AURA STUDY – 48 WEEK COMPLETE REMISSION BY ETHNIC, SEX AND AGE SUBGROUPS IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS TREATED WITH VOCLOSPORIN D. Wofsy, D. Isenberg, F. Houssiau, M.A. Dooley, N. Solomons, S. Randhawa
Disclosures Member, Independent Data Monitoring Board - GSK Consultant - UCB, Celgene, Sanofi Aventis, Anthera 2
Recent Studies of CNIs In Active Lupus Nephritis Multitarget Therapy Tacrolimus vs MMF Tacrolimus/MMF vs CTX (Mok CC et al: Ann Rheum Dis (Liu Z et al: Ann Intern Med 2015;162:18) 2016;75:30) N=368 N=150 Outcome at 24 weeks Outcome at 60 weeks MTT CTX TAC MMF CR 46% 26% CR 62% 59% PR 27% 21% NR 11% 20% 3
CNIs May Have Synergistic Mechanisms of Action CNIs block IL-2 expression CNIs stabilize podocytes, and T cell – mediated which protects against immune responses proteinuria Actin CNI CNIs protect the cytoskeleton CNI actin cytoskeleton APC of podocytes Synaptopodin Cytoplasm T cell receptor Damage Nucleus IL-2 Cell-mediated IFN- g responses Glomerular Basement Membrane 4
Voclosporin – A Novel Calcineurin Inhibitor Less variability in Increased potency plasma concentration vs. cyclosporine VOCLOSPORIN Lower risk of Better lipid profile hyperglycemia 5
Key Inclusion Criteria • ACR criteria for SLE • Biopsy-proven LN - Class III, IV, or V • Class III/IV: UPCR>1.5 • Class V: UPCR>2 6
Study Design: Phase IIB Randomized, Double-blind Placebo-controlled Trial Primary endpoint Secondary endpoint 24 weeks 48 weeks VOCLOSPORIN 23.7 mg bid VOCLOSPORIN 23.7 mg bid N=265 VOCLOSPORIN 39.5 mg bid VOCLOSPORIN 39.5 mg bid PLACEBO PLACEBO MMF 2 g + oral corticosteroids 20-25 mg/d 15-20 mg/d Rapid steroid taper 10-15 mg/d 5 mg/d 2.5 mg/d 8 24 Week 16 48 7
Primary Outcome Measure Primary Outcome – Frequency of complete response • UPCR <0.5 • Stable normal renal function or no decrease from baseline >20% • Prednisone dose <10 mg/d from weeks 16-24 • No use of rescue medication 8
Baseline Demographic Characteristics Age, Sex and Race were similar across treatment groups White – 108 (41%) Asian – 72 (27%) Indian subcontinent – 60 (23%) Other (Black, NA, Pacific Islander) - 25 (9%) 9
Baseline Renal Characteristics Voclosporin Voclosporin Control (low-dose) (high-dose) N = 88 N=89 N=88 Baseline eGFR 100 ± 27 95 ± 28 105 ± 28 Mean ± SD 100 95 109 Median Baseline UPCR 4.4 ± 3.6 5.2 ± 4.2 4.5 ± 3.0 Mean ± SD 3.1 3.8 3.7 Median Biopsy Class 75 (85%) 77 (86%) 74 (84%) Class III or IV (+/- V) Pure Class V 13 (15%) 12 (14%) 14 (16%) 10
Complete Response Rate at Week 24 40% p=.045 Complete Response p=NS 30% 33% 28% 20% 19% 10% 0% Control LD VCS HD VCS 11
Response Rates at 48 Weeks Control Low-Dose VCS High-Dose VCS PR CR PR CR CR PR 80% 60% 20% 32% 37% 39% 40% 24% 30% 49% 20% 40% 33% 27% 24% 19% 0% 24 48 24 48 24 48 Week 100% subjects in CR at 24 weeks remain in CR at 48 weeks (VCS low-dose) 12
Time to Complete Response Control P<0.001 P=0.002 Kaplan-Meyer plot - time to complete remission 13
Oral Steroid Dosing Similar Among Study Arms Voclosporin Voclosporin Control (low-dose) (high-dose) Daily Dose (mg) Duration over 48 Weeks Mean (SD) 8.0 (5.1) 7.9 (6.0) 7.9 (6.4) Median 5.4 5.5 5.4 Week 16 Dose Level ≤2.5mg 58 (72%) 61 (76%) 63 (75%) >2.5mg 15 (18%) 11 (14%) 16 (19%) 8 (10%) 8 (10%) 5 (6%) Withdrew prior to wk 16 14
Complete Response by Race/Geography Low Dose High Dose Placebo 70 Complete Response-week 48 (%) 59 57 60 50 50 40 40 40 33 29 29 26 30 25 22 20 10 0 0 White Indian subcont Asian other Other N= 30 36 42 22 20 18 30 24 18 7 8 10 15
