New Treatments for Lupus by Daniel J. Wallace, MD


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A presentation by Daniel J. Wallace, MD from Lupus LA's 4th Annual Patient Education Conference at Cedars-Sinai in Los Angeles, CA.

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  • New Treatments for Lupus by Daniel J. Wallace, MD

    1. 1. NEW THERAPIES FOR SLE <ul><li>DANIEL J WALLACE MD </li></ul><ul><li>Clinical Professor of Medicine </li></ul><ul><li>Cedars-Sinai Medical Center </li></ul><ul><li>David Geffen School of Medicine at UCLA </li></ul>
    2. 2. 2005 FDA Guidance Document for SLE <ul><li>The drug is safe </li></ul><ul><li>Clinical indices must be improved (BILAG+ either SLEDAI, SLAM or ECLAM) </li></ul><ul><li>Clinical response index (e.g., RIFLE) </li></ul><ul><li>Quality of life improvement </li></ul><ul><li>ACR/SLICC Damage Index </li></ul><ul><li>Organ specific measures </li></ul><ul><li>Subpart H: surrogate markers or biomarkers </li></ul>
    3. 3. SLEDAI (Systemic lupus disease activity index) <ul><li>Evaluates 24 components and emphasizes organ activity as opposed to laboratory abnormalities </li></ul><ul><li>105 possible points---64 of which are central nervous system and 16 are renal </li></ul><ul><li>Anti DNA, C3, Leukopenia, Thrombocytopenia are the only blood determinations and if all abnormal account for only 6 points </li></ul><ul><li>Does not include: hemolytic anemia, pulmonary hypertension, TTP, mesenteric vasculitis, pulmonary hemorrhage </li></ul><ul><li>SLEDAI Flare Index requires a change of 4 points </li></ul>
    4. 4. BILAG (British Isles Lupus Assessment Group) <ul><li>8 organ systems with 86 items weighted as 0-4 (not present to new or improved) </li></ul><ul><li>Organ systems: constitutional, musculoskeletal, renal, nervous system, hematologic, cutaneous, cardiopulmonary, eye, gastrointestinal </li></ul><ul><li>Rated A-E (life threatening to not present) </li></ul><ul><li>BLIPS software </li></ul><ul><li>End points as new BILAG A or B </li></ul>
    5. 5. Clinical validation of the CLASI <ul><li>An ACR and dermatology group derived the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) (J Inv Derm 2005; 125:889-94) for use in assessing skin scores in clinical trials (analagous to the PASI for psoriasis) fulfills the FDA guidance document’s requirements for validated organ specific measures in following lupus patients </li></ul><ul><li>Index contains weighted anatomic locations, activity (erythema, scale/hypertrophy), damage (dyspigmentation, scarring, atrophy, panniculitis), mucous membranes and alopecia </li></ul><ul><li>First attempt to validate it (abst #1010) in a pilot study of 9 patients at U of Penn given drug interventions was promising but needs much greater experience </li></ul>
    6. 6. Newer agents for SLE <ul><li>Mycophenolate mofetil </li></ul><ul><li>Topical pinecrolimus and tacrolimus </li></ul><ul><li>Tacrolimus </li></ul><ul><li>Leflunomide </li></ul><ul><li>Infliximab and other TNFi </li></ul>
    7. 7. Lupus Nephritis <ul><li>Cost </li></ul><ul><ul><li>Direct medical costs are 4x higher for lupus nephritis pts compared with SLE pts without nephritis ($19,250–$42,174/yr vs $4700–$10,015/yr) </li></ul></ul><ul><ul><li>Extra costs due to hospitalizations and/or dialysis </li></ul></ul><ul><li>Response to standard therapy </li></ul><ul><ul><li>80% respond to IV cyclophosphamide </li></ul></ul><ul><ul><li>35% relapse rate </li></ul></ul><ul><ul><li>10% dialysis </li></ul></ul><ul><li>Poor prognostic factors </li></ul><ul><ul><li>AA race does not respond as well to IV cyclophosphamide </li></ul></ul><ul><ul><li>Poor initial response </li></ul></ul><ul><ul><li>Renal relapse </li></ul></ul>Houssiau F, 71 st ACR , Boston 2007, ACR Clinical Symposium; Clarke A. ibid , #503; Li T, et al. ibid , #1255;Ginzler E, #L13 <ul><li>Efficacy and safety study to demonstrate superiority of MMF over IVCy in Lupus nephritis (WHO III, IV) </li></ul><ul><li>Induction protocol (370 pts randomized to one of two therapies for 24 wks) </li></ul><ul><ul><li>MMF 3 g/d (185 pts) </li></ul></ul><ul><ul><li>IV cyclophosphamide 0.5–1.0 g/m 2 monthly (185 pts) </li></ul></ul><ul><ul><li>All pts received prednisone 60 mg/d with taper </li></ul></ul><ul><li>Response: stable/improved Cr and improved proteinuria </li></ul>Aspreva lupus management study (ALMS)
