Lucy S. Hodge’s research while affiliated with Columbia University and other places

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Publications (21)


Comparison of a voclosporin-based triple immunosuppressive therapy to high-dose glucocorticoid-based immunosuppressive therapy: a propensity analysis of the AURA-LV and AURORA 1 studies and ALMS
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November 2024

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25 Reads

Lupus Science & Medicine

Maria Dall'Era

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Kenneth Kalunian

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Neil Solomons

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Introduction High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy. Methods Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months. Results There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months. Conclusions Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

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BACKGROUND LUPUS NEPHRITIS AND DISEASE PATHOGENESIS Immunologic Changes over Time in Repeat Kidney Biopsies from the AURORA Studies of Voclosporin in Lupus Nephritis

October 2024

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13 Reads

Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus with a heterogenous pathophysiology 1 • While histological data is helpful in guiding diagnosis and treatment of LN, there remains a known discordance between histology and clinical outcomes in patients with LN 2-5 • Multiplex immunofluorescence (mIF) is a useful tool for assessing immune cell infiltration over time in diseased kidney tissue and, when correlated with clinical findings, can provide insight into disease pathogenesis and the impact of treatment 6,7 • Previous investigations using mIF in LN have proven successful in revealing novel aspects of the pathogenesis of this disease 8-10 AURORA 1 AND AURORA 2 • The Phase 3 AURORA 1 and AURORA 2 studies investigated the use of voclosporin in combination with standard-of-care (SOC; mycophenolate mofetil [MMF] and low-dose glucocorticoids) for the treatment of LN in adult patients 11,12 • Repeat biopsies were collected on a subset of patients to assess how the histology of the kidney changed in response to treatment 13 STUDY OBJECTIVE METHODS AURORA 1 AND AURORA 2 STUDY DESIGNS • Key inclusion criteria for AURORA 1 included biopsy-proven active LN, urine protein creatinine ratio (UPCR) ≥1.5 g/g (≥2 g/g for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m 2 • Patients completing AURORA 1 were eligible to enter AURORA 2 on the same blinded therapy (voclosporin or placebo) combined with MMF (target of 2 g/d) and glucocorticoids (20-25 mg/day tapered to 2.5 mg/d by Week 16) for an additional 2 years • All patients in AURORA 1 had a baseline kidney biopsy prior to enrollment (Bx1), and a subset of patients agreed to having a second biopsy after approximately 18 months of treatment (Bx2) 13





OP0059 VOCLOSPORIN-BASED, TRIPLE-IMMUNOSUPPRESSIVE REGIMEN VERSUS HIGH-DOSE GLUCOCORTICOID AND MYCOPHENOLATE MOFETIL-BASED THERAPY FOR LUPUS NEPHRITIS: A PROPENSITY ANALYSIS OF THE ALMS, AURA-LV AND AURORA 1 STUDIES

June 2024

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12 Reads

Annals of the Rheumatic Diseases

Background Lupus nephritis (LN) is characterized by proteinuria, which is not only a marker of active kidney inflammation, but also a driver of progressive kidney injury. Early reduction in proteinuria following treatment initiation has been shown to be a predictor of long-term kidney survival and overall mortality. The AURA-LV and AURORA 1 clinical trials have shown that voclosporin-based triple therapy with lower-dose MMF, and low-dose glucocorticoids (GCs) led to early and significant reductions in proteinuria with an acceptable safety profile. However, dual-immunosuppressive regimens containing high-dose glucocorticoids (GCs) and higher doses (>2 g/day) of mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) are still frequently used for the management of active LN in the belief that they may be more efficacious and safer. Objectives To compare the safety and efficacy of a voclosporin-based, triple immunosuppressive regimen to a dual-immunosuppressive regimen for the treatment of active LN, we analyzed outcomes in propensity-matched participants from the ALMS, AURA-LV, and AURORA 1 studies. We hypothesized that a voclosporin-based, triple therapy approach would reduce exposure to the toxicities associated with higher doses of GCs, MMF, and IVC, resulting in an improved safety profile without compromising efficacy. Methods All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 participant pairs with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants in ALMS over the 6-month period. More participants in AURA-LV and AURORA 1 reported hypertension and anemia. Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; a greater number of events of GFR decreased were reported by AURA-LV/AURORA 1 participants. The incidence of serious AEs was similar across groups. UPCR ≤0.5 mg/mg was achieved by 52% of voclosporin-treated participants compared to 41.1% of IVC- or MMF-treated participants of ALMS; the median time to this endpoint for the voclosporin group was 142 days; a median time was not determinable for ALMS participants as less than 50% achieved the endpoint within the study period (hazard ratio [HR] 1.41; 95% confidence interval [CI] 1.03, 1.94; p=0.0324; Table 1, Figure 1). More voclosporin-treated participants achieved a 50% reduction in UPCR from baseline at any point during the study; this endpoint was met significantly earlier by voclosporin-treated patients as well (29 vs. 84 days; HR 1.88, 95% CI 1.48, 2.39; p<0.0001). Conclusion Participants treated with voclosporin in combination with low-dose GCs and MMF 2g/day demonstrated an improved safety profile and earlier reductions in proteinuria compared to participants treated with high-dose GCs and MMF up to 3 g/day or IVC. These findings support the recommendation that a voclosporin-based, triple-immunosuppressive regimen should be considered as an initial therapy in patients with active LN. REFERENCES NIL • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Acknowledgements NIL Disclosure of Interests Anca Askanase Consultant for Aurinia Pharmaceuticals Inc., AstraZeneca, GSK plc., Eli Lilly, Kenneth C. Kalunian: None declared, Maria Dall’Era Consultant for Annexon Biosciences, AstraZeneca, Aurinia Pharmaceuticals Inc., Biogen, GSK plc., and Pfizer, Grant/research support from Annexon Biosciences, GSK plc., Neil Solomons Shareholder of Aurinia Pharmaceuticals Inc., Former employee of Aurinia Pharmaceuticals Inc., Lucy Hodge Shareholder of Aurinia Pharmaceuticals, Inc., Employee of Aurinia Pharmaceuticals, Inc., Matt Truman Consultant for Aurinia Pharmaceuticals, Inc., Ernie Yap Shareholder of Aurinia Pharmaceuticals Inc., Employee of Aurinia Pharmaceuticals Inc.


