TREATMENT OF ACTIVE LUPUS NEPHRITIS WITH VOCLOSPORIN: RAPID - - PowerPoint PPT Presentation

TREATMENT OF ACTIVE LUPUS NEPHRITIS WITH VOCLOSPORIN: RAPID REMISSION OVER 48 WEEKS: DATA FROM THE AURA-LV STUDY

SV Parikh1, WF Pendergraft2, JA Tumlin3, R Saxena4, N Solomons5, RB Huizinga5 The Ohio State University Wexner Medical Center1 University of North Carolina, Chapel Hill2 South East Renal Research Institute3 UT Southwestern Medical Center4 Aurinia Pharmaceuticals5

Disclosures

2

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

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
• f 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

5

Mok et al, Arthritis Rheum 2013

Standardized mortality ratio SLE patients w/renal damage and ESRD have 14-fold and >60-fold increased risk, of premature death, respectively

5

Early Clinical Response is Critical to Maintaining Long- Term Kidney Health in LN

6 8% 57% 87%

0% 20% 40% 60% 80% 100% 120% Complete Remission Partial Remission No Response

LN patient survival without ESRD based on treatment response1

Not on Dialysis @ 10 years On Dialysis at 10 years

92% 43% 13%

• 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..

% of Patients

Rapid control & reduction of proteinuria in lupus patients may show a reduction in the need for dialysis1

STANDARD INITIAL THERAPY for PROLIFERATIVE LN:

IV Cyclophosphamide 0.5-1g/m2 Monthly for 6 months

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:

Oral MMF 2-3g/d for 6 months PO Cyclophosphamide 1-1.5mg/kg/d, maximum 150 mg/d for 2-4 months IV Cyclophosphamide 500 mg every 2 weeks for 3 months: LOW-DOSE- EURO-LUPUS REGIMEN Or Or Or

24 week Partial Response & Complete Remission Rates with Cyclophosphamide and MMF2

0% 10% 20% 30% 40% 50% 60% Partial Response Complete Remission Cyclophosphamide MMF 9% 53% 56%

% of Patients

8% *

Results of the Aspreva Lupus Management Study (ALMS) showed that the majority of patients failed to achieve CR at 24 weeks for both of these first-line therapeutics2 A better solution is needed to improve renal response rates for LN

• 1. Hahn BH, et al. Arthritis Care Res (Hoboken). 2012;64(6):797-808.
• 2. Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112

Drug Class Target Clinical Trial Status Abatacept-BMS CTLA4-Ig CTLA4-B7 Phase 3-FAILED Abatacept- ACCESS CTLA4-Ig CTLA4-B7 Phase 2-FAILED 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

Recently Completed Clinical Trials

Parikh et al JASN 2016

What About Calcineurin Inhibitors for LN Induction?

Synergistic Impact of Calcineurin Inhibition 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
• Med. 2008;14(9):931-938.

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 responses1,2 CNI’s have shown an ability to stabilize podocytes in the kidney, which protects against podocytopathy and proteinuria3-5

Cytoplasm T cell receptor APC Nucleus IL-2 INF-gamma TNF-alpha Cell-mediated immune response Voclosporin

Voclosporin Actin cytoskeleton Dephosphorylated synaptopodin breaks up and destabilizes the actin cytoskeleton

• f the podocyte

Glomerular basement membrane

Synaptopodin

Stabilization of the actin cytoskeleton within the podocyte via calcineurin inhibition has the potential to be disease modifying in LN

Tissue damage

10

CNIs as Part of a Multi-Target Induction Regimen

Liu et al, Ann Int Med, 2015

LN IV MP 500mg/d X3d Oral Steroid Taper 0.6mg/kg/d IV Pulse CYC 0.75g/m2 MMF 1g/d+TAC 4mg/d Complete Renal Remission

N=368

P < 0.001

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

*Existing CNI’s (cyclosporine & tacrolimus) are not approved for Lupus Nephritis in the EU/US

