AURA STUDY 48 WEEK COMPLETE REMISSION BY ETHNIC, SEX AND AGE - - PowerPoint PPT Presentation

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Nov 27, 2022 532 likes •776 views

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,

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SLIDE 1

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
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SLIDE 2

Disclosures

Member, Independent Data Monitoring Board - GSK Consultant - UCB, Celgene, Sanofi Aventis, Anthera

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SLIDE 3

Recent Studies of CNIs In Active Lupus Nephritis

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Tacrolimus vs MMF

(Mok CC et al: Ann Rheum Dis 2016;75:30)

N=150 Outcome at 60 weeks TAC MMF CR 62% 59% PR 27% 21% NR 11% 20% Multitarget Therapy Tacrolimus/MMF vs CTX

(Liu Z et al: Ann Intern Med 2015;162:18)

N=368 Outcome at 24 weeks MTT CTX CR 46% 26%

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SLIDE 4

CNIs May Have Synergistic Mechanisms of Action

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CNIs block IL-2 expression and T cell–mediated immune responses CNIs stabilize podocytes, which protects against proteinuria

Actin cytoskeleton CNIs protect the actin cytoskeleton

  • f podocytes

Glomerular Basement Membrane

Synaptopodin

Cytoplasm T cell receptor APC

Nucleus

IL-2 IFN-g Cell-mediated responses

CNI

Damage

CNI

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SLIDE 5

Voclosporin – A Novel Calcineurin Inhibitor

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Increased potency

  • vs. cyclosporine

Less variability in plasma concentration Lower risk of hyperglycemia Better lipid profile VOCLOSPORIN

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SLIDE 6

Key Inclusion Criteria

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  • ACR criteria for SLE
  • Biopsy-proven LN - Class III, IV, or V
  • Class III/IV: UPCR>1.5
  • Class V: UPCR>2
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SLIDE 7

Randomized, Double-blind Placebo-controlled Trial

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

Secondary endpoint 48 weeks Primary endpoint 24 weeks

N=265

Study Design: Phase IIB

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

24 48

Rapid steroid taper

8 16 Week

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SLIDE 8

Primary Outcome Measure

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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
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SLIDE 9

Baseline Demographic Characteristics

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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%)

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SLIDE 10

Control N = 88 Voclosporin (low-dose) N=89 Voclosporin (high-dose) N=88

Baseline eGFR

Mean ± SD

100 ±27 95 ±28 105 ±28

Median

100 95 109 Baseline UPCR

Mean ±SD

4.4 ± 3.6 5.2 ± 4.2 4.5 ± 3.0

Median

3.1 3.8 3.7 Biopsy Class

Class III or IV (+/- V)

75 (85%) 77 (86%) 74 (84%)

Pure Class V

13 (15%) 12 (14%) 14 (16%)

Baseline Renal Characteristics

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SLIDE 11

Complete Response Rate at Week 24

19% 33% 28%

0% 10% 20% 30% 40%

Complete Response Control LD VCS HD VCS

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p=.045 p=NS

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SLIDE 12

Response Rates at 48 Weeks

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Control Low-Dose VCS High-Dose VCS

19% 24% 33% 49% 27% 40% 30% 24% 37% 20% 39% 32% 0% 20% 40% 60% 80% 24 48 24 48 24 48

CR PR CR PR CR PR

100% subjects in CR at 24 weeks remain in CR at 48 weeks (VCS low-dose)

Week

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SLIDE 13

P=0.002 P<0.001

Time to Complete Response

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Kaplan-Meyer plot - time to complete remission

Control

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SLIDE 14

Control

Voclosporin (low-dose) Voclosporin (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%)

Withdrew prior to wk 16

8 (10%) 8 (10%) 5 (6%)

Oral Steroid Dosing Similar Among Study Arms

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SLIDE 15

57 59 40 29 50 40 29 25 26 33 22 10 20 30 40 50 60 70

White Indian subcont Asian other Other

Complete Response-week 48 (%)

Low Dose High Dose Placebo

Complete Response by Race/Geography

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N= 30 36 42 22 20 18 30 24 18 7 8 10

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SLIDE 16

44 50 54 37 23 24

10 20 30 40 50 60

Latino Non Latino

Complete Response-week 48 (%)

Low Dose High Dose Placebo

Complete Response Rate by Ethnicity

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N= 9 13 13 80 75 75 Hispanic Non Hispanic

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SLIDE 17

51 38 44 57 38 57 39 40 22 33 27 22

10 20 30 40 50 60

Female Male Age<=30 Age>30

Complete Response–week 48 (%)

Low Dose High Dose Placebo

Complete Response by Gender/ Age

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N= 76 81 73 13 7 15 52 51 37 37 37 51

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SLIDE 18

UPCR Decreased vs Control

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4.4 5.2 4.5 1.8 0.7 1.1 Control Low dose VCS High dose VCS

UPCR

Baseline 48 weeks p=<.001 (vs. control) p=<.009 (vs. control)

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SLIDE 19

Anti-dsDNA Decreased Significantly vs Control Complement Levels Were Similar

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25 45 65 85 105 125 145

dsDNA Antibody (IU/mL)

LD VCS HD VCS

p=.011 p=.006

5 10 15 20 25 30

C4

25 45 65 85 105 125 145

C3

Low Dose High Dose

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SLIDE 20

Adverse Events (AE) Control N = 88 n (%) VCS (low-dose) N = 89 n (%) VCS (high-dose) N = 88 n (%) Any AE 78 (89%) 82 (92%) 85 (97%) Serious AEs 14 (16%) 25 (28%) 22 (25%) Deaths 1 (1.1%) 10 (11%) 2 (2.3%)

Adverse Events

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SLIDE 21

Deaths

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Placebo

  • Cerebrovascular accident

Low-dose VCS

  • Acute respiratory distress (2)
  • Pulmonary embolism (2)
  • Pneumonia (2)
  • Multi organ failure
  • Cardiac tamponade
  • TB pericarditis
  • Pulmonary alveolar hemorrhage

High-dose VCS

  • Sepsis
  • Pulmonary embolism

Geographic Location

  • 7 Bangladesh
  • 2 Sri Lanka
  • 2 Philippines
  • 2 Russia
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SLIDE 22

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.

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SLIDE 23

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

Thanks to the Principal Investigators

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