    8. 8. ALMS: Efficacy and Safety Results <ul><li>Conclusions </li></ul><ul><ul><li>MMF equal to IVCy for induction </li></ul></ul><ul><ul><li>AA and Hispanics may respond better to MMF than to IVCy </li></ul></ul><ul><ul><li>Safety </li></ul></ul><ul><ul><ul><li>MMF: 24 AEs; 12 infections; 9 deaths (7 from infection) </li></ul></ul></ul><ul><ul><ul><li>IVCy: 13 AEs; 4 infections; 5 deaths (2 from infection) </li></ul></ul></ul>Ginzler E, et al . 71 st ACR , Boston 2007, #L13 38.8 (p=0.011) 38.5 (p=0.033) 54/64 (p=NS) 53 (p=NS) IVCy 60.9 60.4 56/53 56 MMF Hispanic (%) AA (%) Caucasian/Asian (%) Total (%)
    9. 9. Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells, CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
    10. 10. How are T-cells activated? <ul><li>CD80/86:CD28 is one of the best characterized co-stimulatory pathways </li></ul><ul><ul><li>Signal 2 </li></ul></ul>CD80/86:CD28 facilitates T-cell activation, proliferation, survival and cytokine production CD28 constitutively expressed on T-cell surface; CD80/86 on APC binds CD28 on T-cell = signal 2 Site of action of abatacept Antigen CD28 Activated T-cell
    11. 11. Survival of Lupus Mice Treated with CTLA4Ig and Anti-CD40L Wang et al. J Immunol. 2002;168:2046–2053. Control CTLA4Ig/anti-CD40L CTLA4Ig Anti-CD40L Weeks % Alive 28 38 48 58 68 78 88 100 80 60 40 20 0
    12. 12. Phase 2 Trial of Abatacept <ul><li>Randomized, double-blind, placebo-controlled, phase 2 study </li></ul><ul><li>Abatacept compared with Placebo on a background of oral glucocorticosteroids for subjects with SLE and the prevention of subsequent lupus flares </li></ul><ul><li>Primary objective of this study will be to assess the proportion of subjects with new clinical flare of SLE (BILAG &quot;A&quot; or &quot;B&quot;) during the 1 year double-blind treatment period </li></ul><ul><li>Secondary objective of this study will be to assess proportion of subjects with a new clinical flare of SLE (BILAG A or B) within the initial 6 months of the double-blind treatment period and evaluate the proportion of subjects who during the study experienced a BILAG A or B flare </li></ul><ul><li>Expected Total Enrollment is 180 </li></ul>Source: Accessed January 29, 2007.
    13. 13. T-lymphocyte co-stimulatory modulation: Importance of the T-cell subsets Adapted from Janeway CA Jr, et al. Immunobiology: The Immune System in Health and Disease. 6th e. New York, NY: Garland Science Publishing: 1994. p347 CTLA-Ig Less dependent CTLA-Ig More dependent Anti-viral / anti-tumor immunity CD8 T-cells: Peptide + class I CD4 T-cells: Peptide + class II Inflammation / Ab production T T Dougados M, et al. EULAR 2007, Barcelona, #SP0068
    14. 14. T-lymphocyte costimulatory modulation consequences <ul><li>Activation of the co-stimulation </li></ul><ul><ul><li>Anti-tumoral effect? </li></ul></ul><ul><ul><li>Autoimmune disorders </li></ul></ul><ul><li>Inhibition of the costimulation? </li></ul><ul><ul><li>Pro-tumoral effect? </li></ul></ul><ul><ul><li>Prevention of autoimmune disorders? </li></ul></ul>Dougados M, et al. EULAR 2007, Barcelona, #SP0068
    15. 15. Selective co-stimulation modulators in clinical development ** * in Rilex, June 2005; * in Dillon 2006 Dougados M, et al. EULAR 2007, Barcelona, #SP0068 Tumors CD28 agonist Myeloma CC-5012 (CD28 activator) Renal cancer Leukemia Anti-CD28 (TGN1412) Tumors Anti-CLA-4 (Ipilimumab, ticilimumab) Activation Crohn's disease Multiple sclerosis Anti- α 2 integrine (natalizumab) RA BR3-Fc SLE RA Anti-BAF (AM6, G3) SLE, Multiple sclerosis RA, Lymphoma TACI-Ig SLE RA Anti-BAFF (belimumab) SLE Psoriasis Anti-CD80 Organ transplantation Anti-CD80/86 Organ transplantation LEA29Y (belatacept) Juvenile Chronic Arthritis, Multiple sclerosis RA (registration) SLE CTLA-4 Ig (abatacept) Inhibition Human diseases Co-stimulation modulator