Altered functional group on CsA

Voclosporin

Impacts binding to the latch region on calcineurin

Modification results in:

1) Predictable PK/PD relationship 2) Increased potency 3-4 fold (vs. CSA) 3) Altered metabolic profile and faster elimination of resultant metabolites

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)

N HO O H N N O O N O N O N O N H O H N O N O H N O N O

12

Voclosporin compared to other CNIs

Limited inter & intra patient variability – allowing flat dosing 1,3

2 4 6 8 100 200 300 400 500 600 Time (h) Concentration (ng/mL) VCS CsA 5 10 15 20 Cases of new onset diabetes (12 months) Low conc. Mid conc. Voclosporin Tacrolimus

13

Concentration (ng/mL)

10 20 30 40 50 60 10 20 30 40 50 60 70 80 90 100 r = 0.5

%CNI

Concentration (ng/mL)

250 500 750 1,000 1,250 1,500 25 50 75 100

%CNI

r = 0.7

Concentration (ng/mL)

100 200 300 400 500 600 700 800 900 25 50 75 100 r = 0.8

%CNI

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 Increased Potency vs. cyclosporine A, allowing lower dosing requirements 1 Limited incidence of glucose intolerance & diabetes at targeted doses vs. tacrolimus 2

4.5 5.0 5.5 6.0 6.5 –10 10 20 30 40 50 60 70 80 Week Drug therapy ends Total Cholesterol (Study Isa05-25) Mean ±95% CI VCS CsA

Mean total cholesterol

Less cholesterolemia than cyclosporine A 1

AURA-LV (AURA) Study Design: Phase IIB

14

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

VOCLOSPORIN 23.7 mg bid VOCLOSPORIN 23.7 mg bid MMF 2 g + oral corticosteroids VOCLOSPORIN 39.5 mg bid VOCLOSPORIN 39.5 mg bid MMF 2 g + oral corticosteroids PLACEBO PLACEBO MMF 2 g + oral corticosteroids

Secondary endpoint 48 weeks Primary endpoint 24 weeks

1:1 Randomization N=265

20-25 mg/daily 15-20 mg/daily 10-15 mg/daily 5 mg/daily 2.5 mg/daily

Week

2 4 6 12 24 48

AURA - rapid steroid taper

8

AURA-LV Key Inclusion Criteria & Outcome Measures

Indicative of active disease KEY INCLUSION CRITERIA Diagnosis of SLE according to ACR criteria Biopsy proven LN [Class III, IV

• r Class V (alone or in

combination w/Class III/IV)] Proteinuria of ≥1.5 mg/mg OR ≥2 mg/mg* PRIMARY OUTCOME MEASURES CR is defined as: Confirmed urinary protein/creatinine ratio of ≤0.5 mg/mg Normal, stable renal function (≥60 mL/min/1.73m2 or no confirmed decrease from baseline in eGFR of ≥20%) The proportion of subjects achieving complete remission (CR) at 24 weeks 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

Presence of sustained, low dose steroids (≤10mg prednisone from week 16-24) No administration of rescue medications

15

Control N = 88 Voclosporin 23.7 mg BID N=89 Voclosporin 39.5 mg BID N=88 Total N = 265 Race n (%) 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) Asian (Indian sub- continent) 18 (20.5) 22 (24.7) 20 (22.7) 60 (22.6) Asian (Other) 18 (20.5) 30 (33.7) 24 (27.3) 72 (27.2) Other 5 (5.7) 4 (4.5) 2 (2.3) 11 (4.2) Hispanic n (%) Hispanic or Latino 13 (14.8) 9 (10.1) 13 (14.8) 35 (13.2) Not Hispanic or Latino 75 (85.2) 80 (89.9) 75 (85.2) 230 (86.8)

