TREATMENT OF ACTIVE LUPUS NEPHRITIS WITH VOCLOSPORIN: RAPID REMISSION OVER 48 WEEKS: DATA FROM THE AURA-LV STUDY SV Parikh 1 , WF Pendergraft 2 , JA Tumlin 3 , R Saxena 4 , N Solomons 5 , RB Huizinga 5 The Ohio State University Wexner Medical Center 1 University of North Carolina, Chapel Hill 2 South East Renal Research Institute 3 UT Southwestern Medical Center 4 Aurinia Pharmaceuticals 5
Disclosures SV Parikh: Research grant WF Pendergraft: Research grant JA Tumlin: Research grant, consultant for Aurinia R Saxena: Research grant N Solomons: Employee of Aurinia RB Huizinga: Employee of Aurinia 2
Objectives • Describe the potential benefits of Voclosporin, a new generation calcineurin inhibitor, compared to existing CNIs • Review the study design of the Phase IIb Aura-LV study for treatment of Lupus Nephritis • Describe the 24 and now 48-week results from the AURA-LV study • Review the safety data and next steps
Lupus Nephritis – Defining the Scope • Lupus Nephritis is a heterogeneous and severe complication of SLE that develops as a result of immune complex accumulation in the glomeruli • Clinically important kidney disease is present in up to 60% of adults with SLE • Despite improvement in treatment, approximately 10-30% of patients with LN will still progress to ESRD within 15 years of diagnosis • Still, there are no FDA or EMA approved therapies for LN
The Severity of Lupus Nephritis SLE patients w/renal damage and ESRD have 14-fold and >60-fold increased risk, of premature death, respectively Standardized mortality ratio Mok et al, Arthritis Rheum 2013 5 5
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 LN patient survival without ESRD based on treatment response 1 120% 100% 8% 80% 57% % of Patients 60% 87% 92% 40% 43% 20% 13% 0% Complete Remission Partial Remission No Response Not on Dialysis @ 10 years On Dialysis at 10 years 1. Chen YE, et al. Clin J Am Soc Nephrol. 2008;3(1):46-53. Response = 50% reduction in proteinuria; Remission = proteinuria <.33 g/24 hrs.. 6
STANDARD INITIAL THERAPY for PROLIFERATIVE LN: Proliferative LN: Give IV Methylprednisolone 0.5-1g/d for 1-3 days followed by Oral Prednisone 1mg/kg/d ideal body weight, Maximum 80 mg/d, Taper Over Weeks PLUS: PO Cyclophosphamide IV Cyclophosphamide IV Cyclophosphamide Oral MMF 0.5-1g/m 2 Monthly 1-1.5mg/kg/d, 500 mg every 2 weeks for Or Or Or 2-3g/d for maximum 150 mg/d for 3 months: LOW-DOSE- for 6 months 6 months 2-4 months EURO-LUPUS REGIMEN 24 week Partial Response & Complete Remission Rates with Cyclophosphamide and MMF 2 Results of the Aspreva Lupus Management Study (ALMS) showed that the majority of 60% 56% 53% patients failed to achieve CR 50% at 24 weeks for both of these 40% first-line therapeutics 2 % of Patients 30% 20% A better solution is needed to 8% 9% 10% improve renal response rates for LN 0% * Partial Response Complete Remission 1. Hahn BH, et al. Arthritis Care Res (Hoboken ). 2012;64(6):797-808. Cyclophosphamide MMF 2. Appel GB, et al. J Am Soc Nephrol . 2009;20(5):1103-1112
Recently Completed Clinical Trials Drug Class Target Clinical Trial Status Abatacept-BMS CTLA4-Ig CTLA4-B7 Phase 3-FAILED Abatacept- CTLA4-Ig CTLA4-B7 Phase 2-FAILED ACCESS Laquinamod Small Molecule Inflammation Phase 2-ENCOURAGING Rituximab Monoclonal Antibody CD20 Phase 3-FAILED Ocrelizumab Monoclonal Antibody CD20 Phase 3 - STOPPED Sirukumab Monoclonal Antibody IL-6 Phase 2-FAILED Bortezomib Proteasome Inhibitor Plasma Cells Phase 4-STOPPED Anti-CD40 Ligand Monoclonal Antibody CD40 Ligand Phase 2-STOPPED Tabalumab Monoclonal Antibody BLyS Phase 3-FAILED Anti-TWEAK Monoclonal Antibody TWEAK Phase 2-FAILED Parikh et al JASN 2016
What About Calcineurin Inhibitors for LN Induction?
