• View in gallery

    Numerous dysmorphic RBCs were noted on the urine sediment

  • View in gallery

    Lupus nephritis class III with focal crescentic (white arrow) and necrotizing lesions (red arrow)

  • View in gallery

    Voclosporin characteristics and clinical trial progress

  • 1.

    Wang L, et al. Calcineurin (CN) activation promotes apoptosis of glomerular podocytes both in vitro and in vivo. Mol Endocrinol 2011; 25:13761386. doi: 10.1210/me.2011-0029

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Shen X, et al. Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep 2016; 6:32087. doi: 10.1038/srep32087

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Li Y, et al. Pharmacokinetic disposition difference between cyclosporine and voclosporin drives their distinct efficacy and safety profiles in clinical studies. Clin Pharmacol 2020; 12:8396. doi: 10.2147/CPAA.S255789

    • Search Google Scholar
    • Export Citation
  • 4.

    Sanders ML, Langone AJ. Drugs in development for prophylaxis of rejection in kidney-transplant recipients. Transpl Res Risk Manag 2015; 7:5969. doi: 10.2147/TRRM.S61446; https://www.dovepress.com/drugs-in-development-for-prophylaxis-of-rejection-in-kidney-transplant-peer-reviewed-fulltext-article-TRRM

    • Search Google Scholar
    • Export Citation
  • 5.

    Rovin BH, et al. 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. Kidney Int 2019; 95:219231. doi: 10.1016/j.kint.2018.08.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Rovin BH, et al. Management of lupus nephritis (LN) with voclosporin: An update from a pooled analysis of 534 patients. American Society of Nephrology Kidney Week 2020. October 22, 2020. Abstract PO1917. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3446491

    • Search Google Scholar
    • Export Citation
  • 7.

    Arriens C, et al. Scientific Abstracts, Oral Presentations: Other orphan diseases. OP0277: AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN). Ann Rheum Dis 2020; 79:172173. https://ard.bmj.com/content/79/Suppl_1/172.2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Bensman A, Niaudet P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol 2010; 25:11971199. doi: 10.1007/s00467-010-1469-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Furie R, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020; 383:11171128. doi: 10.1056/NEJMoa2001180

Voclosporin: Hope on the Horizon for Lupus Nephritis?

  • 1 Anna Gaddy, MD, is a nephrology fellow at Indiana University School of Medicine, Indianapolis.
Full access

Ms. H is a 33-year-old Hispanic woman referred from a primary care clinic for proteinuria. Her only past medical history is hypertension on a single agent, amlodipine. She has had three children and had a tubal ligation for contraception. She reports that her pregnancies were uncomplicated with no history of preeclampsia or gestational diabetes. Her physical exam was unremarkable with blood pressure 130/70 mm Hg, and she has no edema.

Her laboratory data revealed a normal comprehensive metabolic panel with serum creatinine of 1.6 mg/dL and complete blood counts, although her serologies were noted for the following:

  • ■ double-stranded DNA titer 1:320 IU/mL

  • ■ C3 10 mg/dL (reference range 88−201 mg/dL), C4 5 mg/dL (reference range 15−45 mg/dL)

  • ■ spot urine protein/creatinine ratio of 4450 mg/g (reference range 0−200 mg/g)

  • ■ urinalysis was notable for 30 red blood cell/high-power field (RBC/hpf) (Figure 1)

A kidney biopsy shows class III lupus nephritis (LN) with occasional crescents (<50%) (Figure 2). Ms. H asks you about treatment options. Her sister had LN, and cyclosporine caused gastrointestinal discomfort, hirsutism, and required multiple lab draws (for monitoring of levels), so she wants to avoid this regimen if possible. One year ago, your choice would have been mycophenolate mofetil (MMF) with a steroid taper for induction or perhaps rituximab or even a cyclophosphamide-based regimen. However, in 2021, treatment options for LN are quickly evolving. Kidney Week 2020 was rife with new developments in glomerular disease, including a session on the phase 3 clinical trial of voclosporin (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events [AURORA]) for induction of remission in patients with LN).

Figure 1.
Figure 1.

Numerous dysmorphic RBCs were noted on the urine sediment

Citation: Kidney News 13, 2

Courtesy Florian Buchkremer for Renal Fellow Network.
Figure 2.
Figure 2.

Lupus nephritis class III with focal crescentic (white arrow) and necrotizing lesions (red arrow)

Citation: Kidney News 13, 2

A background of mild segmental mesangial hypercellularity is noted (silver stain, ×400). Courtesy Sam Albadri for Renal Fellow Network.

Voclosporin is a semi-synthetic analogue of cyclosporin A with enhanced potency and more predictable metabolism. This is because voclosporin is metabolized into smaller metabolites that do not competitively antagonize the parent compound like cyclosporine does. Thus, voclosporin does not require monitoring of levels. Like tacrolimus and cyclosporine, voclosporin inhibits calcineurin and prevents interleukin-2 (IL-2)-mediated T-cell activation. There are also data that calcineurin inhibitors (CNIs) can potentially directly stabilize podocyte foot processes and protect against injury (1, 2). Voclosporin achieves its immunomodulatory effect at lower doses than cyclosporine (3). Therefore, the hope is that heart- and kidney-associated toxicity seen with traditional CNIs will be lower (4). Because of this, voclosporin has the potential to improve remission rates and long-term outcomes (Figure 3).

Figure 3.
Figure 3.

Voclosporin characteristics and clinical trial progress

Citation: Kidney News 13, 2

Anna Gaddy, MD, is a Nephrology Fellow at Indiana University School of Medicine, Indianapolis.

