voclosporin and Lupus-Nephritis

This study aimed to compare the effectiveness and safety of voclosporin + mycophenolate mofetil (MMF), tacrolimus + MMF, and monotherapy with MMF or cyclophosphamide as induction treatment for lupus nephritis.. The study included randomized controlled trials (RCTs) that evaluated the effectiveness and safety of voclosporin + MMF, tacrolimus + MMF, and monotherapy for induction treatment in patients with lupus nephritis. To incorporate direct and indirect evidence from RCTs, we used a Bayesian network meta-analysis.. Four RCTs, including 936 participants, met the inclusion criteria. Tacrolimus + MMF substantially increased the incidence of complete remission relative to that following monotherapy (odds ratio [OR] 2.85; 95% credible interval [CrI] 1.87-4.39). Tacrolimus + MMF was also more effective than voclosporin + MMF (OR 1.43; 95% CrI 0.80-2.57). Tacrolimus + MMF showed the greatest chance of being the optimal treatment for overall response (surface under the cumulative ranking curve [SUCRA] = 0.942), followed by voclosporin + MMF (SUCRA = 0.558) and monotherapy (SUCRA = 0.001). In terms of safety based on severe event rates, monotherapy had the greatest chance of being the safest treatment (SUCRA = 0.903), followed by voclosporin + MMF (SUCRA = 0.517) and tacrolimus + MMF (SUCRA = 0.081).. Tacrolimus + MMF and voclosporin + MMF were more effective than monotherapy, and tacrolimus + MMF was the most effective induction treatment for lupus nephritis patients. However, tacrolimus + MMF did pose a greater risk of serious adverse events than monotherapy.. ZIEL DER ARBEIT: Ziel der vorliegenden Studie war es, die Wirksamkeit und Sicherheit von Voclosporin + Mycophenolat-Mofetil (MMF) zum einen, Tacrolimus + MMF zum anderen und einer Monotherapie mit MMF oder Cyclophosphamid als Induktionstherapie bei Lupusnephritis zu vergleichen.. In die Studie wurden randomisierte kontrollierte Studien (RCT) einbezogen, in denen die Wirksamkeit und Sicherheit von Voclosporin + MMF, Tacrolimus + MMF und einer Monotherapie als Induktionstherapie bei Patienten mit Lupusnephritis verglichen wurde. Um direkte und indirekte Evidenz aus RCT zu erfassen, wurde eine Bayes-Netzwerk-Metaanalyse durchgeführt.. Von 4 RCT mit 936 Teilnehmern wurden die Einschlusskriterien erfüllt. Tacrolimus + MMF führten zu einer wesentlich erhöhten Inzidenz kompletter Remissionen im Verhältnis zur Situation nach Monotherapie (Odds Ratio [OR] 2,85; 95%-Glaubwürdigkeitsintervall, Credibility Interval [CrI] 1,87–4,39). Tacrolimus + MMF erwiesen sich auch als wirksamer denn Voclosporin + MMF (OR 1,43; 95%-CrI 0,80–2,57). Bei Tacrolimus + MMF bestand die höchste Wahrscheinlichkeit, die optimale Therapie in Bezug auf das Gesamtansprechen darzustellen (Oberfläche unter der kumulativen Ranking-Kurve [SUCRA] = 0,942), dann folgten Voclosporin + MMF (SUCRA = 0,558) und die Monotherapie (SUCRA = 0,001). In Hinsicht auf die Sicherheit, basierend auf der Rate schwerer unerwünschter Ereignisse, bestand die höchste Wahrscheinlichkeit, die sicherste Therapie darzustellen, für die Monotherapie (SUCRA = 0,903), dann folgten Voclosporin + MMF (SUCRA = 0,517) und Tacrolimus + MMF (SUCRA = 0,081).. Tacrolimus + MMF und Voclosporin + MMF waren wirksamer als die Monotherapie, und Tacrolimus + MMF erwies sich als die wirksamste Induktionstherapie bei Patienten mit Lupusnephritis. Allerdings war das Risiko schwerer unerwünschter Ereignisse unter Tacrolimus + MMF größer als unter Monotherapie.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Network Meta-Analysis; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus; Treatment Outcome

Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney's filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug-drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Lupus Nephritis

