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What’s New in Lupus

MEDICINE OF THE HIGHEST ORDER. What’s New in Lupus. Jennifer H. Anolik, MD, PhD Associate Professor of Medicine Division of Allergy, Immunology & Rheumatology University of Rochester Medical Center 2011. Systemic Lupus Erythematosus.

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What’s New in Lupus

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  1. MEDICINE OF THE HIGHEST ORDER What’s New in Lupus Jennifer H. Anolik, MD, PhD Associate Professor of Medicine Division of Allergy, Immunology & Rheumatology University of Rochester Medical Center 2011

  2. Systemic Lupus Erythematosus • Inflammatory multisystem disease primarily seen in females (90%), but can be seen at any age in either sex • Highly variable course and prognosis, ranges from mild to life threatening • ~50% of patients can have severe internal organ involvement which can be life threatening without treatment • Characterized by flares and remissions • Associated with characteristic autoantibodies

  3. Updates • Treatments on the horizon • Diagnosis • Biomarkers • What causes lupus?

  4. What we’re doing at the U of R: Basic and Translational Research • The Rochester Autoimmunity Center of Excellence • University-wide NIH-funded multidisciplinary center • One of only 9 in the country • Ongoing Lupus projects in the division under this center (Sanz, Looney, Anolik) include: • Unraveling the mechanisms that underlie the breakdown of B-cell tolerance in SLE • Defining abnormalities in B cells in SLE • Biomarkers • Delineating the role of cytokines like interferon and BAFF in SLE • Understanding the immunological consequence of B-cell depletion and other targeted therapies in the treatment of SLE • Role of T and B cells in diabetes; Mechanisms of RA • Clinical Trials: Vitamin D (ALE02), cellcept discontinuation

  5. What we’re doing at the U of R: Clinical Cohorts • Lupus Clinical Trials Consortium • 20 centers • Infrastructure grants to support clinical trials • Collaborative Longitudinal Lupus Registry • Which medications are effective for which features of lupus? • How do lupus disease manifestations change over the course of time • How does lupus differ in various racial/ethnic groups and in different geographical areas?

  6. What we’re doing at the U of R: Clinical Trials • Investigation of new, targeted biological interventions in SLE • The AIR unit has an active program in clinical trials in systemic lupus erythematosus • B cell targeted therapies: rituximab, anti-BAFF, anti-CD22 • Antagonism of cytokines: IL6, interferon alpha • Blockade of co-stimulatory pathways: anti-ICOS, anti-ICOSL

  7. Why do we need clinical trials? • We need to know what works • We need better medications for lupus • Many lupus patients have progressive damage to vital organs • Many lupus patients have ongoing symptoms that limit function • Many lupus patients suffer toxicity from medications • We need FDA approval • We need to get insurance companies to pay for medications

  8. Steps for drug approval • Pre-clinical studies – Non-Human • Phase I studies – 1st time in humans <100 people • What are the side effects and what dose should be given? • Phase II studies – 100+ people • Does the drug work and are there other side effects? • Phase III studies – 1000+ people • Does the drug work and is it safe long term?

  9. New Treatments for Lupus • Why is it so difficult? • Lupus is hard to study: • Clinical expression is heterogeneous • Pathology is diverse • Disease activity is intermittent • Lack of agreed upon disease activity measures and endpoints • Small patient populations- rare disease • Development costs: Estimated $1 billion to take a drug from the research stage to FDA approval • Lack of a clinical trial infrastructure

  10. Recent work has focused on identifying biologic molecules critical to the lupus disease process and strategies to remove or neutralize them: ‘targets’ DC CD22 CTLA4 B7 CD20 T-cell B-cell CD40 TACI BCMA BAFFR CD40L FcRIIb

  11. Clinical trials in SLE • Company Agent Mechanism Outcome • ___________________________________________________________________________ • Biogen BG9588 Anti-CD154 SAEs • IDEC IDEC-131 Anti-CD154 Endpoints not met • Aspreva Cellcept Anti-metabolite Endpoints not met • HGS Belimumab Anti-BAFF Endpoints not met • LJP Abetimus Multivalent DNA Endpoints not met • Genentech Ritux (SLE) Anti-CD20 Endpoints not met • BMS Abatacept CTLA4-Ig Endpoints not met • UCB Epratuzumab Anti-CD22 Manufact. issues • Teva Edratide DNA idiotype Endpoints not met • Genentech Ritux (LN) Anti-CD20 Endpoints not met • HGS Belimumab Anti-BAFF Endpoints MET