    16. 16. Targeted therapeutics: Approaches in SLE Ng KP, et al. EULAR 2007, Barcelona, #OP0020 APC T B Y CTLA4-Ig  CD22 B-cell toleragen  BlySS TACI-IG  CD20  IL-10 Peptide Antibody IL-10 Apoptotic material 1 2 Costimulatory Factors, eg, BlyS
    17. 17. Potential targets in B-cell lineage Antigen Independent Phase Antigen Dependent Phase Targets for BLyS/BAFF inhibitors Targets for Rituximab, Ocrelizumab, Ofatumumab CD45 (AKA B220) surface marker Activated B-cell Plasma cell Secreted IgG, IgA, IgE, or IgM Mature B-cell Pro-B-cell Pre-B-cell Immature B-cell Surrogate light chain D H J H IgM IgM I g D Antigen IgM, IgD, IgA, or IgE CD40L and cytokines CD40 V H D H J H V L J L Adapted from Sell S, et al. Immunology, Immunopathology, and Immunity . 6th ed. Washington, DC: ASM Press; 2001
    18. 18. Uncontrolled Data of Rituximab in SLE and SS <ul><li>Two placebo-controlled trials underway in SLE (SS?) (EXPLORER and LUNAR) </li></ul><ul><li>9 uncontrolled studies presented in lupus and Sjogren’s </li></ul><ul><li>New insights from in uncontrolled studies include: </li></ul><ul><ul><li>NK cell levels surge just as B-cell recovery begins </li></ul></ul><ul><ul><li>Persistence of B-cells predicts a poorer outcome </li></ul></ul><ul><ul><li>Drug may be more effective when used with CTX </li></ul></ul><ul><ul><li>In membranous nephritis, rebiopsy shows resorption of immune depositions </li></ul></ul><ul><ul><li>20% with SLE develop with HACA (3x that reported with RA) </li></ul></ul><ul><ul><li>Responses can last up to 1 y. 1/3 don’t require further immune suppressive Rx </li></ul></ul><ul><ul><li>16 patients with primary Sjogren’s: salivary gland B-cell morphology returned to baseline after 18 months (ISRs and serum sickness reported in some pts) </li></ul></ul><ul><ul><li>Drug is safe in children with lupus </li></ul></ul>Ng KP, et al. ACR, Washington DC 2006, #536; Tanaka Y , et al. ibid , #537; Gunnarsson I , et al. ibid , #538; Jónsdóttir T , et al. ibid , #539; Luning Prak ET , et al. ibid , #540; Dass S , et al. ibid , #541; Pers JO , et al. ibid , #1770; Gunnarsson I , et al. ibid , #2097
    19. 19. B-cell depletion is variable Anolik JH, et al. EULAR 2007, Barcelona, #SP0033 0.1 1 10 100 0 3 6 9 12 Months CD19+ (lymphocytes/uL) Non-depleters (n=6) Depleters (n=11) Recovery to 60% of baseline at 12 months Full recovery at 2–3 years in all but 1
    20. 20. Ocrelizumab: Humanized anti-CD20 mAb is effective in RA – 24 Week Phase 1/2 1 <ul><li>237 patients: All RF+; IR to MTX: </li></ul><ul><ul><li>Ocrelizumab 10, 50, 200, 500, 1000 mg IV Day 1 and 15 or Pbo </li></ul></ul><ul><li>Dose dependent B-cell depletion and increases in serum BAFF ² </li></ul><ul><li>Most frequent AEs: infusion-associated HA, nausea, chills, pyrexia, dizziness </li></ul><ul><ul><li>SAEs and SIEs similar between active and placebo </li></ul></ul><ul><li>HAHAs Wk 24: 10mg: 19%; 50mg: 10%; 200mg: 0; 500mg: 0; 1000mg: 2.5% </li></ul><ul><li>Conclusions: </li></ul><ul><ul><li>No apparent dose response </li></ul></ul><ul><ul><li>progressing to phase 2/3 </li></ul></ul>1. Genovese M, et al. EULAR 2007, Barcelona, #SAT0008; 2. Manning W, et al. ibid, #SAT0018 ACR response EULAR response
    21. 21. Synthetic anti-CD 20 – TRU-015: Ongoing Phase II RCT <ul><li>CD20-directed SMIP (single-chain polypeptides), smaller than antibodies </li></ul><ul><li>Mediates ADCC and CDC </li></ul><ul><li>36 patients w/ active disease despite MTX </li></ul><ul><li>5 mg/kg IV x1 or 2.5 or 7.5 mg/kg IV q week x2 </li></ul><ul><li>Study ongoing; interim data </li></ul><ul><li>Generally well tolerated </li></ul><ul><li>No infectious or non-infectious SAEs </li></ul><ul><li>B-cell depletion in all cohorts </li></ul><ul><li>B-cell recovery starts at 16 weeks </li></ul>ACR20 at Week 24 Burge DJ, et al. ACR, Washington DC 2006, #463
