REMISSION OF ACTIVE LUPUS NEPHRITIS WITH VOCLOSPORIN: RESULTS OF THE AURA-LV STUDY

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1 REMISSION OF ACTIVE LUPUS NEPHRITIS WITH VOCLOSPORIN: RESULTS OF THE AURA-LV STUDY V. Dobronravov* 1, M. A. Dooley 2, S. A. Haq 3, I. Adzerikho 4, O. Bugrova 5, D. Isenberg 6, F. Houssiau 7, N. Solomons 8, R. Huizinga 8 on behalf of AURA-LV Study Group 1 First St.Petersburg Pavlov State Medical University, St. Petersburg, Russian Federation 2 UNC, Chapel Hill, United States 3 Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh 4 Minsk Regional Clinical Hospital, Minsk, Belarus 5 Orenburg Regional Clinical Hospital, Orenburg, Russian Federation 6 University College Hospital, London, United Kingdom 7 Université catholique de Louvain, Brussels, Belgium 8 Aurinia Pharmaceuticals, Victoria, Canada

2 DISCLOSURES Grant/research support/lecture honoraria from: Aurinia Alexion Amgen Abbott Fresenius-Kabi Sandoz

3 Systemic Lupus Erythematosus (SLE) & Lupus Nephritis (LN) ~40-50% of SLE patients develop lupus nephritis LN is immunecomplex inflammation of the kidney caused by SLE If left untreated or inadequately treated, LN can lead to end stage renal disease, dialysis, renal transplant and death LN portends higher risk of treatment-related complications and toxicities, especially given heavy and long-term corticosteroid burden *Rees F, Doherty M, Grainge M, et al Annals of the Rheumatic Diseases 2016;75:

4 The Severity of Lupus Nephritis SLE patients with renal damage and ESRD have 14-fold and >60-fold increased risk of premature death, respectively Standardized mortality ratio Mok et al, Arthritis Rheum

5 % of Patients Early Clinical Response is Critical to Maintaining Long-Term Kidney Health in LN Rapid control & reduction of proteinuria in lupus patients may show a reduction in the need for dialysis 1 Diffuse LN patient survival without ESRD based on treatment response 1 Death at 10 yr On Dialysis at 10 years 87% 57% 54% 92% 24% 5% 8% Complete Remission Partial Remission No Response Partial remission = 50% reduction in proteinuria; Complete Remission = proteinuria <.33 g/24 hrs 1. Chen YE, et al. Clin J Am Soc Nephrol. 2008;3(1): Houssiau F.A., Ann Rheum Dis Jan 2010; 69: pp

6 Remission/response rate Complete Remission/response rates at weeks range from 8-31% for US 2,4 and Global studies 1, Partial response Complete response 48% 8% ALMS 15% 31% LUNAR 24 weeks 52 weeks 31% 8% ABATACEPT Abatacept 6 28% 31% ACCESS 52 weeks 24 weeks ALMS MMF+CS 1 / LUNAR MMF + CS 2, / Abatacept + MMF + CS 3, / ACCESS Abatacept + IVC+ CS 4 1. Appel GB, et al. J Am Soc Nephrol. 2009;20(5): Rovin BH,et al, for the LUNAR Investigator Group. Arthritis Rheum 2012; 64: Furie R, et al. ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 2, February 2014, pp ACCESS Trial group. Arthritis Rheumatol Nov;66(11): doi: /art Current ACR guideline: Proliferative LN: Give IV M-P 0.5-1g/d for 1-3 days, prednisone 1mg/kg/day, Maximum 80 mg/d, Taper Over Weeks PLUS: MMF 2-3g daily OR IV cyclosphosphamide (NIH regimen OR IV cyclosphosphamide (EUROLUPUS) OR Oral cyclophosphamide A better solution is needed to improve renal response rates for active LN

7 CNIs as Part of a Multi-Target Treatment Regimen (1) Steroids (1) Inhibition of cytokine synthesis, IL-1/IL-2 CNIs (2) Control Th-mediated humoral/cellular immune response MMF (3) Control of already activated/proliferating T/B cells

8 CNIs as Part of a Multi-Target Treatment Regimen (2) risk ratio of complete or partial remission TAC vs. IVCYC TAC + MMF vs. IVCYC TAC vs. MMF Autoimmunity Reviews, 2016, 15, 1,

9 Voclosporin: A Novel Calcineurin Inhibitor Providing Significant Clinical Differentiation Voclosporin has a modified functional group on amino acid 1 which allows the molecule to offer several advantages over other CNis * Altered functional group on CsA Impacts binding to the latch region on calcineurin Modification results in: N N O O N H O O N H N HO O O N N O O H N H N O O N N O 1) Predictable PK/PD relationship 2) Increased potency 3-4 fold (vs. CSA) 3) Altered metabolic profile and faster elimination of resultant metabolites Voclosporin *Legacy CNI s (cyclosporine & tacrolimus) are not approved for LN in the EU/US 9