In 2018, the phase 2 Aurinia Urinary Protein Reduction Active-Lupus with Voclosporin (AURA-LV) trial (5) demonstrated that voclosporin was efficacious when combined with MMF and a rapid steroid taper to induce remission in LN. The AURA-LV trial was composed of 265 patients with a kidney biopsy showing active class III, IV, or V LN within 6 months of screening. All patients received daily MMF and oral corticosteroids. The three comparison groups were 88 patients who received placebo, 89 patients receiving low-dose voclosporin (23.7 mg twice daily), and 88 patients receiving high-dose voclosporin (39.5 mg twice daily). In this study, significantly more individuals achieved complete remission with either low- or high-dose voclosporin than with placebo, and this effect persisted at 48 weeks in the low-dose group. Overall, with the addition of low-dose voclosporin, complete kidney remission was achieved by just under 30% of participants compared to only 20% of participants in the placebo group.

Not all of the AURA-LV results were encouraging, as both high-dose voclosporin and low-dose groups experienced significantly more serious adverse events (25.0% in low dose and 28.1% in high dose) compared to the placebo group (15.9%). Particularly concerning was that 10 deaths (11.2%) occurred in the low-dose voclosporin arm, compared to two in the high-dose arm and one in the placebo arm. However, only 3 of the 12 deaths in patients receiving voclosporin were related to infections. The most common serious adverse events in the AURA-LV trial were infection and gastrointestinal side effects.

The wait for phase 3 data came to an end as the AURORA trial data were presented at the Annual European Congress of Rheumatology (EULAR); then, at ASN Kidney Week 2020 Reimagined, the pooled results from phases 2 and 3 were presented (5). This pooled analysis combined data from the low-dose arm of the AURA-LV trial with data from the AURORA trial, as all study patients in the latter trial received 23.7 mg daily, randomized with placebo on a background of steroids and MMF—a total of 534 patients. The efficacy seen in AURORA was re-demonstrated, as voclosporin significantly improved the kidney response by 18% at one year (40.8% versus 22.5% in placebo). Subgroup analysis of the AURORA trial showed that 38.6% of Hispanic/Latinx participants receiving voclosporin achieved kidney remission (6, 7) compared to only 18.6% of those in the control arm. This is an exciting finding given the historically poor outcomes in this patient population.

Importantly, the increase in adverse events and death seen in the phase 2 AURA-LV trial was not appreciated in the phase 3 trials, with only 20.8% of participants taking voclosporin experiencing serious adverse events compared to 21.3% in the control group. It is worth noting that the definition of complete kidney remission of LN is defined as a urine protein-to-creatinine ratio of equal to or less than 0.5 mg/g, an estimated glomerular filtration rate (eGFR) of greater than or equal to 60 mL/min/1.73 m2, or no loss of eGFR more than 20% of baseline and importantly, no rescue medications. Since CNIs are known to decrease proteinuria by nonimmunologic mechanisms (8), the endpoint of proteinuria may not tell a complete story, as immune damage may still be occurring even with diminished proteinuria. We await the final peer-reviewed publication of this trial before we can make any major conclusions.

Overall, the unpublished data of voclosporin appear to show improved remission rates and facilitate the early taper of corticosteroids, with no apparent increase in adverse events in phase 3 clinical trials. Important questions still remain about the long-term effects of voclosporin on cardiovascular and kidney function. However, the potential to give a medication without the need for monitoring has made voclosporin the first FDA-approved CNI for the treatment of LN. The encouraging results demonstrated in AURORA, along with data on the novel monoclonal antibody belimumab as an add-on therapy in the Efficacy and Safety of Belimumab in Patients with Active LN (BLISS-LN) trial (9), made 2020 an exciting year for the advancement of management of LN.

The author reports no conflict of interest.

References

  • 1.

    Wang L, et al. Calcineurin (CN) activation promotes apoptosis of glomerular podocytes both in vitro and in vivo. Mol Endocrinol 2011; 25:13761386. doi: 10.1210/me.2011-0029

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Shen X, et al. Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep 2016; 6:32087. doi: 10.1038/srep32087

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Li Y, et al. Pharmacokinetic disposition difference between cyclosporine and voclosporin drives their distinct efficacy and safety profiles in clinical studies. Clin Pharmacol 2020; 12:8396. doi: 10.2147/CPAA.S255789

    • Search Google Scholar
    • Export Citation
  • 4.

    Sanders ML, Langone AJ. Drugs in development for prophylaxis of rejection in kidney-transplant recipients. Transpl Res Risk Manag 2015; 7:5969. doi: 10.2147/TRRM.S61446; https://www.dovepress.com/drugs-in-development-for-prophylaxis-of-rejection-in-kidney-transplant-peer-reviewed-fulltext-article-TRRM

    • Search Google Scholar
    • Export Citation
  • 5.

    Rovin BH, et al. 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. Kidney Int 2019; 95:219231. doi: 10.1016/j.kint.2018.08.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Rovin BH, et al. Management of lupus nephritis (LN) with voclosporin: An update from a pooled analysis of 534 patients. American Society of Nephrology Kidney Week 2020. October 22, 2020. Abstract PO1917. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3446491

    • Search Google Scholar
    • Export Citation
  • 7.

    Arriens C, et al. Scientific Abstracts, Oral Presentations: Other orphan diseases. OP0277: AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN). Ann Rheum Dis 2020; 79:172173. https://ard.bmj.com/content/79/Suppl_1/172.2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Bensman A, Niaudet P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol 2010; 25:11971199. doi: 10.1007/s00467-010-1469-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Furie R, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020; 383:11171128. doi: 10.1056/NEJMoa2001180

Save