Henry Leher’s research while affiliated with Aurinia Pharmaceuticals and other places

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.

Background In a phase 3 study of adults with active lupus nephritis, addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids led to significant improvements in the proportion of participants achieving complete and partial renal response as well as a sustained reduction in proteinuria. This analysis examined the efficacy and safety of voclosporin in a subgroup of the phase 3 study with proliferative lupus nephritis and high levels of proteinuria. Methods Participants were randomized to oral voclosporin (23.7 mg BID) or placebo for 12 months; all participants received MMF and low-dose glucocorticoids. The current analysis includes participants with Class III or IV (± Class V) lupus nephritis and baseline urine protein creatinine ratio (UPCR) ≥3 g/g. Efficacy endpoints included complete renal response (UPCR ≤0.5 g/g with stable estimated glomerular filtration rate (eGFR), low-dose glucocorticoids, and no rescue medication), partial renal response (≥50% reduction from baseline UPCR) and UPCR over time. Safety outcomes were also assessed. Results A total of 148 participants were in the voclosporin (n=76) and control (n=72) arms. At 12 months, 34% and 11% of participants in the voclosporin and control arms achieved a complete renal response (odds ratio [OR] 4.43 [95% confidence interval (CI) 1.78, >9.99] p=0.001). A partial renal response was achieved by 65% of the voclosporin arm and 51% of the control arm at 12 months (OR 1.60 [95% CI 0.8, 3.20] p=0.18). More voclosporin- than control-treated participants achieved UPCR ≤0.5 g/g (51% vs. 26%) and voclosporin-treated participants met this endpoint significantly earlier (hazard ratio 2.07 [95% CI 1.19, 3.60] p=0.01). The incidence of adverse events was similar between arms; mean eGFR values remained stable and within normal range in both arms. Conclusions Addition of voclosporin to MMF and low-dose glucocorticoids resulted in a significantly higher proportion of participants with proliferative lupus nephritis achieving complete and partial renal responses as well as earlier reductions in proteinuria, with no evidence of worsening kidney function.

Background Voclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN significantly increased rates of complete renal response at 52 weeks. Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 study. Methods Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, IV, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m². Patients who completed AURORA 1 were eligible to enter AURORA 2 to continue on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed. Results In total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%]; table 1). Eight patients in each arm experienced serious adverse events of infection; serious coronavirus infections were observed in two patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2; four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m² at 4 weeks following study drug discontinuation (figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation. Conclusion Voclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period and the significant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a long-term treatment benefit of VCS in patients with LN.View this table: • View inline • View popup Abstract 1202 Table 1 Overall Summary of Adverse Events • Download figure • Open in new tab • Download powerpoint Abstract 1202 Figure 1 LS Mean eGFR over Time. Analysis of AURORA 2 patients includes data from pre-treatment baseline of AURORA 1, 12 months in AURORA 1 and up to 25 months in AURORA 2 (including 4- week post-treatment visit). Renal function assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL/min/1.73 m2. Cl, confidence interval; eGFR, estimated glomerular filtration rate; FUP, follow-up visit (4-week post-treatment visit); LS Mean, least squares mean. Disclosures AS reports payments for Aurinia Pharmaceuticals Inc. speaker bureaus; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; advisory fees from Eli Lilly, AstraZeneca, GlaxoSmithKline and Kezar Life Sciences. YKOT reports research grants from commercial organizations including an unrestricted research grant from GlaxoSmithKline and Aurinia Pharmaceuticals Inc.; primary investigator for Aurinia Pharmaceuticals Inc. clinical trials; consultancy fees paid to institution from Aurinia Pharmaceuticals Inc., Novartis, GlaxoSmithKline, KezarBio, Vifor Pharma and Otsuka Pharmaceuticals. CC, NE, and HL are employees and shareholders of Aurinia Pharmaceuticals, Inc. HL is an employee and shareholder of Aurinia Pharmaceuticals, Inc. Data first presented by Saxena A et al. at the EULAR Congress June 1-4, 2022. Editorial support provided by MediComm Partners Ltd. Aurinia Pharmaceuticals Inc. provided funding for the study and presentation.

Background Pooled data from the Phase 2 AURA-LV and Phase 3 AURORA 1 studies demonstrated that adding voclosporin, a novel calcineurin inhibitor, to mycophenolate mofetil (MMF) and low-dose steroids resulted in significantly higher complete renal response rates at 24 weeks in AURA-LV (32.6% vs 19.3%; odds ratio [OR] 2.03; p=0.045) and 52 weeks in AURORA 1 (40.8% vs 22.5%; OR 2.65; p< 0.0001) in patients with lupus nephritis.The European League Against Rheumatism and European Renal Association (EULAR/ERA) published updated treatment recommendations for lupus nephritis with targeted reductions in proteinuria over the course of the first year of therapeutic intervention. Here we report on a post-hoc analysis of pooled data from the similarly-designed 48-week AURA-LV and 52-week AURORA 1 studies based on the recommended treatment targets. Methods AURA-LV and AURORA 1 enrolled patients with biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Pooled data included 268 patients in the voclosporin arm and 266 patients in the control arm; all patients received MMF (target dose 2 g/day) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). We assessed the following EULAR/ERA treatment targets: ≥25% reduction in urine protein creatinine ratio (UPCR) at 3 months, ≥50% reduction in UPCR at 6 months, UPCR ≤0.7 mg/mg at 12 months, and steroid dose ≤7.5 mg/day at 12 months. Results After 3 months of treatment, 78.4% of patients in the voclosporin group and 62.4% of patients in the control group achieved ≥25% reduction in UPCR (odds ratio [OR] 2.25; 95% confidence interval [CI] 1.52, 3.33; p< 0.0001). The percentage of patients achieving a reduction of ≥50% in UPCR at 6 months was significantly greater in the voclosporin arm (66.0% vs 47.0%, respectively; OR 2.24; CI 1.57, 3.21; p< 0.0001). At 12 months, 52.6% and 33.1% of the voclosporin and control arms, respectively, had achieved a UPCR ≤0.7 mg/mg (OR 2.52; CI 1.75, 3.63; p< 0.0001). A total of 89.6% and 82.8% of patients in the voclosporin and control arms, respectively, had reached the recommended steroid dose of ≤7.5 mg/day at 12 months. The proportion of patients achieving a UPCR ≤0.7 mg/mg and having a steroid dose ≤7.5 mg/day at 12 months was 44.4% in the voclosporin arm and 27.1% in the control arm (OR 2.42; CI 1.66, 3.53; p< 0.0001). Conclusions The addition of voclosporin to a background regimen of MMF and low-dose steroids in patients with LN significantly increased the likelihood of achieving the 3-, 6-, and 12-month UPCR targets of therapy recommended by EULAR/ERA.