voclosporin
ISA247, ISAtx-247, R1524, voclosporin (INN)
Voclosporin is a semi-synthetic cyclic undecapeptide calcineurin inhibitor, made by adding a single carbon to one side chain of ciclosporin. That small change increases calcineurin binding potency and produces a cleaner metabolite profile, which is why it can be given at a fixed dose without therapeutic drug monitoring. It is licensed with mycophenolate mofetil for active lupus nephritis, and is an immunosuppressant rather than an oncology drug.
Mechanism
Voclosporin is ciclosporin with one modification: the amino acid-1 residue MeBmt carries a one-carbon extension of its side chain, giving a terminal diene. It is supplied as a defined mixture of the trans and cis isomers of that extension, with trans predominating. Everything upstream and downstream of that change is ciclosporin biology. Voclosporin diffuses into the cell, binds cyclophilin A, and the composite drug-cyclophilin surface docks onto calcineurin and occludes substrate access. Calcineurin can then no longer dephosphorylate NFAT, so NFAT stays phosphorylated and cytoplasmic, interleukin-2 transcription never starts, and T-cell clonal expansion is blocked.
The consequences of the single extra carbon are pharmacological rather than mechanistic. Calcineurin inhibition is several-fold more potent than ciclosporin on a molar basis, so lower plasma concentrations suffice. The modification also redirects metabolism: voclosporin produces a smaller burden of active metabolites than ciclosporin, and the concentration-effect relationship is tight enough that a fixed dose is used with no routine whole-blood level monitoring, a genuine practical difference from every other calcineurin inhibitor. A second, non-immunological action is important in lupus nephritis specifically: calcineurin dephosphorylates synaptopodin in the podocyte, marking it for degradation, so calcineurin inhibition stabilises the podocyte actin cytoskeleton and reduces proteinuria directly, independently of any effect on lymphocytes. That is why proteinuria falls faster on a calcineurin inhibitor than the immunological timescale would predict, and it is also a reason to be careful about reading early proteinuria responses as evidence of disease control.
What the research shows
AURA-LV, a phase 2 randomised double-blind placebo-controlled trial in 265 patients across 79 centres in 20 countries, tested two doses of voclosporin against placebo, each added to mycophenolate mofetil 2 g/day and rapidly tapered low-dose oral corticosteroids. Complete renal remission at 24 weeks was achieved by 32.6% on the lower dose, 27.3% on the higher dose and 19.3% on placebo (odds ratio 2.03 for low dose versus placebo), with the advantage persisting to 48 weeks. AURORA 1 then randomised 357 patients 1:1 to voclosporin or placebo on the same background regimen: complete renal response at 52 weeks occurred in 73 of 179 (41%) on voclosporin versus 40 of 178 (23%) on placebo, an odds ratio of 2.65 (95% CI 1.64-4.27, p < 0.0001). AURORA 2 continued 216 of those patients on blinded treatment for a further two years and found renal response in 50.9% versus 39.0% at three years, with estimated glomerular filtration rate remaining within the normal range in both arms and a mean eGFR slope of about −0.2 mL/min/1.73 m² per year.
The negatives deserve equal billing. In AURA-LV, deaths were more frequent on low-dose voclosporin (11.2%) than on high-dose voclosporin (2.3%) or placebo (1.1%), an imbalance that was concentrated in a small number of participating regions, was not dose-related in the expected direction, and has never been fully explained; the phase 3 programme did not reproduce it (six deaths across both arms of AURORA 1, none judged treatment-related by investigators). More fundamentally, the entire licensed benefit rests on complete renal response, a composite surrogate built around proteinuria and preserved eGFR. That is a reasonable surrogate in lupus nephritis, but no trial has yet shown that voclosporin reduces progression to end-stage kidney disease or death, and part of the proteinuria effect is a direct podocyte action rather than a measure of immunological control. Calcineurin inhibitors as a class also carry a long-term nephrotoxicity signal, and the three-year AURORA 2 eGFR data are reassuring but are not the same as decades of follow-up.
Evidence assessment
High-quality evidence
Full (not conditional) marketing authorisation in both the US and EU, supported by a randomised double-blind placebo-controlled phase 2 dose-ranging trial (AURA-LV, n = 265) and an adequately powered randomised double-blind placebo-controlled phase 3 trial (AURORA 1, n = 357) that met its primary endpoint, with a blinded continuation study to three years (AURORA 2, n = 216). All four citations verified against PubMed. Two honest caveats belong alongside the tier: the primary endpoint is complete renal response, a surrogate rather than a hard outcome, with no data yet on progression to kidney failure or death; and the phase 2 trial showed an unexplained excess of deaths in the low-dose voclosporin arm that was not reproduced in phase 3.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis Preclinical only
Complete renal remission at 24 weeks in 32.6% (low dose), 27.3% (high dose) and 19.3% (placebo); odds ratio 2.03 for low dose versus placebo, with the advantage persisting at 48 weeks. Serious adverse events were more frequent on voclosporin, and deaths were higher in the low-dose arm (11.2%) than the high-dose (2.3%) or placebo (1.1%) arms, an unexplained imbalance concentrated in a few regions.
Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial Preclinical only
Complete renal response at 52 weeks in 73 of 179 (41%) versus 40 of 178 (23%); odds ratio 2.65 (95% CI 1.64-4.27, p < 0.0001). Serious infection rates were similar between arms; six deaths occurred overall, none considered treatment-related by investigators.
Safety and efficacy of long-term voclosporin treatment for lupus nephritis in the phase 3 AURORA 2 clinical trial Preclinical only
Renal response in 50.9% versus 39.0% of controls, with estimated glomerular filtration rate remaining within the normal range in both arms and a mean eGFR slope of approximately −0.2 mL/min/1.73 m² over the two-year extension. No new safety signals over three years.
Update on the efficacy and safety profile of voclosporin: an integrated analysis of clinical trials in lupus nephritis Preclinical only
Pooled analysis confirmed higher complete renal response rates and faster reduction in proteinuria with voclosporin, with the safety profile driven by the expected calcineurin inhibitor effects on eGFR and blood pressure.
Safety
The most consistent finding is a small, early, largely reversible fall in estimated glomerular filtration rate, typically around 10% within the first weeks and stable thereafter, which reflects the haemodynamic effect of calcineurin inhibition on the afferent arteriole rather than structural injury; nonetheless eGFR is monitored and treatment is interrupted or stopped if the fall exceeds defined thresholds. Hypertension is common and often needs treatment. Other frequent adverse effects are headache, anaemia, cough, urinary tract infection, upper abdominal pain, diarrhoea and gingival hyperplasia. The US label carries a boxed warning for increased susceptibility to serious infection and for malignancy, particularly lymphoma and skin cancer, which is the class warning for calcineurin-inhibitor immunosuppression. QT prolongation has been seen at supratherapeutic exposures. Concomitant strong CYP3A4 inhibitors are contraindicated and moderate inhibitors require dose reduction; strong inducers should be avoided. It is not recommended in combination with cyclophosphamide, and caution applies in significant renal impairment. Live vaccines should be avoided.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | European Commission marketing authorisation granted 15 September 2022 (a standard, not conditional, authorisation) in combination with mycophenolate mofetil for adults with active class III, IV or V (including mixed class III/V and IV/V) lupus nephritis (verified against the EMA record). Licensed in Great Britain by the MHRA. NICE has appraised voclosporin with mycophenolate mofetil for lupus nephritis; the recommendation in force and any eligibility restrictions should be checked against current NICE guidance rather than assumed. |
| United States | FDA approved January 2021 in combination with a background immunosuppressive therapy regimen for the treatment of adults with active lupus nephritis. Oral capsule, prescription-only. The label carries a boxed warning for malignancies and serious infections, the class warning applied to calcineurin-inhibitor immunosuppressants. Not recommended for use with cyclophosphamide, and efficacy has not been established in severe renal impairment. |
| WADA (sport) | Not on the WADA Prohibited List. Voclosporin is an immunosuppressant with no anabolic, hormonal, stimulant, diuretic or masking activity. |
Questions
By one carbon atom. The side chain of the first amino acid residue is extended, which makes the molecule several-fold more potent at inhibiting calcineurin and gives it a cleaner metabolite profile. Ten of the eleven residues are identical. The practical consequences are a fixed dose without routine blood level monitoring, and a shorter half-life of around 30 hours.
No. It is an immunosuppressant licensed for active lupus nephritis, an autoimmune kidney disease. It appears in this collection because it is a cyclic peptide medicine closely related to ciclosporin, and the two are frequently searched together.
That has not been shown. The trials measured complete renal response (a composite of proteinuria reduction with preserved kidney function) at one year, with a blinded extension to three years. That is a reasonable surrogate, and the three-year kidney function data are reassuring, but no trial has yet demonstrated a reduction in progression to end-stage kidney disease or in death.
Partly for a reason that has nothing to do with immunosuppression. Calcineurin also dephosphorylates synaptopodin in the kidney's podocytes, marking it for degradation and destabilising the cell's actin cytoskeleton. Inhibiting calcineurin protects that structure directly, so protein leak falls faster than any immunological effect could account for. It is a real benefit, but it means early proteinuria response is not a pure readout of disease control.
Because the extra carbon changes how it is metabolised. Voclosporin generates fewer active metabolites than ciclosporin and its exposure-response relationship is predictable enough that a fixed dose works. Ciclosporin and tacrolimus, by contrast, have narrow therapeutic indices and highly variable absorption, which is why whole-blood trough monitoring is routine for those two.