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RituximabRAVE Trial Results (and more)

Ulrich Specks, MDProfessor of Medicine

Division of Pulmonary and Critical Care Medicine,Thoracic Diseases Research Unit,Mayo Clinic, Rochester, MN, USA

Vasculitis FoundationAll Star Vasculitis Symposium,

Long Beach, CAGeneral Session #1

New and emerging Therapies in VasculitisJuly 31, 2010

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• Remission can be achieved (at any time): 91% Newly diagnosed : 92% Existing disease: 90.5%

• Sustained remission (longer than 6 months): 72%• Remission off prednisone at 6 months* 66%• Relapse over median of 22 months > 50%• Suffered at 1 or more severe adverse events: 57%• Higher relapse rate with: PR3-ANCA than MPOWG than MPA

BackgroundEfficacy of Standard Therapy To Date

NEJM 352:351, 2005

* Severe Dz in WGET - unpublished

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• Precursors of (auto) antibody-secreting plasma cells

• Regulation of immune responses Modify immunoglobulin

production Cytokine production Expression of

costimulatory molecules Antigen presentation Differentiation &

regulation of T cells and dendritic cells

Salama A and Pusey C: Nature Clin Prac 2:221, 2006

Functions of B Lymphocytes

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B Lymphocytes are “Bad Actors” in Wegener’s Granulomatosis

• Efficacy of cyclophosphamide attributed to profound effect on B lymphocytes

Cupps et al: J Immunol 128:2453, 1982

• Correlation between frequency of activated peripheral blood B cells (but not T cells) and

Disease activity of WG Disease extent (severe/generalized vs limited)

Popa et al: J Allergy Clin Immunol 103:885, 1999

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Mouse IgG Antibody Human IgG Antibody

Rituximab: Chimeric anti-IgG Antibody

Variable regionHeavy chain

Variable regionLight chain

Adapted from Silverman & Weisman Arthritis Rheum 2003

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Rituximab vs Cyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis

A Randomized Controlled Trial (RAVE)

Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CGM, St. Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo L, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, and Specks U for the RAVE-ITN Research Group

ACR 2009 Annual MeetingPhiladelphia, PA

Plenary Session I: Discovery 2009Sunday, October 18, 2009

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AcknowledgementsCo-Protocol Chairs• Ulrich Specks, MD (Mayo Clinic)• John H. Stone, MD, MPH (Massachusetts General Hospital)

Mayo Clinic• Steven R. Ytterberg, MD• Fernando C. Fervenza, MD• Karina A. Keogh, MD• Tobia Peikert, MD• Jason Golbin, DO• Lorenzo Klein, MD• Kathleen Mieras, CCRP• Cynthia Beinhorn• Susan Fisher, RN• Mary Lou Clawson, RN• Sharon Bendel, RN• Amber M. Hummel• Mayo Clinic Eisenberg

Research Pharmacy

Boston University• Peter A. Merkel, MD, MPH• Eugene Y. Kissin, MD• Paul A. Monach, MD, PhD• Manuella R. Clark-Cotton, MA• Carol A. McAlear, MS• Jessica L. Pettit• Maureen B. Sutton, MPH• Russell L. Widom, PhD• Giuseppina A. Farina, MD, PhD• Michael J. DiMarzio• Sharlene P. Johnson, MAT

Johns Hopkins University• Philip Seo, MD, MHS• David Hellmann, MD• Duvuru Geetha, MD• Assil Saleh, MD, MPH• Peter Wung, MD• Lourdes P. Sejismundo, RN, BSN• Charlotte Humphrey, RN, BSN• Matthew Marriott, PA-C• Yavette Goldsborough• Alexander Pinachos• Karen Gauss, RN, MLA• Linda King, RN

Cleveland Clinic Fdn.• Carol A. Langford, MD• Gary S. Hoffman, MD• Debora Bork, MFA• Tiffany Clark, RN• Katie Tuthill• Teresa Markle• John Petrich, RPh

Hospital for Special Surgery• Robert Spiera, MD• Deborah R. Alpert MD, PhD• Stephen J. DiMartino, MD, PhD• Jessica K. Gordon, MD• Neal K. Moskowitz, MD, PhD• Kyriakos A. Kirou, MD• Jonathan Samuels, MD• Stacey A. Kloiber, RN• Elvedin Julevic• Margaret O'Donohue, RN• Avni Patel, PharmD