Baseline Demographic and Clinical Characteristics

16

• Age and Sex were similar across treatment groups

Control N = 88 Voclosporin 23.7 mg BID N=89 Voclosporin 39.5 mg BID N=88 Total N = 265 Biopsy Class n (%) Pure Class V 13 (15.0) 12 (13.5) 14 (15.9) 39 (14.7) Non Class V 75 (85.0) 77 (86.5) 74 (84.1) 226 (85.3) Baseline eGFR CKD-EPI (mL/min/1.73m²) Mean ± SD 100 ±26.9 95 ±28.4 105 ±27.5 100 ± 27.8 Median 100 95 109 101 Min/Max 49, 153 41, 148 42, 165 41, 165 Baseline uPCR (mg/mg) Mean ±SD 4.4 ± 3.58 5.2 ± 4.15 4.5 ± 3.03 4.7 ± 3.62 Median 3.1 3.8 3.7 3.5 Min/Max 0.8, 19.3 0.8, 29.7 1.0, 17.4 0.8, 29.7

Baseline Demographic and Clinical Characteristics

17

24 and 48 Week Results

Renal Response (Remission) at 24 and 48 Weeks

Endpoint Treatment 24 weeks Odds ratio (95% CI) P-value* 48 weeks Odds Ratio (95% CI) P-value* Complete Remission (CR) 23.7mg VCS BID 32.6% 2.03 (1.01, 4.05) p=.045 49.4% 3.21 (1.68, 6.13) p<.001 39.5mg VCS BID 27.3% 1.59 (0.78, 3.27) p=.204 39.8% 2.10 (1.09, 4.02) p=.026 Control 19.3% NA NA 23.9% NA NA Partial Remission (PR) 23.7mg VCS BID 70% 2.33 (1.68, 6.13) p=.007 68% 2.34 (1.27, 4.33) p=.007 39.5mg VCS BID 66% 2.03 (1.10, 3.76) p=.024 72% 2.68 (1.43, 5.02) p=.002 Control 49% NA NA 48% NA NA

First global trial in active LN to meet its primary endpoint

20

23.7mg BID VCS demonstrates statistically significant CR & PR rates at 24 & 48 weeks

Improved CR & PR Over Time with Voclosporin

0% 10% 20% 30% 40% 50% 60%

Patients achieving CR

Progression to Complete Remission

Control VCS 23.7mg BID VCS 39.5mg BID

p=.045 p<.001

0% 10% 20% 30% 40% 50% 60% 70% 80% Baseline 24 weeks 48 weeks

Progression to Response (CR or PR)

Control VCS 23.7mg BID VCS 39.5mg BID

p=.007 p=.007 p=.026 p=.002 p=.024

100% of patients in the low-dose arm in complete remission at 24 weeks stay in CR

AURA: Time to Complete and Partial Response

21

A statistically significant faster time to CR & PR compared to the control group

P-Value <0.001 for both LD-VCS and HD-VCS

22

AURA-LV: UPCR (mg/mg) (Mean ± SD) Over Time

1 2 3 4 5 6 7 8 9 10 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48 Week 50

UPCR (mg/mg) Visit

UPCR (Mean ± SD) Over Time

P<.001 for LD-VCS p=.009 for HD-VCS

23

Mean Change from Baseline in SELENA-SLEDAI Score 24/48 weeks

• 4.5
• 5.3
• 6.3
• 7.9
• 7.1
• 8.3
• 9
• 8
• 7
• 6
• 5
• 4
• 3
• 2
• 1

Change from Baseline to Week 24 Change from Baseline to Week 48

Control Voclosporin 23.7 mg BID Voclosporin 39.5 mg BID

p=.003 p=.003 p<.001 p=.003

A statistically significant improvement in reduction of SLEDAI score vs. baseline in both VCS arms vs. patients in the control group

AURA Pre-specified Analysis: Ds-DNA Antibody & Serum Albumin (Mean ± SD) Over Time

