Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis

Figures & data

Table 1. Clinical trials of voclosporin in lupus nephritis.

Study		Design	Cohort	N	Treatment	Primary endpoint	Outcome
AUVCS-2018-01		Phase I, open-label, multicenter	Adults with SLE ± history of LN; on MMF 2 g/day for ≥28 days	24 (8 with history of LN)	Voclosporin 23.7 mg BID for 7 days + 2 g/day MMF	Effect of voclosporin on PK of MPA	No effect of voclosporin on MPA plasma concentration–time profile; no effect on MPA Cmax, AUC0–12 or Tmax
NCT02141672 (AURA-LV)		Phase II, double-blind, placebo-controlled; 79 centers in 20 countries across North and Latin America, Europe, and Asia	Adults with SLE and Class III, IV or V LN as evidenced by kidney biopsy within 6 months of screening, proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V), and eGFR >45 mL/min/1.73 m^2	265	Voclosporin 23.7 mg or 39.5 mg BID or placebo, + MMF 2 g/day and rapidly tapered low-dose corticosteroid	CRR at 24 weeks	13% increase in CRR rate at 24 weeks voclosporin 23.7 mg BID (32.6%) vs placebo (19.3%) (P = 0.046); CRR at 24 weeks maintained at 48 weeks in 100% patients 26%; increase in CRR at 48 weeks (49.4% vs 23.9%) (P < 0.001)
NCT03021499 (AURORA 1)		Phase III, double-blind, placebo-controlled; 142 centers in 27 countries across North and Latin America, Europe, South Africa, and Asia	Adults with SLE and Class III, IV or V LN with kidney biopsy within 6 months of screening or within 2 years of screening + at least a doubling of UPCR in the 6 months before screening, proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V), and eGFR >45 mL/min/1.73 m^2	357	Voclosporin 23.7 mg BID or placebo, + MMF 2 g/day and rapidly tapered low-dose corticosteroids	CRR at 52 weeks	18% increase in CRR rate at 52 weeks with voclosporin (40.8%) vs placebo (22.5%) (P < 0.0001)
NCT03597464 (AURORA 2)		Phase III, double-blind, placebo-controlled continuation study	Subjects who have completed 52 weeks in AURORA 1 continue the same randomized treatment in AURORA 2 for 2 additional years	216	Voclosporin 23.7 mg BID or placebo, + MMF and low-dose corticosteroids starting at the same dose as at the end of AURORA 1	Long-term safety	Study ongoing. Interim analysis: reductions in proteinuria maintained with no change in mean eGFR at 30 months

AUC, area under the concentration–time curve; BID, twice daily; C_max, maximum serum concentration; CRR, complete renal response; eGFR, estimated glomerular filtration rate; LN, lupus nephritis; MMF, mycophenolate mofetil; MPA, mycophenolic acid; P, probability value; PK, pharmacokinetics; SLE systemic lupus erythematosus; T_max, time to maximum serum concentration; UPCR, urine protein-to-creatinine ratio.

Figure 1. In T-cells, voclosporin (VCS) binds cyclophilin A (CyP), and the resulting complex (VCS–CyP) binds and competitively inhibits calcineurin (Cal) from dephosphorylating phosphorylated nuclear factor of activated T-cells (NFAT-P) to nuclear factor of activated T-cells (NFAT) [46]. When dephosphorylated, NFAT activates translation and transcription of various cytokines (IL-2, TNF-α, others), which promotes T-cell proliferation [40]. In podocytes, calcineurin activity is involved in destabilization of the podocyte actin cytoskeleton. Phosphorylated synaptopodin (SYN-P) binds with 14-3-3 protein, which stabilizes the actin cytoskeleton of the podocyte. When activated, calcineurin dephosphorylates synaptopodin, which marks it for destruction by cathepsin L, subsequently leading to podocyte cytoskeleton destabilization and increased proteinuria. By inhibiting this dephosphorylation pathway, VCS maintains SYN-P, which protects synaptopodin from destruction and thus promotes actin cytoskeleton stabilization [50,53].

Table 2. Efficacy of voclosporin in clinical trials in lupus nephritis [18,39].