Complete Response Rate by Ethnicity Low Dose High Dose Placebo Complete Response-week 48 (%) 60 54 50 50 44 37 40 30 24 23 20 10 0 Non Hispanic Hispanic Latino Non Latino N= 9 13 13 80 75 75 16
Complete Response by Gender/ Age Low Dose High Dose Placebo 57 57 60 Complete Response – week 48 (%) 51 50 44 40 39 38 38 40 33 27 30 22 22 20 10 0 Female Male Age<=30 Age>30 13 7 15 N= 76 81 73 52 51 37 37 37 51 17
UPCR Decreased vs Control UPCR 5.2 4.5 4.4 p=<.009 p=<.001 (vs. control) 1.8 (vs. control) 1.1 0.7 Control Low dose VCS High dose VCS Baseline 48 weeks 18
Anti-dsDNA Decreased Significantly vs Control Complement Levels Were Similar Low Dose High Dose 145 125 145 105 LD VCS HD VCS dsDNA Antibody (IU/mL) C3 85 125 65 45 105 25 85 65 30 p=.011 25 45 20 p=.006 C4 25 15 10 5 19
Adverse Events VCS VCS Control (low-dose) (high-dose) Adverse Events (AE) N = 88 N = 89 N = 88 n (%) n (%) n (%) Any AE 78 (89%) 82 (92%) 85 (97%) 14 (16%) 25 (28%) 22 (25%) Serious AEs Deaths 1 (1.1%) 10 (11%) 2 (2.3%) 20
Deaths Placebo • Cerebrovascular accident Low-dose VCS • Acute respiratory distress (2) Geographic Location • Pulmonary embolism (2) • 7 Bangladesh • Pneumonia (2) • 2 Sri Lanka • Multi organ failure • 2 Philippines • Cardiac tamponade • 2 Russia • TB pericarditis • Pulmonary alveolar hemorrhage High-dose VCS • Sepsis • Pulmonary embolism 21
Summary • Voclosporin added to MMF and steroids demonstrated a significantly higher complete response rate compared to the standard-of-care control group. • The high complete response rate was achieved despite a less aggressive steroid regimen than usual. • Key secondary endpoints supported the primary outcome. • Subgroup analyses demonstrated consistency of results across age, gender, race, and ethnicity. • There was increased mortality in the low-dose VCS group for reasons that are unclear. Enhanced safety monitoring is being implemented in the ongoing phase 3 trial. 22
Thanks to the Principal Investigators Principal Investigators Ihar Adzerikhko Arturo Reyes Loaeza Olga Bugrova Samir Parikh Tak Mao Daniel Chan Elena Mikhailova Sergio Ramon Urena Tatiana Chenykh Nancy Olsen Mo Yin Mok Natalya Mitkovskaya Juanita Romero Diaz Tatiana Kameneva Ellen Ginzler Sergey Pimanov Pablo Estaley Sanson Lidia Lysenko James Tumlin Harold Michael P. Gomez Nikolay Soroka Rodolfo Araiza Casillas Tatiana Raskina Amit Saxena Joseph Antigua Magdalena Rovalo Olga Reshetko Ramesh Saxena Bernadette Heizel Reyes Boris Iliev Bogov Natalia Vezikova Richard Lafayette Llewellyn T. Hao Boriana Deliyska Stanislaw Niemczyk Tatiana Kropotina William Pendergraft III Linda Charmaine Roberto Valentin Ikonomov Antoni Sokalski Adelya Maksudova Amber Podoll Eric Amante Eduard Tilkiyan Andrezj Wiecek Vyacheslav Marasaev Michael Bubb Sandra Navarra Marian Klinger Vladimir Dobronravov Jennifer Grossman Allan Lanzon Ruth Almeida Ivan Gordeev Alejandro I Oporta Fernando Jimenez Dragan Jovanovic Mikhail Batyushin Alireza Nami Jung-Yoon Choe Faud Teran Branka Mitic Vladimir Ryasnyansky Tae Young Kang Irma Tchokhonelidze Milan Radovic Ashot Essaian Shamila De Silva Yon Su Kim Nino Tsiskarishvili Goran Radunovic Alexey Frolov Chula Herath Seung-Geun Lee Anura Hewageegana Ji Soo Lee Maynor Herrera Mendez Patricia Carreira Iryna Dudar Abdul Latiff Mohamed Nilmo Noel Chavez Federico Gonzalez Olga Godlevska Nazar Jason Choo Chon Jun Perez Xavier Fulladosa Svitlana Korneyeva A.W.M Wazil Archana Vasudevan Eduardo Ucar Viktoriia Vasylets Shue-Fen Luo Nataliya Sydor Mujibur Rahman Tien-Tsai Cheng Brancha Satirapoj Mykola Kolesnyk Syed Atiqul Haq Kajohnsak Noppakun 23
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