24

1.75 21.75 41.75 61.75 81.75 101.75 121.75 141.75 161.75 181.75 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48

dsDNA Antibody (IU/mL) Visit

Anti-dsDNA (Mean ± SD) Over Time p=.006 p=.01

SAFETY

Summary of Treatment Emergent Adverse Events and Historical Comparison

26

Treatment Emergent Adverse Events (TEAE)*

*includes TEAES following treatment period

Control N = 88 n (%) Voclosporin 23.7 mg BID N = 89 n (%) Voclosporin 39.5 mg BID N = 88 n (%) Any TEAE 78 (88.6) 82 (92.1) 85 (96.6) Any Serious TEAE 17 (19.3) 25 (28.1) 22 (25.0) Any TEAE with Outcome of Death 4 (4.5) 10 (11.2) 2 (2.3) Any Treatment-Related TEAE 15 (17.0) 45 (50.6) 55 (62.5) Any Serious Treatment-Related TEAE 1 (1.1) 4 (4.5) 7 (8.0)

AURA-LV4 N=265 (to Dec 18th/16) ALMS Induction2 N=364 Abatacept Study1 MMF N = 298 Ocrelizumab Study3 N=378 SAE’s, Subjects, n (%) 59 (22.3%) (25.3%) 92 (30.9%) 107 (28.3%) Serious Infections, Subjects n (%) 29 (10.9%) (10.9%) 58 (19.5%) 64 (16.9%) Deaths, Subjects, n (%) 13 (4.9%) 14 (3.8%) 14 (4.7%) 14 (3.7%)

1.Furie R. et al., Arthritis and Rheumatology, Vol. 66, No 2, February 2014

• 2. Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112 – Aspreva Lupus Management Study (Induction)

3.Mysler, E. et al., Arthritis and Rheumatism, Vol. 65, No 9, September 2013, 2368-2379

• 4. AURA-LV Study results – Aurinia data on file

eGFR (mL/min/1.73m²) Returns to Baseline After 48 Weeks of Treatment

27

Blood Pressure (BP) (Mean ± SD) Over Time to 48 Weeks

28

80 90 100 110 120 130 140 150 160 Baseline Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24

Systolic Blood Pressure (mmHg) Visit

Systolic BP (Mean ± SD) Over Time

Week 48 50 60 70 80 90 100 110 Baseline Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 Week 20 Week 24 Week 48

Diastolic Blood Pressure (mmHg) Visit

Diastolic BP (Mean ± SD) Over Time

No significant difference in blood pressure over the 48-week treatment period

29

Control N = 88 n (%) VCS 23.7 mg BID N = 89 n (%) VCS 39.5 mg BID N = 88 n (%) Diarrhea 14 (15.9) 16 (18.0) 14 (15.9) Nausea 7 (8.0) 16 (18.0) 11 (12.5) Cough 3 (3.4) 16 (18.0) 5 (5.7) Vomiting 10 (11.4) 15 (16.9) 9 (10.2) Anemia 7 (8.0) 13 (14.6) 14 (15.9) Upper respiratory tract infection 14 (15.9) 12 (13.5) 18 (20.5) Urinary tract infection 5 (5.7) 8 (9.0) 6 (6.8) Pneumonia 2 (2.3) 7 (7.9) 7 (8.0) Pyrexia 1 (1.1) 6 (6.7) 10 (11.4) Dyslipidemia 6 (6.8) 6 (6.7) 7 (8.0) Edema 1 (1.1) 2 (2.2) 5 (5.7) Leukopenia 6 (6.8) 1 (1.1) 3 (3.4)

Key Adverse Events

AURA-LV Safety Summary

30

1 Furie R. et al., Arthritis and Rheumatology, Vol. 66, No 2, February 2014 2 Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112 – Aspreva Lupus Management Study (Induction) 3.Mysler, E. et al., Arthritis and Rheumatixm, Vol. 65, No 9, September 2013, 2368-2379

• The overall safety profile is consistent with other immunomodulators

No new safety signals were observed with the use of voclosporin in LN patients; voclosporin was well-tolerated