	Voclosporin		Placebo (n = 88)	OR (95% CI) 23.7 mg BID	P	OR (95% CI) 39.7 mg BID	P
Phase II AURA-LV	23.7 mg BID (n = 89)	39.5 mg BID (n = 88)
CRR at 24 weeks (primary endpoint), %	32.6	27.3	19.3	2.03 (1.01–4.05)	0.046	1.59 (0.78–3.27)	0.204
CRR at 48 weeks, %	49.4	39.8	23.9	3.21 (1.68–6.13)	<0.001	2.10 (1.09–4.02)	0.026
Median time to CRR, weeks	19.7	23.4	NC^a	NC		NC
Phase III AURORA 1	Voclosporin23.7 mg BID (n = 179)^b		Placebo (n = 178)	OR (95% CI)		P
CRR at 52 weeks (primary endpoint), %	40.8		22.5	2.65 (1.64–4.27)		<0.0001
CRR at 24 weeks, %	32.4		19.7	2.23 (1.34–3.72)		0.002
PRR at 24 weeks, %	70.4		50.0	2.43 (1.56–3.79)		<0.001
PRR at 52 weeks, %	69.8		51.7	2.26 (1.45–3.51)		<0.001
				HR (95% CI)
Median time to UPCR ≤0.5 mg/mg, days (95% CI)	169 (141–214)		372 (295–NC)	2.02 (1.51–2.70)		<0.001
Median time to 50% UPCR reduction, days (95% CI)	29 (29–32)		63 (57–87)	2.05 (1.62–2.60)		<0.001
CRR components				OR (95% CI)
UPCR ≤0.5 mg/mg at 52 weeks, %	45.2		23.0	3.11 (1.93–5.00)		<0.001
eGFR component of CRR^c, %	82.1		75.8	1.50 (0.89–2.52)		0.129
No rescue medication, %	91.1		86.5	1.62 (0.82–3.20)		0.164
Steroid component of CRR^d, %	87.2		85.4	1.26 (0.68–2.34)		0.465

BID, twice daily; CI, confidence interval; CRR, complete renal response; eGFR, estimated glomerular filtration rate; HR, hazard ratio; NC, non-calculable; OR, odds ratio; P, probability value; PRR, partial renal response; UPCR, urine protein-to-creatinine ratio

^aCould not be calculated as the control group did not reach 50% probability of UPCR ≤0.5 mg/mg in Kaplan–Meier analysis.

^bIntent-to-treat population.

^ceGFR ≥60 mL/min/1.73 m², eGFR <60 mL/min/1.73 m² with no confirmed decrease >20%, or eGFR <60 mL/min/1.73 m² with confirmed decrease of >20% but with no disease-related or treatment-related eGFR-associated adverse event at time of assessment.

^dDid not receive >10 mg/day prednisone for ≥3 consecutive days or for ≥7 days in total during Week 44–52.

Figure 2. Probability of UPCR of ≤0.5 mg/mg and ≥50% reduction from baseline in UPCR in the AURORA 1 trial of voclosporin in combination with MMF and low-dose steroids (intention-to-treat population) in lupus nephritis [18]. Reproduced from The Lancet, with permission (doi: 10.1016/S0140-6736(21)00578-X).

Figure 3. Subgroup analysis for complete renal response at 52 weeks in the AURORA 1 trial of voclosporin in combination with MMF and low-dose steroids (intention-to-treat) population in Iupus nephritis [18]. Reproduced from The Lancet, with permission (doi: 10.1016/S0140-6736(21)00578-X).

Table 3. Safety of voclosporin in clinical trials in lupus nephritis [18,20,39].

Phase II AURA-LV	Voclosporin		Placebo
	23.7 mg BID (n = 89) n (%)	39.5 mg BID (n = 88) n (%)	(n = 88) n (%)
AE	82 (92.1)	85 (96.6)	75 (85.2)
Serious AE	25 (28.1)	22 (25.0)	14 (15.9)
Treatment-related AE	45 (50.6)	55 (62.5)	15 (17.0)
Serious treatment-related AE	4 (4.5)	7 (8.0)	1 (1.1)
AE leading to study drug discontinuation	16 (18.0)	14 (15.9)	9 (10.2)
AE with outcome of death	10 (11.2)	2 (2.3)	1 (1.1)
Phase III AURORA 1	Voclosporin23.7 mg BID (n = 178)^a n (%)		Placebo (n = 178) n (%)
AE	162 (91.0)		158 (88.8)
Serious AE	37 (20.8)		38 (21.3)
Serious AE of infections and infestations	18 (10.1)		20 (11.2)
Treatment-related serious AE	8 (4.5)		8 (4.5)
AE leading to study drug discontinuation	20 (11.2)		26 (14.6)
Death	1 (0.6%)		5 (2.8)
Treatment-related AE leading to death	0		0
Integrated safety analysis	Voclosporin		Placebo
	23.7 mg BID (n = 267) n (per 100 pt-yrs)	39.5 mg BID (n = 88) n (per 100 pt-yrs)	(n = 266) n (per 100 pt-yrs)
Infections	166 (135.2)	58 (167.5)	146 (107.4)
Serious infections	27 (11.9)	10 (14.4)	27 (12.0)
Opportunistic infections	3 (1.3)	1 (1.4)	2 (0.9)
Decreased GFR	70 (37.1)	27 (48.7)	25 (11.3)
Renal AE^b	26 (11.3)	11 (16.5)	22 (9.5)
Serious renal AE	13 (5.6)	0 (0)	9 (3.7)
Hypertension	51 (25.2)	16 (26.0)	23 (10.3)
Serious hypertension	5 (2.1)	2 (2.8)	1 (0.4)
Neurotoxicity	74 (38.9)	24 (42.5)	44 (21.6)
Serious neurotoxicity	9 (3.9)	3 (4.3)	2 (0.9)
Adverse reactions in ≥10% of patients treated with voclosporin	Voclosporin 23.7 mg BID (n = 267) %		Placebo (n = 266) %
GFR decreased	26		9
Hypertension	19		9
Diarrhea	19		13
Headache	15		8
Anemia	12		6
Cough	11		2
Urinary tract infection	10		6

AE, adverse event; BID, twice daily; GFR, glomerular filtration rate; pt-yrs, patient-years.