Synergistic Impact of Calcineurin Inhibition in LN 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) CNI’s have shown an ability to stabilize By inhibiting calcineurin, voclosporin blocks IL-2 expression podocytes in the kidney, which protects and T cell – mediated immune responses 1,2 against podocytopathy and proteinuria 3-5 Actin Dephosphorylated cytoskeleton Voclosporin synaptopodin breaks up and APC Voclosporin Synaptopodin destabilizes the actin cytoskeleton Cytoplasm of the podocyte T cell receptor Tissue damage Glomerular basement membrane Nucleus IL-2 INF-gamma Cell-mediated TNF-alpha immune Stabilization of the actin cytoskeleton within the podocyte via response calcineurin inhibition has the potential to be disease modifying in LN APC, antigen-presenting cell; IL, interleukin; INF, interferon; LN, lupus nephritis; NFAT, nuclear factor of activated T-cells; TNF, tumor necrosis factor. 1.Mak A, Kow NY. J Immunol Res. 2014;2014:419029. doi:10.1155/2014/419029.; 2. Cooper JE, et al. Clin Nephrol . 2010;73(5):333-343. 3. Zhang B, Shi W . Int J Nephrol . 2012;2012:809456. ; 4. Wang Y, et al. J Am Soc Nephrol . 2010;21(10):1657-1666.; 5.Faul C. et al. Nat 10 Med. 2008;14(9):931-938.
CNIs as Part of a Multi-Target Induction Regimen LN IV MP 500mg/d X3d Oral Steroid Taper 0.6mg/kg/d N=368 MMF 1g/d+TAC 4mg/d IV Pulse CYC 0.75g/m 2 Complete Renal Remission P < 0.001 Liu et al, Ann Int Med, 2015
Voclosporin: A Best in Class 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 CNI’s Altered functional Impacts binding to the group on CsA Clinical benefits*: latch region on calcineurin Modification results in: • Allows for flat dosing 1) Predictable PK/PD • Improved lipid profile HO relationship (vs. CSA) O O H 2) Increased potency 3-4 • Reduced risk of N N N N N fold (vs. CSA) O O diabetes (vs. TAC) O O 3) Altered metabolic profile • No impact on MPA N O O O N and faster elimination of H H levels when used in N N resultant metabolites N N H combination (vs. CsA) O O Voclosporin *Existing CNI’s (cyclosporine & tacrolimus) are not approved for Lupus Nephritis in the EU/US 12
Voclosporin compared to other CNIs Limited inter & intra patient variability – allowing flat dosing 1,3 Increased Potency vs. cyclosporine A, allowing lower dosing requirements 1 100 100 90 80 600 75 70 VCS 60 CsA %CNI %CNI 50 50 500 40 30 Concentration (ng/mL) 25 400 20 r = 0.5 r = 0.7 10 0 0 300 0 10 20 30 40 50 60 0 250 500 750 1,000 1,250 1,500 Concentration (ng/mL) Concentration (ng/mL) 200 100 75 100 %CNI 50 0 0 2 4 6 8 25 r = 0.8 Time (h) 0 0 100 200 300 400 500 600 700 800 900 Concentration (ng/mL) Less cholesterolemia than cyclosporine A 1 Limited incidence of glucose intolerance & diabetes at 20 targeted doses vs. tacrolimus 2 Total Cholesterol (Study Isa05-25) Mean ± 95% CI Cases of new onset diabetes (12 months) 6.5 VCS Drug therapy ends 15 CsA Mean total cholesterol 6.0 10 5.5 5 5.0 0 4.5 Low conc. Mid conc. – 10 0 10 20 30 40 50 60 70 80 Voclosporin Tacrolimus 13 Week 1.Aurinia Data on file; 2.Busque S, et al. Am J Transplant . 2011;11(12):2675-2684 & AURA LV Data; 3. AURA-LV Data on file
AURA-LV (AURA) Study Design: Phase IIB Randomized, Controlled, Double Blind Study to evaluate whether voclosporin added to SoC can increase speed of remission & overall remission rates in the presence of low steroids Primary endpoint Secondary endpoint 24 weeks 48 weeks VOCLOSPORIN 23.7 mg bid VOCLOSPORIN 23.7 mg bid 1:1 Randomization MMF 2 g + oral corticosteroids N=265 VOCLOSPORIN 39.5 mg bid VOCLOSPORIN 39.5 mg bid MMF 2 g + oral corticosteroids PLACEBO PLACEBO MMF 2 g + oral corticosteroids 20-25 mg/daily AURA - rapid steroid taper 15-20 mg/daily 10-15 mg/daily 5 mg/daily 2.5 mg/daily 48 Week 2 4 6 12 24 8 14
AURA-LV Key Inclusion Criteria & Outcome Measures KEY INCLUSION CRITERIA Proteinuria of ≥1.5 Diagnosis of SLE Biopsy proven LN [Class III, IV Indicative of active mg/mg according or Class V (alone or in disease OR ≥2 mg/mg* to ACR criteria combination w/Class III/IV)] PRIMARY OUTCOME MEASURES The proportion of subjects achieving complete remission (CR) at 24 weeks Normal, stable renal function (≥60 CR is defined as: Confirmed urinary + mL/min/1.73m 2 or no confirmed decrease protein/creatinine ratio of ≤0.5 mg/mg from baseline in eGFR of ≥20%) Presence of sustained, low dose steroids No administration of rescue medications (≤10mg prednisone from week 16 -24) KEY SECONDARY OUTCOMES Partial Remission, Time to Remission, Time to Partial Remission, Durability of remission and extra-renal activity (SLEDAI) at 24 & 48 weeks *≥2 mg/mg refers to Class V patients 15
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