2024 guidelines
Voclosporin is an analog of cyclosporine that exhibits enhanced potency in calcineurin inhibition. Voclosporin was noninferior to tacrolimus in the prevention of biopsy-proven acute rejection in a 6-month multicenter open-label phase 2b trial that involved 334 low-risk kidney transplant recipients.164 Voclosporin for the treatment of active biopsy-proven Class III, IV, and V LN was investigated in the AURA-LV trial,107 a phase 2 RCT of 265 subjects and the AURORA 1 trial,108,165 a phase 3 RCT of 357 subjects. Both trials included patients of diverse ancestry. Voclosporin was compared to placebo, and all patients received glucocorticoids and MMF (target dose: 2 g/d) as background therapy. The rapidly tapered corticosteroid regimen used was novel. All patients received 2 doses of i.v. methylprednisolone (500 mg/dose) followed by 20–25 mg prednisone that was rapidly tapered to 2.5 mg/d by 16 weeks. The primary endpoint of these trials was renal response (RR), defined as urine PCR =0.5 mg/mg [50 mg/mmol], eGFR =60 ml/min per 1.73 m2, or no decline of >20% from baseline, and prednisone dose of <10 mg/d for the 8 weeks prior to endpoint measurement.
In AURA-LV, 33% of patients treated with voclosporin 23.7 mg twice per day reached an RR at 24 weeks compared to 19% of placebo-treated patients (odds ratio [OR] 2.03, P <0.05).107 Similarly, in AURORA, 41% of voclosporin-treated patients achieved RR at 52 weeks, compared to 23% of placebo-treated patients (OR 2.65, P < 0.001).108,165 A pooled analysis of the 2 trials showed that patients treated with voclosporin added to standard therapy had an RR rate of 44% at 1 year, compared to 23% in placebo patients (P < 0.0001).166 The incidences of adverse events were similar between the placebo and voclosporin arms.
Compared to other CNIs, such as cyclosporine and tacrolimus, voclosporin has a more consistent pharmacokinetic–pharmacodynamic relationship due to enhanced binding of the voclosporin–cyclophilin complex to calcineurin and reduced drug and metabolite load. Preliminary evidence, based on data from the AURA-LV and AURORA trials, suggests that therapeutic drug monitoring is not necessary in the studied patient population.167 Note that there are no data on voclosporin given together with cyclophosphamide.
Results from the pivotal trials led to the U.S. FDA approval of voclosporin to treat adult patients with LN in January 2021. Of note, voclosporin is not recommended for patients with a baseline eGFR >45 ml/min per 1.73 m2, and these patients were excluded from the trials. ( my emphasis ) Similarly, significant impairment of kidney function is often an exclusion criterion in clinical trials of CNIs. The use of a CNI in patients with severe CKD requires careful individualized consideration of risk versus potential benefit, and should be done with caution and careful monitoring, and at reduced drug exposure.
The positive results of AURA-LV and AURORA coupled with those of the Asian studies of tacrolimus and cyclosporine suggest triple immunosuppressive therapy incorporating a CNI can be an effective treatment regimen for LN. An advantage of a CNI-based regimen is the more rapid reduction of proteinuria. However, outstanding issues on the duration of the CNI, its tapering and suspension, and the long-term efficacy and safety of CNI triple therapy regimens remain under study.
Kiwi