University of Groningen• Cees Kallenberg, MD, PhD• Coen Stegeman, MD, PhD• Peter Rasker, RN• Katinka Mulder• Pieter Limburg, PhD• Jos Kosterink, PharmD

Duke University• E. William St. Clair, MD • Nancy B. Allen, MD • Edna Scarlett, RN• Martin Tochacek, PhD

University of Alabama-Birmingham• Anthony Turkiewicz, MD• Barri Fessler, MD• Winn Chatham, MD• Anita Turner, RN

Rho• David Ikle, PhD• David Weitzenkamp, PhD

PPD• Wei Wu, PhD• Tammy D’Lugin• Cathy Jacob

NIAID• Lisa Webber, RN• Linna Ding, MD, PhD• Steven Adah, PhD

ITN• Nadia Tchao, MD• Vicki-Seyfert Margolis, PhD• Patti Tosta• Mark Mueller, BS, CCRP• Kasia Bourcier, PhD• Adam Asare, PhD• Nancy B. Skeeter• Claire L. Anderson• Adelaide N. Archampong

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Hypotheses

• Rituximab is as effective as conventional therapy (cyclophosphamide) for the induction of remission in severe ANCA-associated vasculitis

• Rituximab offers other substantial advantages over standard therapy

• B cell depletion by anti-CD20 therapy induces stable remissions by re-establishing tolerance to ANCA target antigens

NEJM 2010; 363:221-32

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Primary Outcome Measure

• Percentage of patients who have achieved clinical remission (BVAS/WG = 0) andcompleted the steroid taper by 6 months (“complete remission”)

• Longer-term follow-up (to 18 months) to gauge duration of rituximab-induced remissions and effects of B cell depletion on immune tolerance

NEJM 2010; 363:221-32

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Secondary Outcome Measures

• Remission on <10 mg prednisone• Safety• Restoration of tolerance

• Duration of remission

• Longitudinal (cumulative) disease activity

• Damage

• Quality of life (SF-36)

NEJM 2010; 363:221-32

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Study Design

Severe WG or MPAPR3- or MPO-ANCA positive

n=200 (197)

PredRTX infusions (375 mg/m2 x 4)

CYC-placebo for 3-6 mo

PredRTX-placebo infusions

CYC (2 mg/kg po) for 3-6 mo

AZA-placebo for 15-12 mo AZA for 15-12 mo

1-3 g IV methylprednisolone

NEJM 2010; 363:221-32

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0

10

20

30

40

50

60

70

80

0 30 60 90 120 150 180

Prednisone in RAVE

Glucocorticoid dose (mg)

Study day

Permitted dose range

NEJM 2010; 363:221-32

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98 available for analysis

98 allocated to CYC/placebo• 24 with microscopic polyangiitis• 74 with Wegener’s granulomatosis

Evaluated for endpoint• 81 completed 6 mo as randomized• 17 people with 20 early outcomes

2 early treatment failures7 blinded crossovers2 on best medical judgment2 deaths4 withdrawals, defined as failures

99 allocated to rituximab/placebo• 24 with microscopic polyangiitis• 74 with Wegener’s granulomatosis• 1 not specified

Evaluated for endpoint• 84 completed 6 mo as randomized• 15 people with 22 early outcomes

7 early treatment failures6 blinded crossovers7 on best medical judgment1 death1 withdrawal, defined as failure

Randomize 1:1

RTX

99 available for analysis

197 participants enrolled

CYC

NEJM 2010; 363:221-32

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Primary Efficacy Endpoint AnalysisComplete Remission at 6 Months

RTX CYC Differencen=99 n=98 (%) P

Yes 63 (63.6%) 52 (53.1%) 10.6 0.089

95% CI (%) 54.1, 73.2 43.1, 63.0

ITT analysis, worst case imputation

BVAS/WG = 0 and prednisone = 0 mg

NEJM 2010; 363:221-32

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Secondary Efficacy Endpoint AnalysisRemission at 6 Months