  12. SLE Clinical Trials: Summary • Anti-B cell • Rituximab studies completed • Ocrelizumab in nephritis on hold (Roche; phase III) • TRU-015 small molecule anti-CD20 under development by Pfizer • Anti-B cell growth factors • Belimumab in non-renal lupus (studies completed) • Atacicept in non-renal lupus on hold (Serono; phase II) • Blisibimod (BAFF binder) (Anthera Phase Iib PEARL complete) Phase III P • LY2127399 (Eli Lily anti-BAFF) • Anti-interferon α • Anti-interferon α (Genentech; phase II completed) • MEDI-545 (Medimmune anti-IFN phase I completed, phase II ongoing) • Anti-costimulation • Anti-ICOSL (Amgen; initial studies completed; arthritis study to start) • Anti-ICOS (Medimmune, early stage) • Abatacept and cytoxan for nephritis: Phase II ITN • Other • Tacrolimus and cellcept in lupus nephritis www.clinicaltrials.gov

  13. SLE Clinical Trials: B cell targeted • Targeting B cell with anti-CD20 • Initial studies • Rituximab in general lupus (Genentech; phase II/III): completed • Rituximab in proliferative lupus nephritis (LN) (Genentech; phase II/III): completed • Ocrelizumab in LN (Roche; phase III): terminated • Other small molecular anti-CD20: in development • Cytokine blockade: BAFF blockade • Anti-CD22: phase IIb trial reported superior response rates compared to placebo at week 12 in recent press release; phase III EMBODY study starting

  14. Anti-CD22: Epratuzumab EMBODY • Phase 3 randomized by UCB • Moderate to severe disease activity (SLEDAI>6, BILAG A, 2 BILAG B) • Four 12 week treatment cycles 1:1:1 (2 treatment groups, 1 PB)

  15. SLE Clinical Trials: Costimulatory blockade • Targeting costimulation • CD28 • Abatacept plus standard of care (Bristol-Myers-Squibb; phase II/III): recently completed • Abatacept plus low dose cyclophosphamide in LN (NIH ITN) • ICOSL • AMG557 (Amgen; phase I)

  16. Abatacept for Treatment of SLE • Approved for the treatment of rheumatoid arthritis to treat joint pain and inflammation. • Great promise in murine SLE: reversal of disease, including synergy with cyclophosphamide (Daikh, Wofsy, Davidson et al.) • Long-Term Phase III Data On Investigational Biologic Orencia® (Abatacept) • Bristol-Myers Squibb, 6/23/2006

  17. Placebo (n=57) Abatacept (n=118) New BILAG A or B Flare* after Start of Steroid Taper and Over 1 Year (Primary Endpoint) 100 Treatment diff:–3.5 (–15.3, 8.3) 90 80 70 82.5% (47/57) 79.7% (94/118) 60 Patients with new BILAG A or B flare at any one visit (%) 50 40 30 20 10 0 *Adjudicated; ITT analysis; Relative risk and treatment difference adjusted for randomization strata using CMH methods

  18. Placebo Abatacept New Flare (Assessed by Treating Physician) Over 1 Year Treatment diff: –28.3 (–46.1, –10.5) Treatment diff: –11.3 (–35.6, 13.1) Treatment diff: –9.4 (–32.1, 13.3) Treatment diff: –19.3 (–30.6, –8.0) 100 90 80 70 82.5% 47/57 84.4% 27/32 60 Patients with new physician-assessed flare at any one visit (%) 78.9% 15/19 78.6% 11/14 50 63.6% 75/118 68.3% 28/41 83.3% 5/6 57.1% 36/63 40 30 20 10 0 Polyarthritis* Serositis* All patients Discoid lesions* Post-hoc analysis; *Primary manifestation at entry to the study

  19. SLE Clinical Trials: Cytokines • Targeting cytokines of pathogenic importance • Targeting Interferon α • Anti-interferon α (Genentech; phase I): enrollment complete, ROSE • Targeting IL6

  20. Ig Activated B Cell Hepatocyte HIG FIB AAT C-RP IL-6 Biological Activities IL2 Receptor Activated T Cell IL-6 Osteoclast Endothelial Cell Activation ICAM-1