    22. 22. Mechanism of Anti-CD20 (Rituximab) and Anti-CD22 (Epratuzumab) Monoclonal Antibodies <ul><li>Antibody-dependent cell-mediated cytotoxicity </li></ul><ul><li>Complement-dependent cytotoxicity </li></ul><ul><li>Apoptosis </li></ul><ul><li>Modest antibody-dependent cell-mediated cytotoxicity </li></ul><ul><li>No complement-dependent cytotoxicity </li></ul><ul><li>Immunomodulatory and antiproliferative effect </li></ul>Anti-CD20 MAb Rituximab Chimeric IgG1 κ Anti-CD22 MAb Epratuzumab Humanized IgG1 Carnahan et al. Mol Immunol . 2007;44:1331–1341. CD22 CD20 B cell
    23. 23. B-cell–targeted therapies <ul><li>Anti-CD20 agents: </li></ul><ul><ul><li>Rapidly deplete peripheral B-cells via ADCC and CDC </li></ul></ul><ul><ul><li>First dose infusion reactions due to rapid cell death, cytokine release </li></ul></ul><ul><ul><li>Immunogenicity in part related to cell death/debris </li></ul></ul><ul><ul><li>Despite fully human or SMIP -single chain polypeptides, smaller than antibodies ; expect immunogenicity </li></ul></ul><ul><li>B-cell growth factors (BLyS/BAFF/APRIL) antagonists </li></ul><ul><ul><li>Slower depletion of B-cells </li></ul></ul><ul><ul><li>Peripheral and germinal center B-cells undergo apoptosis due to absence of growth factors </li></ul></ul><ul><ul><li>Onset of benefit generally occurs over 3-6 months </li></ul></ul><ul><ul><li>Less severe infusion reactions </li></ul></ul><ul><ul><li>Less immunogenicity </li></ul></ul>
    24. 24. B-cell growth factors Ligands Receptors BAFF-R BCMA TACI BLyS APRIL Heterotrimer Proteoglycans <ul><li>Increased B-cell survival Costimulation of B-cell prolferation </li></ul><ul><li>Ig class switch recombination </li></ul><ul><li>Enhanced APC function </li></ul><ul><li>Germinal center formation </li></ul><ul><li>Regulation of B-cell tolerance </li></ul><ul><li>Sequester APRIL at cell surface to improve TACI and/or BCMA signalling? </li></ul><ul><li>Mediate plasma cell trafficking </li></ul>Issacs JD, et al. EULAR 2007 , Barcelona #SP0069
    25. 25. Belimumab (lymphoStat-B) <ul><li>Fully-human monoclonal antibody </li></ul><ul><li>Selectively targets and inhibits soluble BLyS </li></ul><ul><ul><li>TNF family member that promotes B-cell differentiation, proliferation, and survival </li></ul></ul><ul><ul><li>Plays critical role in physiologic B-cell development and induces B cells to secrete immunoglobulins </li></ul></ul><ul><li>Inhibition of BLyS can result in autoreactive B-cell apoptosis </li></ul>
    26. 26. Systemic Lupus: Belimumab <ul><li>Phase 2: 52-week, randomized, double-blind, placebo-controlled trial. </li></ul><ul><li>n=449…but subset analysis using 71.5% of patients defined by ANA>1:80 or dsDNA >30 IU. Moderately ill SLE: baseline mean SELENA SLEDAI= 9.6. </li></ul>Ginzler E, et al. EULAR 2007, Barcelona, #OP0018
    27. 27. Belimumab reduced CD20+ B cells by 61% at Week 76 p<0.01 for the comparison between all active vs placebo from Day 56 through Day 364 Furie R, et al. ACR, Washington DC 2006, #535; Wallace D, et al. ibid , #2012; Stohl W, et al. ibid , #1985
    28. 28. Novel combined endpoint* <ul><li>> 4 point improvement in SELENA SLEDAI score </li></ul><ul><ul><li>AND </li></ul></ul><ul><ul><li>No new BILAG 1A/2B flares </li></ul></ul><ul><ul><li>AND </li></ul></ul><ul><ul><li>No worsening in Physician’s Global Assessment (<0.3 point increase) </li></ul></ul>Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 * Accepted by Regulatory Authorities for Phase 3 Trials
    29. 29. Combined response rate for belimumab patients significantly higher Ginzler E, et al. EULAR 2007, Barcelona, #OP0018 46% combined response rate for serologically active patients on belimumab vs 29% for placebo at Week 52 56% combined response rate for patients on belimumab at Week 76 * p=0.0059 at Week 52, p=0.02 at Week 56 0 10 20 30 40 50 60 70 0 28 84 140 224 280 336 392 476 532 Visit day Responder rate in serologically active pts (%) Placebo Placebo to 10 mg/kg All active