#468 Voclosporin-based, triple-immunosuppressive therapy vs high-dose glucocorticoid-based dual-immunotherapy for lupus nephritis: a propensity analysis

May 2024

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2 Reads

Nephrology Dialysis Transplantation

Background and Aims Voclosporin is a second generation calcineurin inhibitor (CNI) approved for the treatment of adults with active lupus nephritis (LN) in combination with immunosuppressive therapy. An integrated analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies concluded that combining voclosporin with lower-dose mycophenolate mofetil (MMF, 2 g/day) and low-dose glucocorticoids (GCs) led to significantly greater and earlier reductions in proteinuria when compared to MMF and GCs alone. This is an important finding as early reduction in proteinuria is associated with improved long-term kidney survival and mortality. Yet, dual-immunosuppressive regimens consisting of high-dose glucocorticoids and either intravenous cyclophosphamide (IVC) or higher doses of MMF (>2 g/day) continue to be frequently used for the initial management of active LN despite their association with incomplete efficacy and dose-dependent toxicities. Method All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month × 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 pairs of participants with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS, although more participants in AURA-LV and AURORA 1 reported hypertension and anemia (Table 1). Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; AURA-LV/AURORA 1 participants also had an increased rate of events of GFR decreased. The incidence of serious AEs was similar across treatments. In the first 3 months of treatment, significantly more AURA-LV/AURORA 1 participants achieved a reduction in UPCR >25% from baseline (91.6% vs 69.3%; odds ratio [OR] 4.75, 95% confidence interval [CI] 2.56, 8.84; p < 0.0001). Over six months of treatment, mean (SD) change from baseline in UPCR was −3.1 (2.9) g/g in voclosporin-treated patients in AURA-LV and AURORA 1 compared to −2.4 (3.3) g/g in IVC- or MMF-treated participants in ALMS (Fig. 1). Conclusion Voclosporin-based, triple immunosuppressive therapy was associated with an improved safety profile as well as greater and earlier reductions in proteinuria compared to more conventional dual immunosuppressive regimens. These data support treatment guidelines for active LN that recommend both minimizing patient exposure to GCs and use of a multi-targeted treatment regimen as initial therapy.


1007 Voclosporin for lupus nephritis: assessment of long-term safety and efficacy including renal outcome over three years of treatment in the phase 3 AURORA 1 and AURORA 2 studies