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. Standard-of-care immunosuppressive therapies achieve poor complete renal response (CRR) rates, with considerable toxicity. This article reviews voclosporin, a novel oral calcineurin inhibitor (CNI) approved for treatment in adults with active LN by the US Food and Drug Administration (the FDA) in January 2021.. This review summarizes the chemical properties, pharmacokinetics, and pharmacodynamics of voclosporin, and its efficacy and safety in LN, based on literature review covering PubMed searches, manufacturers' websites, and documents produced by the FDA.. Voclosporin is a CNI with a consistent pharmacokinetic-pharmacodynamic relationship resulting from enhanced calcineurin binding and reduced drug and metabolite load. This profile permits therapeutic efficacy in LN at a dose associated with relatively low calcineurin inhibition, and therefore a potentially improved safety profile. Pivotal trials demonstrated a significant benefit of adding voclosporin to standard therapy, with rapid reduction in proteinuria, and a clinically meaningful and significantly higher CRR rate at 1 year. At approved doses for LN, potential advantages of voclosporin versus historical experience with CNIs include lack of need for therapeutic drug monitoring, benign metabolic, lipid and electrolyte profile, and no impact on mycophenolate mofetil levels.

Topics: Adult; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis

Topics: Administration, Oral; Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; T-Lymphocytes

Despite ground-breaking innovations for most autoimmune diseases, the treatment of lupus nephritis has remained largely the same for decades because none of the tested drugs demonstrated superiority over standard-of-care in randomized controlled clinical trials.. Recently, the Belimumab in Subjects with Systemic Lupus Erythematosus - Lupus Nephritis trial tested belimumab, an inhibitor of B-cell activating factor, as an add-on therapy to steroids and either mycophenolate mofetil (MMF) or cyclophosphamide when given IV monthly over a period of 104 weeks at an effect size of 11% for a Primary Efficacy Renal Response. The NOBILITY trial reported positive results for the B-cell-depleting agent obinutuzumab as an add-on therapy to steroids and MMF when given IV every 6 months over a period of 76 weeks at an effect size of 22% for a complete renal response (CRR). The AURORA trial reported positive results for the calcineurin inhibitor voclosporin as an oral add-on therapy to low dose steroids and MMF when given twice daily over a period of 52 weeks at an effect size of 18.5% for a CRR.. These studies will change the treatment landscape of lupus nephritis. In which way is discussed in this article.

Topics: Antibodies, Monoclonal, Humanized; B-Lymphocytes; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Treatment Outcome

Voclosporin (Lupkynis

Topics: Animals; Calcineurin Inhibitors; COVID-19; COVID-19 Drug Treatment; Cyclosporine; Drug Approval; Humans; Immunosuppressive Agents; Kidney Transplantation; Lupus Nephritis

Kidney survival rates in lupus nephritis (LN) remain suboptimal, with 10-20% of patients progressing to end-stage kidney disease by 10-20 years. Recently, the landscape of LN management has changed with the advent of new molecules that have demonstrated safety and efficacy in clinical trials.. In this review, we approach the current state of LN management, the unmet therapeutic needs, and deep dive into voclosporin, a novel calcineurin inhibitor (CNI) that has demonstrated improved efficacy when added to a mycophenolate mofetil (MMF) and glucocorticoid regimen, without an increase in adverse events. We focus on the characteristics of this new CNI and the studies that led to its approval by the US FDA.. Voclosporin adds to therapeutic options for LN. This drug offers potential advantages over other CNIs. The addition of voclosporin to a standard-of-care regimen of MMF/glucocorticoids demonstrated higher and faster response rates. As other regimens, a combination of CNI, MMF, and glucocorticoids must be individualized and is not appropriate for all patients. Some questions remain to be answered for this regimen, such as the length of treatment, the tapering schedule, and its long-term safety and efficacy for preserving kidney function.

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid

Lupus nephritis (LN) is associated with significant morbidity and mortality. Current treatment outcomes remain suboptimal. No disease modifying medications are licensed for the treatment of LN. Voclosporin, a novel calcineurin inhibitor, has been investigated as induction therapy in LN in combination with myocophenolate mofetil (MMF) and a glucocorticoid (GC). Two phase II trials of voclosporin were the first trials of a potential treatment of active LN that met their primary endpoints. Areas covered: This article reviews the pharmacology of voclosporin and the efficacy and safety data from the two existing phase II trials. In the phase IIb randomized controlled trial AURA-LV, voclosporin was shown to be superior to placebo, when used in combination with MMF (1-2 g/day) and GC, in achieving remission in active LN. Expert opinion: While the positive outcome of existing trials is promising, further data confirming its efficacy and evaluating its safety are required. A phase III trial is currently recruiting. Importantly, the positive results were achieved despite a novel and rapid GC taper regime, suggesting that rapid taper of GC may be a viable treatment option in active LN which merits further investigation.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Dose-Response Relationship, Drug; Half-Life; Humans; Kaplan-Meier Estimate; Lupus Nephritis; Treatment Outcome

This integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase II and phase III clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations.. Aurinia Urinary Protein Reduction in Active Lupus with Voclosporin (AURA-LV) (phase II) and Aurinia Renal Response in Active Lupus With Voclosporin (AURORA 1) (phase III) were randomized, placebo-controlled, double-blind trials with similar designs and end points comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately one year (Week 48 data from AURA-LV and Week 52 from AURORA 1). Safety was assessed throughout the trials.. Overall, 534 patients (268 voclosporin; 266 control) were included in the integrated analysis. Significantly more patients achieved a CRR at one year in the voclosporin group than in the control group (43.7% vs. 23.3%; OR 2.76; 95% CI 1.88, 4.05 P < 0.0001). The incidence of adverse events (AEs) was similar (91.4% voclosporin; 87.2% control). Most AEs were mild to moderate in severity; the most commonly reported AEs were classified as infections and infestations (62.2% voclosporin; 54.9% control) and gastrointestinal disorders (45.3% voclosporin; 35.3% placebo). No new or unexpected safety signals were detected.. This integrated analysis demonstrates the efficacy and safety of voclosporin in the treatment of LN across the diverse racial and ethnic groups studied.

Topics: Clinical Trials as Topic; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Mycophenolic Acid; Treatment Outcome

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.. This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m. Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.. Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis.. Aurinia Pharmaceuticals.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Double-Blind Method; Female; Glomerular Filtration Rate; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Treatment Outcome

Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Mycophenolic Acid; Remission Induction; Treatment Outcome; Young Adult

The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20-30% of the patients within 6-12 months, and 5-20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Precision Medicine; Remission Induction

Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis.. A. In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately $150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69% and 49%, respectively. Cost-effectiveness was dependent on assumptions made regarding survival in response states, costs and utilities in active disease, and the utilities in response states. In the analysis from a societal perspective, the incremental ratio for belimumab was estimated to be approximately $66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year.. Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of $100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin.

Topics: Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Cost-Benefit Analysis; Cyclosporine; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Quality-Adjusted Life Years; Renal Insufficiency; United States

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis

Topics: Antibodies, Monoclonal, Humanized; Cost-Benefit Analysis; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Models, Economic

Topics: Antibodies, Monoclonal, Humanized; Biomedical Research; Cost-Benefit Analysis; Cyclosporine; Drug Therapy; Health Equity; Humans; Immunosuppressive Agents; Insurance Coverage; Insurance, Health; Lupus Nephritis

Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Lupus Nephritis

Topics: Clinical Trials, Phase III as Topic; Cyclosporine; Humans; Lupus Nephritis; Treatment Outcome

The problems with the P value as the single metric to summarize the results of a study are being recognized. It captures a single domain-random error-but it is relatively uninformative about more critical domains for deciding whether the results should be applied to clinical care and policy. Alternatives include the components of the outcomes reported (relevance, magnitude, frailty, and net benefit) and confidence (risk of bias and directness).

Topics: Cyclosporine; Double-Blind Method; Humans; Lupus Nephritis

Topics: Clinical Trials Data Monitoring Committees; Cyclosporine; Double-Blind Method; Humans; Lupus Nephritis; Randomized Controlled Trials as Topic; Research Design

Topics: Cyclosporine; Double-Blind Method; Humans; Lupus Nephritis

Lupus nephritis is the most common organ-threatening manifestation of systemic lupus erythematosus. The current standard of care for patients is treatment with a combination of steroids plus either mycophenolate mofetil (MMF) or cyclophosphamide. However, these medications are associated with considerable toxicity and suboptimal efficacy. This retrospective propensity analysis of data from 63 matched patients enrolled in two of the largest active lupus nephritis controlled trials, ALMS and AURA, suggests that the high dose regimen of MMF and steroids as described in the 2012 American College of Rheumatology lupus nephritis guidelines may not be necessary in all lupus nephritis patients. A lower dose regimen may result in better long-term safety, including a reduction in lymphoproliferative disorders, skin cancers and steroid related side effects, without compromising efficacy. An ongoing randomized controlled double-blind phase 3 study, AURORA (NCT03021499), is investigating renal response in 358 patients randomized to receive a low dose regimen containing voclosporin, MMF and steroid therapy as used in the AURA trial. It is anticipated that the AURORA study and its blinded two-year extension will provide important long-term outcome data.

Topics: Adolescent; Adult; Aged; Cyclophosphamide; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Logistic Models; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Propensity Score; Randomized Controlled Trials as Topic; Remission Induction; Retrospective Studies; Standard of Care; Steroids; Time-to-Treatment; Treatment Outcome; Young Adult