Voclosporin

Immunosuppressant / Autoimmune

Also known as: Lupkynis, ISA247, Voclosporin Capsules

Cyclic Peptides (Calcineurin Inhibitors)Research phase: FDA-approvedRegulatory: FDA-approved (2021) for lupus nephritis in combination with background immunosuppressive therapy (Lupkynis). Also EMA-approved.

Mechanism

Voclosporin is a next-generation cyclosporine analog FDA-approved for lupus nephritis. It blocks calcineurin to suppress T-cell activation and the immune response, similar to cyclosporine and tacrolimus, but with improved potency, more predictable pharmacokinetics, and less need for blood level monitoring. It is the first oral calcineurin inhibitor specifically approved for lupus kidney disease.

Technical detail

Voclosporin is a cyclic undecapeptide analog of cyclosporine A with a single amino acid modification (4-carbon trans-unsaturated extension at the amino acid 1 position). Like cyclosporine, it binds cyclophilin A; the voclosporin-cyclophilin complex inhibits calcineurin (a calcium/calmodulin-dependent serine-threonine phosphatase), blocking NFAT dephosphorylation and nuclear translocation, thereby suppressing IL-2 transcription and T-cell activation. The amino acid 1 modification increases calcineurin binding affinity (~4x more potent) and produces a less active primary metabolite, enabling more consistent exposure-response with less therapeutic drug monitoring.

Evidence

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial
Rovin BH et al. (2021) — Lancet — PMID: 33971155
In active lupus nephritis, adding voclosporin to mycophenolate mofetil and low-dose steroids increased complete renal response at 52 weeks versus placebo (41% vs 23%; OR 2.65, 95% CI 1.64-4.27), with a broadly balanced adverse-event profile.
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