    30. 30. Atacicept inhibits the function of BLys and APRIL <ul><li>Atacicept is a fusion protein formed between the extracellular domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1 </li></ul>Atacicept Extracellular domain of TACI receptor Fc domain of human IgG rDNA technology B-cell
    31. 31. Systemic Lupus: Atacicept (TACI-Ig) <ul><li>2 Phase I studies of PK and biologic activity </li></ul><ul><li>Appears tolerated and safety is favorable </li></ul><ul><li>Good signs of biologic effects on B-cells whether IV or SC </li></ul><ul><li>Interestingly, measured atacicept-BLys complexes in peripheral blood </li></ul><ul><li>Further development and trials are planned </li></ul>
    32. 32. Phase I trials for lupus: Tociluzimab <ul><li>anti-IL-6R mAb </li></ul><ul><li>Phase I: 16 patients, 6 doses over 12 weeks (3 dosing regimens) </li></ul><ul><li>Safety signals </li></ul><ul><ul><li>Significant decrease in absolute neutrophil count in 60% of patients at highest dose </li></ul></ul><ul><li>Significant decreases noted in IgG and ds DNA Abs </li></ul><ul><li>Significant improvement in SLEDAI and SLAM scores </li></ul>1. Illei G, et al. ACR, Washington DC 2006, #L20; 2. Dall'Era M, et al. ibid , #L19
    33. 33. Mechanism of LJP 394 (Abetimus) <ul><li>Novel synthetic putative B-cell toleragen </li></ul><ul><ul><li>Four double-stranded oligodeoxyribonucleotides plus non-immunogenic PEG carrier </li></ul></ul><ul><ul><li>Acts as anti-anti DNA to reduce anti-dsDNA antibodies in SLE patients </li></ul></ul><ul><ul><li>Awaiting results of phase III study with an endpoint of time to nephrotic flare </li></ul></ul>Alarcon-Segovia et al. Arthritis Rheum . 2003;48:442-453. Furie. Rheum Dis Clin North Am . 2006;32:149-156. B cell B-cell receptor B-cell toleragen
    34. 34. Cumulative Renal Flare in Phase 3 Cumulative renal flares by week 32 59 82 98 118 153 Placebo 27 50 67 81 111 145 LJP394 88 64 48 32 16 Week 0 Patients
    35. 35. Tolerance Mechanisms: Edratide (TEVA) Tsubata et al. Autoimmunity . 2005;38:331-337. Bone Marrow Peripheral lymphoid organs Reactive to self antigens Self antigen Deletion T-cell zone Self antigen Deletion Anergy Receptor editing Self antigen Deletion Follicle B cell BCR B cell BCR B cell BCR B cell BCR B cell BCR
    36. 36. Innate Immune Responses in SLE <ul><li>Toll-like receptors 7 and 9 in immature DC activated by complexes of self protein + RNA (TLR7) and DNA (TLR9) </li></ul><ul><li>These complexes are normally rapidly cleared, but accumulate in SLE </li></ul><ul><li>Clearance defects in mice or humans -> SLE </li></ul><ul><li>Activation of TLR7/9 induces immature DC secretion of IFN- α immature DC induce T and B cell responses against the RNA and DNA and associated proteins </li></ul>IFNg IL-10 BlyS TNFa IL-1 IL-12 Activated B cell Activated T cell B cell T cell Mature DC Activated mono/macrophage Immature DC INCREASED IFN  Bacteria Viruses SLE DNA/IC CpG DNA ssRNA dsRNA Immune complexes in SLE bind TLR7 and 9
    37. 37. Induction of type I Interferon pathway through Toll-like receptors TLR3 TLR4 TLR7/8 TLR9 Inflammatory Cytokines Type I Interferon Inflammatory Cytokines Inflammatory Cytokines Type I Interferon Potential Endogenous Ligands: dsRNA ∞ RNA-containing Immune Complexes Fibronectin Products CpG DNA-containing Immune Complexes Exogenous Ligands: LPS ssRNA Demethylated CpG DNA dsRNA-containing Immune Complexes TRAM TIRAP Trf Trf MyD88 MyD88 MyD88