RTX CYC Differencen=99 n=98 (%) P

Yes 70 (70.7%) 61 (62.2%) 8.5 0.103

95% CI (%) 61.8, 79.7 52.6, 71.8

BVAS/WG = 0 and prednisone <10 mg

ITT analysis, worst case imputation

NEJM 2010; 363:221-32

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BVAS/WG = 0Pred = 0 mg

Efficacy Endpoint Analysis

ITT analysis, worst case imputation

Treatment effect

-40% -30% -20% -10% 0% 10% 20% 30%

Noninferiority marginP<0.0001

Superiority boundaryP=0.089

-3.2% 10.6% 24.3%( )

Treatment effectNoninferiority margin

P<0.0001Superiority boundary

P=0.103

-4.7% 8.5% 21.7%( )

BVAS/WG = 0Pred <10 mg

-40% -30% -20% -10% 0% 10% 20% 30%

NEJM 2010; 363:221-32

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0

10

20

30

40

50

60

70

80

0 30 60 90 120 150 180

Rituximab Cyclophosphamide

Prednisone in RAVE

Glucocorticoid dose (mg)

Study day

Permitted dose range

Patients remaining in assigned treatment arm throughout 6 months

NEJM 2010; 363:221-32

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Treatment Response by Disease Status at Baseline

0

10

20

30

40

50

60

70

80

New disease Severe flare

%

n=96 n=101

P=0.67 P=0.013

Rituximab Cyclophosphamide

60.4%64.6% 66.7%

42.0%

NEJM 2010; 363:221-32

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Treatment Response by Disease Type

0

10

20

30

40

50

60

70

80

MPA WG

%

n=48 n=148

P=0.76 P=0.14

Rituximab Cyclophosphamide

66.7%62.5% 63.0%

50.0%

NEJM 2010; 363:221-32

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RAVE Primary Results Summary

• Demographic characteristics, disease phenotype and disease activity of patients were distributed equally across both treatment arms

• Rituximab is not inferior to cyclophosphamide for remission induction in patients with severe AAV

• There was no difference in treatment response to rituximab or cyclophosphamide in patients with major renal disease or alveolar hemorrhage

NEJM 2010; 363:221-32

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RAVE Primary Results Summary

• The treatment response to rituximab was superior to cyclophosphamide in patients who entered the trial with a severe disease flare

• There was no difference in severe or limited disease flares by 6 months

• There was no difference in severe adverse events rate by 6 months

• Fewer patients in the rituximab arm had ≥1 of the protocol-selected AEs by 6 months

NEJM 2010; 363:221-32

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Conclusions from RAVE

• Rituximab represents the first proven alternative to cyclophosphamide for remission induction in severe ANCA-associated vasculitis

• This is of particular importance for patients…

who present with a severe disease flare

who want to preserve their fertility

NEJM 2010; 363:221-32

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Another Randomized Controlled Trial: RITUXIVAS

• Randomized (3:1), controlled, open-label• 44 patients (older than in RAVE)• All ANCA-positive, all new diagnosis• All had severe renal disease (more severe than

in RAVE)• Comparing:RTX plus two infusions of CYC (N=33)Intravenous CYC for 6 months,

followed by oral AZA (N=11)• Everybody remained on ~10 mg of prednisone• Primary endpoint: sustained remission at 12 mo

NEJM 2010; 363:211-20

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Main RITUXIVAS ResultsNo difference between treatment arms of:• Mortality high: 18% in each arm• Sustained remission at 12 months: RTX 76% vs CYC 82% (ITT analysis) RTX 93% vs CYC 90% (of survivors)

• Time to remission: RTX - 90 days vs CYC - 94 days• Relapse rate• Time to relapse• Improvement of renal function• Adverse events rate

NEJM 2010; 363:211-20

Conclusion: over 12 months one course of RTX achieves the same results as 6 months of CYC followed by AZA.

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The King is Dead! Long Live the Queen!Does Anybody Still Need Cyclophosphamide in 2010?

• For remission induction in limited WG - NO• For remission maintenance - NO• For MPO-ANCA positive MPA with mild renal disease - PROBABLY

NOT (MMF instead - to be proven in a RCT)• For patients with severe WG or MPA, RTX is as effective (not inferior)

as CYC … maybe with an edge - NO• Young patients wanting to preserve fertility - Definitely NO• For remission induction in severe disease flares - NO• For patients who failed CYC or have contraindications for CYC, RTX

has become the de facto standard of care.• Patients who fail rituximab or don’t tolerate it - maybe some

CAUTION: Rituximab is an immunosuppressive agent!Infection risk seems similar to that of carefully monitored CYC followed by AZA