^aSafety population.

^bRenal impairment, acute kidney injury, blood creatinine increased, azotemia, renal failure, oliguria, and/or proteinuria.

Table 4. Voclosporin usage and precautions in patients with lupus nephritis [20].

Property	Recommendation
Indication	In combination with a background immunosuppressive therapy regimen in adults with active LN
Before initiating voclosporin	Establish accurate baseline eGFR and check BP. Not recommended in patients with baseline eGFR ≤45 mL/min/1.73 m^2 unless benefit outweighs risk. Do not initiate in patients with BP >165/105 mmHg. Contraindicated in patients concomitantly using strong CYP3A4 inhibitors. Avoid coadministration with strong and moderate CYP3A4 inducers. Avoid in patients with severe hepatic impairment
Recommended dose	23.7 mg BID orally. 15.8 mg BID in patients with severe renal impairment. or mild/moderate hepatic impairment. 5.8 mg in the morning and 7.9 mg in the evening in patients using moderate CYP3A4 inhibitors
Modify dose based on eGFR	Assess eGFR every 2 weeks for the first month and every 4 weeks thereafter. If eGFR <60 mL/min/1.73 m^2 and >20% and <30% reduction from baseline, reduce dose by 7.9 mg BID. Reassess eGFR within 2 weeks, if still reduced from baseline by >20%, reduce dose again by 7.9 mg BID. If eGFR <60 mL/min/1.73 m^2 and ≥30% reduction from baseline, discontinue. Reassess within 2 weeks and consider re-initiating at lower dose (7.9 mg BID) when eGFR is ≥80% of baseline. For patients with dose decrease due to eGFR, consider increasing dose by 7.9 mg BID for each eGFR measurement that is ≥80% of baseline, but do not exceed starting dose
BP	Monitor every 2 weeks for the first month, and as clinically indicated thereafter. Discontinue if BP >165/105 mmHg
Serum potassium	Risk of hyperkalemia may be increased with other agents associated with hyperkalemia; periodically monitor serum potassium
QT prolongation	Risk of QT prolongation in combination with other drugs that cause QT prolongation (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers); consider obtaining ECG and monitoring electrolytes in patients at high risk
Neurotoxicity	Monitor for neurologic symptoms and discontinue if neurotoxicity occurs

ACE, angiotensin-converting enzyme; BID, twice daily; BP, blood pressure; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; MMF, mycophenolate mofetil.

Table 5. Comparison of calcineurin inhibitors in lupus nephritis.

	Voclosporin (VCS)	Tacrolimus (TAC)	Cyclosporine (CsA)
US FDA approval in LN	January 2021	Not approved^a	Not approved
Initial dose	23.7 mg twice daily	~0.1mg/kg/day^b	~4mg/kg/day^b
Drug–drug interaction with MMF	No	No	Reduces MPA exposure
Therapeutic drug monitoring	Not required	Recommended	Recommended
Warnings/precautions or AE noted in Prescribing Information^c
Diabetes mellitus	No	Warnings/precautions: NODAT (> CsA)^d	Adverse event, seen in 1–3% of RA patients. NODAT (<TAC)^d
Dyslipidemia	No	Adverse reaction: hyperlipidemia (<CsA)^e	Adverse reaction: hyperlipidemia (>CsA)^e
Hypertension	Warnings/precautions	Warnings/precautions	Warnings/precautions
Metabolic abnormalities	Hyperkalemia	Hyperkalemia, hypomagnesemia, hypophosphatemia, hypokalemia, hyperuricemia	Hyperkalemia, hypomagnesemia, hypophosphatemia, hyperuricemia

AE, adverse event; FDA, US Food and Drug Administration; LN, lupus nephritis; MMF, mycophenolate mofetil; MPA, mycophenolic acid; NODAT, new onset diabetes after transplant.

^aApproved in Japan in 2007 and in some Asian countries thereafter [79].

^bMaintained for one month, with slow tapering to the lowest effective dose; patients should be carefully monitored during the first months of treatment to find the optimal individual dose [40].

^cAs immunosuppressants, voclosporin, tacrolimus, and cyclosporine carry a warning of increased risk for development serious infections and malignancies

^dNo head-to-head comparisons in LN are available. Caused NODAT in clinical trials of kidney, liver, and heart transplantation. In a Phase 3 study of TAC/MMF versus CsA/MMF in renal transplant, incidence of NODAT at 1 year was 75% with TAC and 61% with CsA [29].

^eNo head-to-head comparisons in LN are available. In a Phase 3 study in renal transplant patients, hyperlipidemia was seen in 18% of TAC/MMF patients versus 25% of CsA/MMF patients [29].

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