10 Cases of new onset diabetes (12 months) %CNI Concentration (ng/ml) %CNI %CNI Voclosporin - Compared to Legacy CNIs 1,2,3 Calcineurin inhibition has a dual mechanism of action that has the potential to improve short- and long-term outcomes in LN when added to SoC (MMF) By inhibiting calcineurin, voclosporin blocks IL-2 expression and T cell mediated immune responses 1,2 CNI s have shown an ability to stabilize podocytes in the kidney, which protects against podocytopathy and proteinuria Concentration (PK) 2 VCS CsA Time (h) Total Cholesterol (Study Isa05-25) Mean ±95% CI VCS CsA Drug therapy ends Clinical benefits*: Allows for flat dosing Improved lipid profile (vs. CSA) Reduced risk of diabetes (vs. TAC) No impact on MPA levels when used in combination (vs. CsA) Concentration (ng/ml) 20 TAC 100 r = r = ,000 1,250 1,500 Concentration (ng/ml) Concentration (ng/ml) r = 0.8 CSA VCS CNI Induced Diabetes Week 1. Aurinia Data on fil 2. Busque S, et al. Am J Transplant. 2011;11(12): & AURA LV Data 3. AURA-LV Data on file 0 Low conc. Voclosporin Mid conc. Tacrolimus

11 1:1 Randomization N=265 AURA-LV (AURA) Study Design: Phase IIB Study was designed to evaluate whether voclosporin added to standard of care can increase speed of remission & overall remission rates in the presence of low steroid exposure Primary endpoint 24 weeks Secondary endpoint 48 weeks VOCLOSPORIN 23.7 mg bid VOCLOSPORIN 39.5 mg bid PLACEBO VOCLOSPORIN 23.7 mg bid MMF 2 g + oral corticosteroids MMF 2 g + oral corticosteroids MMF 2 g + oral corticosteroids VOCLOSPORIN 39.5 mg bid PLACEBO LD VCS HD VCS control mg/daily mg/daily mg/daily 5 mg/daily 2.5 mg/daily MP iv 1000 mg AURA - rapid steroid taper Week

12 AURA Key Inclusion Criteria & Outcome Measures KEY INCLUSION CRITERIA Diagnosis of SLE according to ACR criteria Biopsy proven LN: Classes: III, IV, V or V+III/IV A or A/C Proteinuria 1.5 OR 2 mg/mg* Indicative of active disease PRIMARY OUTCOME MEASURE The proportion of subjects achieving complete remission at 24 weeks Urine protein/creatinine ratio 0.5 mg/mg low dose steroids ( 10 mg prednisone) from week egfr 60 ml/min/1.73m 2 or egfr decrease from baseline < 20% No rescue medications Partial Remission 24 & 48 weeks KEY SECONDARY OUTCOMES Time to Remission 24 & 48 weeks Durability of remission at 48 weeks SLEDAI at 24 & 48 weeks * 2 mg/mg refers to Class V patients 12

13 Baseline Demographic and Clinical Characteristics Race n (%) Control N = 88 Voclosporin 23.7 mg BID N=89 Voclosporin 39.5 mg BID N=88 Total N = 265 White 42 (47.7) 30 (33.7) 36 (40.9) 108 (40.8) Black 5 (5.7) 3 (3.4) 6 (6.8) 14 (5.3) Other 5 (5.7) 4 (4.5) 2 (2.3) 11 (4.2) Asian 36 (41.0) 52 (58.4) 44 (50.0) 132 (49.8) Biopsy Class n (%) Pure Class V 13 (15.0) 12 (13.5) 14 (15.9) 39 (14.7) Class III, IV (alone or in combination with V) Baseline upcr (mg/mg) 75 (85.0) 77 (86.5) 74 (84.1) 226 (85.3) Mean ±SD 4.4 ± ± ± ± 3.62 Median Nephrotic range (UPCR 3mg/mg) (%) Baseline egfr CKD-EPI (ml/min/1.73 m²) ± ± ± ±

14 24 & 48-Week Outcomes

15 AURA Primary Outcome: Complete Remission at 24 weeks with Voclosporin 23.7mg BID VCS demonstrates statistically significant CR rate at 24 weeks 80% 70% 60% Complete and Partial Remission Rates 24 week P vs controls P= % P= % 50% 40% 30% 20% 10% 19% P= % P=NS 28% 49% 0% Complete Remission at 24 weeks Partial Remission at 24 weeks Control LD VCS HD VCS 15

16 Patient Remission Complete remission rate at 48 weeks: 49% vs 24% for low dose voclosporin compared to control Control (MMF+steroids) Low-Dose VCS (VCS+MMF+steroids) High-Dose VCS (VCS+MMF+steroids) P=.007 P=.002 Odds Ratios and p-values 39% 32% 48 Weeks vs control Complete Remission P- value 27% 40% Low Dose VCS (23.7 mg BID) High Dose VCS (39.5 mg BID) 3.21 < weeks 48 weeks CR PR 100% subjects in CR at 24 weeks remain in CR at 48 weeks (VCS low-dose) CR = Complete Remission; PR = Partial Remission