Lupus Science & Medicine

Background In AURORA 1, adding voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to signficant reductions in proteinuria at one year in patients with lupus nephritis (LN). We report on the recently completed AURORA 2 study evaluating voclosporin compared to placebo in patients treated for an additional two years after AURORA 1. Methods Patients with LN completing AURORA 1 were eligible to continue on the same double-blinded treatment of voclosporin or placebo in AURORA 2; all patients recieved MMF and low-dose steroids. Outcomes assessed over the three year treatment period of both studies included adverse events (AEs), eGFR, urine protein-creatinine ratio (UPCR), good renal outcome and renal flare. Good renal outcome was defined based on achievement of an adequate response (i.e. sustained reduction in UPCR to ≤0.7 mg/mg) and without renal flare (i.e. an increase to UPCR >1 mg/mg from a post-response UPCR of <0.2 mg/mg or an increase to UPCR >2 mg/mg from a post-response UPCR of 0.2 to 1.0 mg/mg), as adjudicated by a blinded Clinical Endpoints Committee. Results Overall rates of serious AEs in the voclosporin (26.7% of 116 patients) and control arm (28.0% of 100 patients) were similar. There were no deaths in the voclosporin arm during AURORA 2; four deaths occured in the control arm (pulmonary embolism, n=1; coronavirus infection, n=3). Mean corrected eGFR was within the normal range and stable over the study period. The reductions in UPCR achieved in AURORA 1 were maintained in AURORA 2 and significantly more patients in the voclosporin arm achieved a good renal outcome (66.4% in voclosporin vs 54.0% in control; p-value=0.045). Renal flare occurred in 24 of 101 patients with adequate response in the voclosporin arm and 19 of 73 patients in the control arm (23.8% in voclosporin vs 26.0% in control; p-value=0.662); 69.8% of all patients with renal flares completed study treatment. Conclusions Voclosporin was well-tolerated over three years of treatment. The significant reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2 and more patients in the voclosporin arm achieved a good renal outcome. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis.


Select safety outcomes
P87 Comparison of a voclosporin-based, triple immunotherapy regimen to high-dose glucocorticoid-based immunosuppressive therapy: a propensity analysis of the AURA-LV plus AURORA 1 studies and ALMS

Lupus Science & Medicine

Objective Early reduction in proteinuria after initial treatment has been associated with improved long-term kidney outcomes in lupus nephritis (LN). The addition of voclosporin, a second generation calcineurin inhibitor, to MMF and low-dose glucocorticoids (GC)s led to greater reductions in proteinuria compared to conventional therapy in the AURA-LV and AURORA 1 studies with an acceptable safety profile. Using propensity-matched participants from the voclosporin clinical trials and ALMS, we tested the hypothesis that a voclosporin-based, triple immunosuppressive regimen results in improved safety without compromising efficacy. Methods In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS vs. AURA-LV/AURORA 1) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results A total of 179 matched pairs were identified. As expected, cumulative GC exposure was 2-fold higher in ALMS at 3 and 6 months. The incidence of adverse events (AEs) was higher in IVC- and high-dose MMF-treated participants (table 1), although more voclosporin-treated participants reported AEs of GFR decrease and hypertension; the incidence of serious AEs was similar with all treatments. At 6 months, the proportion of participants achieving >50% UPCR reduction from baseline was significantly greater in the voclosporin arm (p=0.005). Conclusion A voclosporin-based triple immunosuppressive regimen (voclosporin, MMF, and low-dose GCs) has a better overall safety profile than double-therapy regimens, with specific AEs attributable to higher-dose GCs, higher-dose MMF and IVC in the latter. Triple therapy is also superior in achieving early proteinuria milestones. These data provide further support for use of combination therapy as initial treatment in patients with active LN and to minimizing patient exposure to GCs, as proposed by the 2023 EULAR guidelines. Acknowledgement This study was funded by Aurinia Pharmaceuticals Inc. View this table: • View inline • View popup Abstract P87 Table 1 Select safety outcomes In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate two groups of matched patients (n=179) from the ALMS (IVC and MMF) and AURA-LV/AURORA 1 (voclosporin) studies based on the following parameters: age, duration of lupus nephritis, duration of SLE, albumin, C3, C4, creatinine, anti-dsDNA, eGFR, UPCR, biopsy class, sex, and geographical region. Adverse events (AEs) occurred on or after the first dose of study drug up to either 3 or 6 months of treatment and coded by System Organ Class and Preferred Term using MedDRA v9.1 (ALMS), v17.0 (AURA-LV) and v20.0 (AURORA 1). AEs were selected for inclusion in this table to evaluate the impact of IVC, MMF, voclosporin, and glucocorticoids on these organ systems. Assignation of AEs of ‘GFR decreased’ were based on the clinical discretion of the study investigator and were not characterized by a specified drop in eGFR from baseline. GFR, glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.


Citations (2)


... The research conducted by Menn-Josephy et al. in 2024, the research conducted is a double-blind, randomized, controlled trial that evaluated the effectiveness of voclosporin for treating proliferative lupus nephritis with significant proteinuria [12]. This research involved 180 patients who were administered voclosporin or a placebo over 52 weeks [12]. ...

Reference:

Navigating Lupus Nephritis: A Comprehensive Review of the Current Treatment Trends
Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria

Clinical Journal of the American Society of Nephrology

... This mechanism on podocytes adds to the immune-mediated anti-proteinuric effect like cyclosporin and tacrolimus. The putative molecular effect on proteinuria takes time, but the response persists for 3 years under voclosporin maintenance therapy [4]. ...

FC056: Early Reductions in Proteinuria with Voclosporin Treatment Across Lupus Nephritis Biopsy Classes: Pooled Data from the AURA-LV AND AURORA 1 Trials
  • Citing Article
  • May 2022

Nephrology Dialysis Transplantation