric Drugs
In health care seings with limited availability or reimbursement of VOC, CsA and
TAC may appear as more affordable alternatives given they have the same mechanism of
action [3]. However, the main advantages of VOC over these drugs are that it lacks the
need for drug level monitoring and the much beer safety profile. Nephrotoxicity
especially limits the use of CsA on the long-term [5], as recently confirmed in the
MENTOR trial where CsA was tested against Rituximab in primary membranous
nephropathy [61]. Other antiproteinuric drugs that might replace VOC in this regard in
the early phase of disease exist, e.g., RAS inhibitors or SGLT2 inhibitors, which reduce
proteinuria by modulating glomerular hemodynamics and filtration pressure [83]. Such
drugs lack any immunosuppressive effects, but it is currently unclear to what extent the
long-term results of the AURORA-1 trial relate to the immunosuppressive effects of VOC
or to their antiproteinuric effects at the filtration barrier [53]. However, in this case, VOC
would be preferentially given in a sequential therapy approach, these drugs may to some
extent substitute for the rapid antiproteinuric effect of VOC and even contribute to a
renoprotective effect by antagonizing the non-immune mechanisms of LN progression
[84,85]. This might be a possibility in seings with limited resources for costly drugs.
However, RAS/SGLT2 blockades may make more sense, when used in combination with
BEL to suppress SLE activity and LN relapses by targeting B cell activity.
5.5. Cost of Voclosporin Treatment
The results from clinical trials related to VOC treatment in LN showed VOC’s clinical
effects on LN. Though the results are more in favor of VOC, the cost-effectiveness of VOC
will be a challenging task in the future as there is uncertainty around the cost-effectiveness
of VOC. According to one study, the cost-effectiveness of VOC is approximately USD
150,000 per quality-adjusted life years (QALYs) in the United States [86]. Notably, the
other emerging drugs, such as BEL, have approximately USD 95,000 per QALY,
suggesting that BEL was more cost effective [86]. Moreover, VOC costs GBP 1000 per 180-
pack of 7.9 mg soft capsules, while standard therapies such as MMF cost around GBP 6.23
per 50-pack of 500 mg tablets
(hps://www.nice.org.uk/guidance/ta882/resources/voclosporin-with-mycophenolate-
mofetil-for-treating-lupus-nephritis-pdf-82613730259141, Accessed on 11 January 2023).
Costs will certainly have an effect on the use and implementation of VOC into clinical
practice especially in limited resource seings.
6. Conclusions
As CsA and TAC remain associated with significant toxicities, the introduction of
VOC into clinical care is an important advancement of treatment options for LN and
possibly other autoimmune and proteinuric kidney diseases. VOC has a different
chemistry, pharmacology, and safety profile compared with CsA and TAC, namely, VOC
seems to lack nephrotoxicity. These aspects are an important asset when considering CNI
for chronic treatment of LN [3]. However, the problem of interference with other drug
classes that can cause additional toxicities in the context of certain co-medications
remains. The available evidence supports rapid and robust proteinuria control, which is
different from other immunosuppressants in use and in development for LN. Whether
rapid proteinuria control prevents irreversible injury beer than standard of care is not
yet known but is possible. This potential advantage would imply immediate and early use
of VOC in LN but may not necessarily argue for continued VOC therapy. Data on the
potential of VOC to control SLE and non-renal SLE manifestations are scarce, while these
Cells 2023, 12, 2440 13 of 16
are robust for alternative drug options such as BEL. How VOC will find its place in the
changing treatment landscape of LN is not yet clear.
Author Contributions: All authors wrote significant parts of the manuscript and have read and
agreed to the published version of the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding: H.-J.A. received funding from the Deutsche Forschungsgemeinschaft (AN372/30-1).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: H.-J.A. received consultancy fees and speaker honoraries from Otsuka and
GSK. The other authors have nothing to declare.
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