    38. 38. Toll-like Receptors in RA and SLE <ul><li>In RA </li></ul><ul><ul><li>increased TLRs 3, 4, 7 on dendritic cells (DC) 1 </li></ul></ul><ul><ul><li>increased viral ds-RNA in joints compared with OA 2 </li></ul></ul><ul><li>In mouse models arthritis </li></ul><ul><ul><li>TLR 2 deficiency decreased susceptibility to arthritis, </li></ul></ul><ul><ul><li>TLR4 deficiency decreased severity, erosions </li></ul></ul><ul><ul><li>Abs to TLR 4 prevented arthritis 1 </li></ul></ul><ul><li>DS-RNA arthritogenic when injected into mouse joint, mediated by type 1 IFN from DC 2 </li></ul><ul><li>CpG DNA sequences, common in bacterial DNA bind TLR 7 and 9 in DCs and B cells. </li></ul><ul><li>Lupus immune complexes bind TLR 7 and Fc γ on DC, releasing cytokine and IFN 3 </li></ul><ul><li>Antimalarials block the activation TLR 7 and 9 </li></ul><ul><li>IFN increase SLE flares and increased in SLE serum </li></ul><ul><li>IFN signaling molecule Stat1 upregulated in SLE 4 </li></ul><ul><li> Genentech, Coley and MEDI-545 clinical trials </li></ul>1. Radstake TR, et al. EULAR 2007 , Barcelona, #SP0136; 2. Magnusson M, et al. ibid, #SP0112; 3. Richez C, et al. EULAR 2007 , Barcelona #OP0179; 4. Karonitsch TM, et al. ibid, #OP0178; 5. Means TK, et al. J Clin Infect 2005;115:407 RA SLE
    39. 39. Hydroxychloroquine, “Antimalarials” are TLR Antagonists <ul><li>Hydroxychloroquine and other “antimalarials” have been used in treating SLE and RA for decades, but MOA was unknown </li></ul><ul><li>Recent discovery: these antimalarials are TLR7/8/9 antagonists at clinically relevant doses </li></ul><ul><li>New approach to treatment – develop improved TLR antagonists </li></ul><ul><ul><li>Small molecule </li></ul></ul><ul><ul><li>Orally available </li></ul></ul>
    40. 40. CPG 52364 showed dose-dependent inhibition of TLR9-mediated IP-10 induction in mice Female adult BALB/c mice (n=5/gp) received different doses of CPG 52364 or chloroquine by IP injection. At 1 h post dose, animals received 100µg CpG-DNA ODN subcutaneously. Plasma was collected at 3 h post agonist injection and used for IP-10 assay by ELISA. Value are presented as percent mean TLR9 agonist activity.  
    41. 41. Hydroxychloroquine (HCQ) and Toll Receptors <ul><li>TLRs 7, 8 and 9 are activated inappropriately by endogenous RNA and DNA in SLE. This is inhibited by HCQ, which was thought to work primarily by diminishing antigen presentation </li></ul><ul><li>Mice were treated with HCQ for 5 days. TLR9 activation was strongly inhibited (and to a lesser extent TLR 7). Ag presentation was incompletely blocked. </li></ul><ul><li>The TLR mechanism is more important than antigen presentation inhibition and TLR antagonists represent a novel approach for SLE therapeutics </li></ul>Weeratna R, et al. 71 st ACR , Boston 2007. #1310
    42. 42. SLE is a Disease of TLR-Driven Amplification of Autoimmunity Dendritic Cells TLR7+ / 8+ / 9+ B cells TLR9+ / TLR7 Inducible Cytokine/Chemokine Induced Activation/Maturation And Damage Apoptotic debris Self-antigen Autoimmune Complex-Driven TLR Cellular Activation TLR signal Anti-self response Cytokine/chemokine Tissue Damage End Organ Failure Inflammation CPG 52364 TLR7/8/9 Antagonist X Complex uptake X CPG 52364 (Coley) is a TLR 7,8,9 antagonist in a Phase I trial with similar actions to hydroxychloroquine Akira S, et al . Nat Imunol 2001;2:675; Lipford G , et al. 71 st ACR, Boston 2007. #1596 T-cell NK cell
    43. 43. Interferons and Systemic Lupus Erythematosus <ul><li>Type I interferons (IFNs) may play a critical role in the pathogenesis of systemic lupus erythematosus (SLE) </li></ul><ul><ul><li>Serum IFN-α levels are elevated in patients with SLE 1 </li></ul></ul><ul><ul><li>Increased expression of type I IFN-induced genes in blood and involved tissues in SLE 2 </li></ul></ul><ul><ul><li>Correlation between IFN levels and expression of type I IFN-induced genes and SLE activity 1,3 </li></ul></ul><ul><ul><li>Development of SLE in patients undergoing IFN-α treatment 4 </li></ul></ul><ul><ul><li>Inhibition of IFN-α may provide therapeutic benefit in the treatment of SLE </li></ul></ul>1 Hooks JJ, et al . New Engl J Med . 1979;301:5-8; 2 Crow M. Arthritis Rheum. 2003;48:2396-2401; 3 Dall’era MC, et al . Ann Rheum Dis. 2005;64:1692-1697; 4 Ioannou Y, Isenberg DA. Arthritis Rheum. 2000;43:1431-1442.