17 Time to complete and partial remission P=0.003 P<0.001 P<0.001 P=0.002 Kaplan-Meyer plot - time to complete remission Kaplan-Meyer plot - time to partial remission

18 Mean duration of Complete Remission Voclosporin 39.5mg BID Voclosporin 23.7mg BID 111 days 123 days p=.001 p=ns p=.012 Placebo 66 days Days Voclosporin (low dose) subjects stayed in CR for approximately twice as long as control 18

19 dsdna Antibody (IU/mL) Anti-dsDNA antibodies levels (Mean) Over Time 48 weeks Mean reduction from baseline in SELENA-SLEDAI Score 48 weeks: Renal and extra-renal LD VCS HD VCS Control SLEDAI non-renal SLEDAI renal controls 0 LD VCS HD VCS p=.011 vs. control p=.006 vs. control Source: Table p<.001* *Total SLEDAI score; vs control p<.001* 19

20 SAFETY

21 Adverse Events by System Organ Class System Organ Class (SOC) Control N = 88 n (%) Voclosporin 23.7 mg BID N=89 n (%) Voclosporin 39.5 mg BID N=88 n (%) Any AE 74 (84.1) 81 (91.0) 84 (95.5) Infections and Infestations 44 (50.0) 50 (56.2) 56 (63.6) Gastrointestinal Disorders 32 (36.4) 37 (41.6) 46 (52.3) General Disorders and Administration Site Conditions 15 (17.0) 27 (30.3) 24 (27.3) Nervous System Disorders 16 (18.2) 26 (29.2) 24 (27.3) Metabolism and Nutrition Disorders 21 (23.9) 25 (28.1) 25 (28.4) Skin and Subcutaneous Tissue Disorders 21 (23.9) 24 (27.0) 26 (29.5) Musculoskeletal and Connective Tissue Disorders Respiratory, Thoracic and Mediastinal Disorders 19 (21.6) 25 (28.1) 23 (26.1) 8 (9.1) 25 (28.1) 11 (12.5) Vascular Disorders 14 (15.9) 17 (19.1) 23 (26.1) 21

22 % Summary of Treatment Emergent Adverse Events and Historical Comparison ALMS BELONG BMS abatacept AURA-LV Mortality SAE Infective SAE Treatment Emergent Adverse Events (AE)* *includes AES following treatment period Control N = 88 n (%) Voclosporin 23.7 mg BID N = 89 n (%) (p-value#) Voclosporin 39.5 mg BID N = 88 n (%) (p-value#) Any Serious AE 17 (19.3) 25 (28.1) (NS) 22 (25.0) (NS) Any TEAE with Outcome of Death 4**(4.5) 10 (11.2) (NS) 2 (2.3) (NS) Any Serious Treatment-Related AE 1 (1.1) 4 (4.5) (NS) 7 (8.0) (NS) ** 3 of 4 deaths reported after study conclusions # - compated to controls NS non-significant 1.Furie R. et al., Arthritis and Rheumatology, Vol. 66, No 2, February Appel GB, et al. J Am Soc Nephrol. 2009;20(5): Aspreva Lupus Management Study (Induction) 22 3.Mysler, E. et al., Arthritis and Rheumatism, Vol. 65, No 9, September 2013, AURA-LV Study results Aurinia data on file

23 AURA Safety Summary 11 of 13 deaths during the study occurred at sites with compromised access to SoC; Patients who died had a statistically different clinical baseline picture, demonstrating a more severe form of LN, comorbid conditions & poor nutrition No significant differences in renal function or BP in voclosporin groups compared to control Mean systolic and diastolic BP lower at 48 weeks than baseline in all groups No new safety signals were observed with the use of voclosporin in LN patients compared to previous studies of this drug with other indications In previous studies (other indications), >2000 patients have been treated with voclosporin with no abnormal or unexpected SAE s this remains the case upon review of the AURA data 1 Furie R. et al., Arthritis and Rheumatology, Vol. 66, No 2, February Appel GB, et al. J Am Soc Nephrol. 2009;20(5): Aspreva Lupus Management Study (Induction) 3.Mysler, E. et al., Arthritis and Rheumatixm, Vol. 65, No 9, September 2013, ^Malignancy (metastatic melanoma) occurred following treatment period 23 *3 deaths occurred following the treatment period (after week 50)

24 CONCLUSIONS Voclosporin with MMF and steroids leads to increased rates and duration of complete remission, in patients with active lupus nephritis AURA is the first global study ever to meet its primary endpoint and all secondary endpoints in patients with active lupus nephritis 12 month CR rate of 49.4% (low-dose voclosporin) higher than other active LN trials This multi-target approach allowed for clinical response to be achieved using a steroid-reduced protocol with appropriate safety profile A global placebo-controlled Phase III trial for voclosporin 23.7mg BID is underway