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

Safety beyond 24 weeks Control N = 88 n (%) VCS 23.7 mg BID N = 89 (n (%) Any Serious Adverse Event 1 (1.1) 2 (2.2) Malignancies 1 (1.1)^ 0 (0) Deaths 3 (3.4)* 0 (0)

^Malignancy (metastatic melanoma) occurred following treatment period *3 deaths occurred following the treatment period (after week 50)

13 deaths have been reported in the AURA study: pattern is consistent with

• ther global Active LN studies1,2,3

11 of 13 deaths occurred at sites with limited access to SOC; patients who died had a statistically different clinical baseline picture, demonstrating a more severe form of LN, potential comorbid conditions & poor nutrition

CONCLUSIONS

 First therapeutic agent to meet ALL KEY 24 & 48 week pre-specified secondary endpoints in global clinical trial for active LN  Voclosporin 23.7mg BID dose demonstrated a statistically significantly higher CR at both weeks 24 & 48 vs. patients in the control group (p=.045); (p<.001)  Voclosporin 23.7mg BID achieved all key secondary endpoints including time to remission/response and statistically significant reduction in UPCR and SLEDAI at 24 and 48 weeks.  This multi-target approach allowed for clinical response to be achieved using a Steroid- reduced protocol  Adverse events were more common in the Voclosporin-treated groups but SAEs were similar to other LN trials.  These findings suggest that Voclosporin in addition to SOC may lead to improved

• utcomes in a multi-ethnic, multi-racial LN Population. A global placebo-controlled

Phase III trial for voclosporin 23.7mg BID is scheduled to begin imminently

Principal Investigators

Ihar Adzerikhko Elena Mikhailova Natalya Mitkovskaya Sergey Pimanov Nikolay Soroka Boris Iliev Bogov Boriana Deliyska Valentin Ikonomov Eduard Tilkiyan Ruth Almeida Fernando Jimenez Faud Teran Irma Tchokhonelidze Nino Tsiskarishvili Maynor Herrera Mendez Nilmo Noel Chavez Perez Shue-Fen Luo Tien-Tsai Cheng Arturo Reyes Loaeza Sergio Ramon Urena Juanita Romero Diaz Pablo Estaley Sanson Rodolfo Araiza Casillas Magdalena Rovalo Stanislaw Niemczyk Antoni Sokalski Andrezj Wiecek Marian Klinger Dragan Jovanovic Branka Mitic Milan Radovic Goran Radunovic Patricia Carreira Federico Gonzalez Xavier Fulladosa Eduardo Ucar Brancha Satirapoj Kajohnsak Noppakun Olga Bugrova Tatiana Chenykh Tatiana Kameneva Lidia Lysenko Tatiana Raskina Olga Reshetko Natalia Vezikova Tatiana Kropotina Adelya Maksudova Vyacheslav Marasaev Vladimir Dobronravov Ivan Gordeev Mikhail Batyushin Vladimir Ryasnyansky Ashot Essaian Alexey Frolov Iryna Dudar Olga Godlevska Svitlana Korneyeva Viktoriia Vasylets Nataliya Sydor Mykola Kolesnyk Samir Parikh Nancy Olsen Ellen Ginzler James Tumlin Amit Saxena Ramesh Saxena Richard Lafayette William Pendergraft III Amber Podoll Michael Bubb Jennifer Grossman Alejandro I Oporta Alireza Nami Shamila De Silva Chula Herath Anura Hewageegana Abdul Latiff Mohamed Nazar A.W.M Wazil Mujibur Rahman Syed Atiqul Haq Tak Mao Daniel Chan Mo Yin Mok Harold Michael P. Gomez Joseph Antigua Bernadette Heizel Reyes Llewellyn T. Hao Linda Charmaine Roberto Eric Amante Sandra Navarra Allan Lanzon Jung-Yoon Choe Tae Young Kang Yon Su Kim Seung-Geun Lee Ji Soo Lee Jason Choo Chon Jun Archana Vasudevan 32