    44. 44. MEDI-545 (Medimmune/AstraZeneca) <ul><li>Fully human anti–IFN- α IgG1k monoclonal antibody </li></ul><ul><li>Inhibits IFN-a signaling through IFN- α receptor (IFNAR) </li></ul><ul><li>Double-blind, placebo-controlled phase I trial of single escalating dose, intravenous MEDI-545 (0.3–30 mg/kg) in patients ≥18 years old with SLE </li></ul><ul><ul><li>2:1 randomization, 84-day follow-up </li></ul></ul><ul><li>There was no safety signal observed </li></ul><ul><li>Effects of MEDI-545 on neutralization of type I IFN gene signature in blood and skin and on disease activity were explored </li></ul>Wallace D, et al . 71 st ACR, Boston 2007. #1315 IFN-a IFNAR1 IFNAR2 P STAT2 P STAT2 P STAT1 P Tyk2 STAT1 P Jak1 IRF-9 IRF-9
    45. 45. MEDI-545 Reduces Type I IFN Gene Signature, Type I IFN–Induced Proteins in Skin, and Improves Disease Activity Day 14 Skin, day 0–28 5/17 29% 1/33 3% MEDI-545 Placebo 0 20 30 40 Pts, N 10 >3 point increase in SLEDAI score <3 point increase in SLEDAI score P =0.0136 Wallace D, et al . 71 st ACR, Boston 2007. #1315 Type I IFN–induced proteins in skin Change in protein Change in transcript 20% 97% 75% 99% 87% 99% HERC5 ISG15 IP10 Improvement in disease activity Day 0 Day 14
    46. 46. MEDI-545 Can Normalize Type I IFN Gene Signature in Blood: Heat Map of Gene Expression Day Neutralization Wallace D, et al . 71 st ACR, Boston 2007. #1315 Calculation based on top 25 type I IFN–inducible genes upregulated in whole blood of one patient treated with 30 mg/kg MEDI-545 (day 0, 1, 4, 7, 14)
    47. 47. Th1/Th2 Paradigm T-bet IL-5 IL-10 IL-13 IL-4 IL-6 Helminth protection (allergy, atopy, SLE) IL-4 IL-12 IL-18 Th 1 cell IFN-  LT-  IL-2 IL-22 Cell-mediated immunity Intracellular pathogens Autoimmunity IL-12R IL-18R Th 2 cell Schulze-Koops H, et al. EULAR, 2006, Amsterdam, #SP0130. Zhu J, et al. Cell Res 2006;16:3 (-) (+) (-) (+) Naïve T-cell STAT6 GATA3 CMAT
    48. 48. T cell subsets: Th17 and T reg cells <ul><li>Th17 cells are abundant in gut, maintain mucosal homeostasis </li></ul><ul><li>Upregulated in inflammatory diseases including MS, RA, IBD </li></ul><ul><li>IL-23 important for the maintenance of the Th17 phenotype </li></ul>FoxP3 T reg cell Self Ag + TGF  IL-10 TGF  PROTECTION IL-17 IL-22 INFLAMMATION Self Ag + TGF  + IL-6 IL-23 (survival) IL-23R CTLA-4 TGF  AITR, GITR Naïve T-cell ROR  t Th17 cell Betelli, et al. Nature 2006;441:235; Ivanov, et al. Cell 2006;26:1121; Tesmer L, et al. 70 th ACR, Washington DC, 2006. #297
    49. 49. T-regs in autoimmune disease <ul><li>CD4+CD25+ regulatory cells prevent the activation of autoreactive T-cells </li></ul><ul><li>T-cells from lupus prone mice are relatively resistant to the suppressive effect of CD4+CD25+  </li></ul><ul><li>Work at the NIH (Lipsky et al) suggests CD4+CD25+ upregulation is a potential therapeutic avenue in lupus management  </li></ul><ul><li>Active as opposed to inactive SLE is associated with less CD4+CD25+ activity (poster and picture represented on the slide </li></ul>Bonelli M, et al. EULAR 2007 , Barcelona #FRI0080