  21. Anti-IL6 (Pfizer) Butterfly study • Well-tolerated in phase I studies in healthy volunteers and subjects with RA (92). • Never used in lupus but similar drug blocking the IL6R (tocilizumab) was well-tolerated in a small number of patients (16) except for reversible neutropenia • Phase 2 study evaluating the safety and efficacy of 3 doses of anti-IL6 compared to PB in 180 SLE patients with moderately active disease (1:1:1:1) (4 doses q8 wk x 24 wk)

  22. Targeting Plasma Cells • Autontibodies in lupus are frequently pathogenic • Current therapies often do not effectively decrease autoantibodies CFZ PR957 BTZ Proteasome inhibition IFN-alpha (pg/ml) No Tx PIs Proteasome inhibitor (nM) Ichikawa and Anolik Arthritis and Rheumatism 2011

  23. Important facts to know about participating in a clinical trial: • Your participation is your decision • You can withdraw from a study at any time and for any reason • All of your questions and concerns will be addressed and answered • Be confident that you understand the risks vs. benefits • What happens if you do experience an adverse event • Know the time requirements for participation • How much flexibility is there? • Be familiar with what happens at each study visit • Sometimes the amount of blood that is taken might be more than you are used to

  24. What questions should you ask? • Who is doing this trial? • Is the company experienced? • Is the investigator experienced? • How much is known about the drug? • Has this drug been approved for other diseases? • Has this drug already been used in lupus patients? • Has this drug been given to anyone before? • Has a similar drug been studied in humans?

  25. Your participation is important! • There are promising therapies that need to be tested • You don’t have to receive a drug to be involved in Clinical Research • Donate blood to a researcher who is studying Lupus • Companies may lose interest in developing drugs for SLE if trials cannot be completed • Recruitment is one of the biggest obstacles

  26. Diagnosis

  27. Lupus Diagnosis: ACR Criteria • CLINICAL • Butterfly rash (face) • Discoid rash (anywhere on body) • Photosensitivity • Oral or nasal ulcers • Arthritis • Serositis (fluid around lungs or heart) • Kidney disease • Brain disease (seizures or psychosis) • LABORATORY • Low blood cell counts (white, red, platelets) • Antinuclear antibodies • Specific autoantibodies (anti-DNA, anti-Sm, antiphospholipid) Definite diagnosis of lupus: 4 of 11 criteria present

  28. Early signs of lupus Clinical criteria for systemic lupus erythematosus precede diagnosis and associated autoantibodies are present before clinical symptoms Arthritis & Rheumatism, Volume 56, Issue 7, July 2007, pp. 2344-235; Arbuckle NEJM 2005

  29. Biomarkers

  30. FDA Biomarker symposium • Indicators to monitor disease diagnosis, progress and treatment succcess • Meeting at the FDA in September focusing on the development of biomarkers to predict acute worsening of disease, called a flare, and their potential for accelerating lupus clinical trials and new drug approvals Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus. Kao AH, Navratil JS, Ruffing MJ, Liu CC, Hawkins D, McKinnon KM, Danchenko N, Ahearn JM, and Manzi S. (2010). Arthritis & Rheumatism 62: 837-844

  31. Interferon dysregulation • Interferon is a key dysregulated cytokine in lupus • Recent serum chemokine (IFN regulated) test that can predict flare now licensed for commercial development • Gene expression transcriptional finger-prints Baechler-Gillespie, Arthritis and Rheum 2009 Pascual, Immunity 2008

  32. Kidney biomarkers • Renal biopsy is the gold standard for diagnosis of renal disease in lupus but is invasive • Two novel and non-invasive tests using biomarkers to assess kidney disease in lupus recently reported • Kidney MRI combined with a novel MRI contrast agent in mice allowed detection of proteins deposited in the kidneys as part of the immune system’s attack, correlation between the amount of these proteins and the severity of kidney inflammation • Urine proteome in diseased mice: identification of 4 promising biomarkers; Cytokines and chemokines in the SLE patient urine elevated in nephritis Thurman, Kidney International 2011 Putterman and Mohan, JI 2010

  33. Is there a biomarker for SLE patients who do well long term after rituximab? • In long term followup a subgroup of patients had complete remission: only anti-dsDNA vs. patients with anti-RBPs • B cell biomarkers • Complete depletion of B cells as measured by high sensitivity flow is associated with better response, memory B cell and plasmablast repopulation was faster in those relapsing Vital…Emery, Arthritis and Rheum 2011