    50. 50. Vitamin D and IL-10: An important potential link in SLE <ul><li>IL-10 is a complex cytokine whose levels are elevated in SLE and has both pro- and anti-inflammatory effects </li></ul><ul><li>Vitamin D levels are decreased in SLE </li></ul><ul><li>Vitamin D independently promotes IL-10 secretion </li></ul><ul><li>Activated B cells produce Vitamin D which down regulates the immune response </li></ul><ul><li>Efforts to produce a Mab to IL-10 are potentially problematic </li></ul>1. Radbruch, et al. EULAR 2007 , Barcelona; 2. Kamen DL, et al. Autoimmune Rev 2006;5: 114–7
    51. 51. Vitamin D May Play a Role in SLE <ul><li>25-OH vitamin D inhibits Th1 cell proliferation, cytokine production, autoantibody production and APC activation in SLE patients; may be clinically relevant </li></ul><ul><li>124 Toronto women with SLE who underwent DEXA scanning had significantly lower levels of 25-OH vitamin D levels compared with other DEXA patients; this finding did not correlate with bone density. </li></ul><ul><li>Among 274 Israeli lupus patients, 38% had low vitamin D levels and higher SLEDAI and ECLAM scores. Hydroxychloroquine-treated patients had higher vitamin D levels, corticosteroids had no impact </li></ul>Insufficient: <30ng/ml of 25-0H vitamin D Deficiency: <15ng/ml of 25-0H vitamin D Amital H, et al. 71 st ACR, Boston 2007. #535; Toloza S, et al. ibid. #1117; Cantorna et al . Exp Biol Med , 2004
    52. 52. IL-18 and SLE <ul><li>A member of the TNF superfamily which supports the expansion of Th1 and NK cells </li></ul><ul><li>Mouse models of SLE overexpress IL-18 </li></ul><ul><li>Increased levels in SLE sera and renal tissue which correlates with TNF levels and disease activity </li></ul><ul><li>Administration of infliximab decreases expression of IL-18. Targeted therapies against IL-18 are in development </li></ul>Aringer M, et al. EULAR 2007 , Barcelona, #OP0177 TN, IL-18 and SLE activity Serum TNF (pg/ml) 0 200 100 300 0 4 8 12 SIS t=0.76, p<0.0001 Serum IL-18 (pg/ml) 0 200 100 300 0 4 8 12 SIS t=0.38, p<0.02
    53. 53. Microparticles and lupus <ul><li>200-700 nm in size surrounded by phospholipid bilayers </li></ul><ul><li>Released by cell death to the surface; taken up by macrophages and induce apoptosis and T cell proliferation </li></ul><ul><li>40 SLE pts and matched controls— increased levels that correlated with SLEDAI scores </li></ul><ul><li>Also increased in Sjogren’s, vasculitis, antiphospholipid syndrome in other studies </li></ul>Huber L, et al. EULAR 2007 , Barcelona #OP0180
    54. 54. Targets for New Therapies in SLE Peptides derived from nucleosomes, Sm Ag, Igs, TEVA (edratide) T cell regulation of autoantibody production Medimmune, Genentech anti-IFN-alpha; Coley blocks TLR7 and 9 Inhibition of interferon, toll receptors Expand CD4+CD25+ cells, CD8+CD28- cells Promote regulatory cells mAbs to IL-10, sIL-6R, IL-6 Cytokines anti C5a (approved for PNH) Complement LJP 394; mAbs to CD20, CD22 antiBLyS, TACI-Ig, BAFF-RFc B cells, anti-dsDNA antibodies CTLA4 Ig; modified CD40L mAb T cells
    55. 55. New therapies for APS <ul><li>Biologics: LJP 1082 </li></ul><ul><li>Oral heparins </li></ul><ul><li>Rituximab </li></ul><ul><li>Glycoprotein IIb/IIIa specific antagonists </li></ul><ul><li>Tissue factor expression inhibitors </li></ul><ul><li>P38 MAPK inhibitors </li></ul><ul><li>Thromboxane A2 inhibitors </li></ul><ul><li>Anti C5a </li></ul>