  34. B cell Biomarkers M T T Naive M N M SLE Short-term responder SLE Long-term responder Healthy adult Neonate T M N CD24 CD38 Fraction of IL10 producing B cells increases Anolik et al. Arthritis and Rheumatism 56:3044, 2007, 2009; Anolik et al. ACR 2011

  35. What causes lupus?

  36. MRL-lpr/lpr JH-/- T-cell activation Tissue infiltration B-cells Serum Ab Disease - - - - B Cells are Postulated to Play Multiple Roles in SLE Pathogenesis • Production of self-reactive antibodies • Secretion of inflammatory cytokines • Antigen presentation • Augmentation of T cell activation • Generation of ectopic lymphogenesis MRL-lpr/lpr T-cell activation Tissue infiltration B-cells Serum Ab Disease + + + +

  37. Peripheral blood B cell abnormalities in SLE 110 SLE 18 HC Cosine Distance Average Linkage Heat map rows=cell populations Heat map columns=samples MEM + TRANS DNA RNP Sm Ro CNS La GI flare / high-SLEDAI Hematologic Musculoskeltal Nephritis Pulmonary 3 Quiescent SACQ Cellcept Serositis 0 Plaquenil Skin Imuran Vasculitis Fk Enbrel -3 Methotrexate Medrol Rituxan Anti-BAFF Cytoxan We are studying B cell abnormalities as biomarkers of: *Disease activity *Prognosis *Treatment response High Prednisone Anolik and Sanz URMC / JHU HC LOW SLEDAI HIGH SLEDAI

  38. A Balanced B cell Compartment Protective B cell functions Pathogenic B cell functions Pathogenic B cell functions Protective B cell functions Disease remission Treatment failure and/or disease exacerbation Plasmablasts HC SLE CD27 CD38

  39. Newer cellular players of the innate immune system • Plasmacytoid dendritic cells (PDCs) • Generate too much type 1 interferons — a contributing cause of lupus and other autoimmune diseases • Two immune system proteins toll-receptors named TLR7 and TLR9 make conditions worse by activating additional PDCs. Steroids act in part by killing PDCs and TLR activation can abate this effect • Blocking agents for TLR7 and TLR9 are already in development and are expected to be ready for clinical trials soon • Neutrophils • Key first line of defense • Neutrophil gene signature • Activation of PDCs by neutrophils- NETosis with release of DNA causing TLR activation Pascal and Barratt, Nature 465, 2010; Bosch, NEJM 2011

  40. NETosis

  41. EBV? Baseline immunological abnormalities Infection Hormonal factors Abnormal (control of) immune responses SLE SLE - Etiology • The etiology of SLE remains unknown • Yet, SLE is clearly multifactorial: • Genetic factors • Immunologic factors • Hormonal factors • Environmental factors Genetic predisposition

  42. Genetics and Lupus • Lupus is more common in families with lupus or other immune system diseases; twin data • Some groups, such as African Americans, Hispanics, and Asians get lupus more commonly and with more severe symptoms • Intense efforts: SLEGEN- consortium to conduct large genome wide association studies with 2.5 million genetic markers • ImmunoChip: technology offers the ability to study 250,000 genes and their variants in each of a large number of participants • Over 40 SLE associated genes identified Kaiser and Criswell, Curr Opin Rheum 2010

  43. Some Take Home Messages • Treatment in the future may be driven by the patient’s genetic makeup: personalized medicine • The pathogenesis of SLE is complex with dysregulation of multiple arms of the immune system • Despite improvement in mortality, new treatments are needed given resistant disease and the side effects of current immunosuppressives • A number of biologic molecules critical to the lupus disease process are emerging as logical targets for treatment • Information about disease pathogenesis is leading to targeted biologic therapies

  44. Learn More • www.lupusresearch.org/research/research_update.html • LupusTrials.org • www.clinicaltrials.gov • www.niams.nih.gov/Health_Info/Lupus/ • The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has developed a strategic plan for reducing health disparities. Lupus is included as an area of research focus. Further information on disparities in lupus and the strategic plan is available at: http://www.niams.nih.gov/an/stratplan/strategicplanhd/strategicplanhd.htm • Some references: Targeted therapies in systemic lupus erythematosus: successes, failures and future. Hahn BH. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i64-i66. Review.; The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i37-43. Review.; Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside.Curr Opin Rheumatol. 2011 May;23(3):305-10; B-cell biology and related therapies in systemic lupus erythematosus. Ahmed S, Anolik JH. Rheum Dis Clin North Am. 2010 Feb;36(1):109-30, viii-ix.

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