Research Targets and Novel Immunology-Based Therapeutic Concepts in Rheumatoid Arthritis

Transkript

1 MAItaG Clinical Lecture Series 12/13/2008 Research Targets and Novel Immunology-Based Therapeutic Concepts in Rheumatoid Arthritis Dpt. of Internal Medicine and Rheumatology 1

2 Lehrstuhl für Innere Medizin New Therapies - Why should we? New = better? "Conventional" DMARDs New Immunomodulating Agents Save lives (letality of Wegener s target defined mechanisms of disease pre CYC: 90% within 2 years) high level of evidence (RCT) Remissions achieved in most instances expensive long-standing experience mechanism(s) of action mostly unclear, have to stand the test of time highly potent immunomodulation Problems in unresponsive cases = potentially high risk of adverse effects 2

3 What s on the Menu? Biologics are all the rage: Biologics are substances, that specifically target and modulate defined biologic molecules/mechanisms are "hypothesis-driven" Most are antibody molecules, or other proteins Examples of novel therapeutics: Eculizumab; PMX53 SCIO-469 Anakinra Ruplizumab; IDEC 131 Infliximab Abatacept Adalimumab Rituximab Etanercept Ocrelizumab Certolizumab Epratuzumab Golimumab Belimumab Tocilizumab Efalizumab AMG 714 Denosumab Pamapimod Imatinib 3

4 New Drugs - New Names Nifty endings: -mab: monoclonal antibodies -ximab: chimeric Ab: Fab generated in mice & Fc of human origin (e.g. infliximab: anti-tnf Ab) -zumab: humanized Ab: murine sequences are exchanged for human ones (e.g. tocilizumab: anti-il-6r Ab) -umab: genetically engineered fully human Ab (e.g. belimumab: anti-blys Ab) -cept: soluble receptor (e.g. abatacept: CTLA4-Ig, soluble receptor for CD80/86) -ra: receptor antagonist (e.g. anakinra: IL-1ra) Letters and numbers: refer to the manufacturer (e.g. AMG 714: Amgen compound 714) 4

5 Novel Therapeutics: Targets Targets in RA synovium: innate and adaptive immunity RANKL 5

6 Novel Therapeutics: Targets Innate immunity: Complement system Ricklin & Lambris, Nat Biotechnol

7 Inhibition of Complement C5 Inhibitors: Eculizmab (anti-c5 mab); PMX53 (C5aR ligand) Rationale: C5a: chemotactic factor for C5aR+ monocytes and neutrophils PMX53 inhibits cytokine production/chemotaxis in vitro Preclinical data: C5 -/- DBA/1 mice are resistant to CIA; anti-c5 mab prevents/treats CIA PMX53 anti-arthritic in rats Clinical data: Eculizumab: approved for paroxysmal nocturnal hemoglobinuria limited data on SLE; no data on RA PMX53: phase Ib RCT good tolerabilty, appropriate serum levels no clinical benefit vs. placebo no decrease in cellular infiltration or biomarkers 7

8 Inhibition of Complement C5 Inhibitors: Eculizmab (anti-c5 mab); PMX53 (C5aR ligand) Clinical data: PMX53 Parameter PMX53 (n=14) Placebo (n=7) p mean change TJC mean change TJC mean change CRP mean change DAS ACR20 responders EULAR responders (moderate)

9 Short Intermission The CIA model in DBA/1 mice DBA/1 mice: developed by C.C. Little, founder of Jackson Laboratory result of experiments on mouse fur color (DBA/1 & DBS/2): Dilute: gene locus responsible for "dilution" of fur color Brown: self explanatory Non-Agouti: mutation of agouti locus (loss of yellow bands in hair) Method Emulsify dissolved CII (100 µg/animal) 1 : 1 by volume in CFA (mineral oil w/ desiccated, ground M. tuberculosis) or IFA (w/o M. tuberculosis) Inject s.c. on d1 (in CFA) and d21 (in IFA) 9

10 Lehrstuhl für Innere Medizin Short Intermission Phenotype of CIA Grade 1 Grade 3 Grade 2 Grade 4 10

11 Novel Therapeutics: Targets Adaptive immunity: APC - T-Cell interaction 11

12 Novel Therapeutics: Targets Adaptive immunity: APC - T-Cell interaction CD20 CD22 BCR MHCII TCR clonal expansion, cytokines (IL-1, TNF, IL-6, IL-10...) autoantibodies immune complexes activation of the complement system CD80/86 CD40 CD28 CD40L TACI BLyS; APRIL 12

13 Novel Therapeutics: Targets Adaptive immunity: APC - T-Cell interaction CD20 CD22 BCR MHCII TCR clonal expansion, cytokines (IL-1, TNF, IL-6, IL-10...) autoantibodies immune complexes activation of the complement system CD80/86 CD40 CD28 CD40L TACI BLyS; APRIL 13

14 Novel Therapeutics: Targets Adaptive immunity: APC - T-Cell interaction CD20 CD22 BCR MHCII TCR clonal expansion, cytokines (IL-1, TNF, IL-6, IL-10...) autoantibodies immune complexes activation of the complement system TACI CD80/86 CD40 BLyS; APRIL CD28 CD40L immune tolerance/anergy 14

15 Novel Therapeutics: Targets Adaptive immunity: APC - T-Cell interaction CD20 CD22 BCR MHCII TCR clonal expansion, cytokines (IL-1, TNF, IL-6, IL-10...) autoantibodies immune complexes activation of the complement system TACI CD80/86 CD40 BLyS; APRIL CD28 CD40L immune tolerance/anergy apoptosis/ cell-lysis 15

16 Novel Therapeutics: Targets Cytokines: IL-1 RANKL 16

17 Inhibition of Cytokines Anakinra (Kineret TM ): recombinant IL-1ra Rationale: IL-1RI mediates immune cell activation IL-1 induces osteoclast activation IL-1 inhibition effective in animal models of RA IL-1ra Clinical data: reduced bone erosion in RA but variable experiences with clincal efficacy daily s.c. injections required, frequent injection site reactions new indications: systemic onset juvenile RA, adult onset Still s disease, periodic fever syndromes gout?osteoarthritis (intraarticular) 17

18 Novel Therapeutics: Targets Cytokines: TNF RANKL 18

19 Inhibition of Cytokines TNF-Inhibitors Rationale: Pro-inflammatory role in RA, PsA, ASP, CD bone destruction: TNF induces osteoclast activation Agents: Infliximab (chimeric antibody), Adalimumab (fully human antibody), Etanercept (soluble fusion protein of two p75 receptor molecules), Certolizumab pegol: humanized Ab, PEG instead of an Fc portion (no in vitro complement activation, ADCC, or apoptosis) Golimumab: fully human Ab, once monthly application Clinical data: established as second line treatment in RA, PsA, ASP, CD prevention of bone destruction in RA increased risk of infections and malignancies (ongoing debate) 19

20 Novel Therapeutics: Targets Cytokines: IL-6 RANKL 20

21 Inhibition of Cytokines Tocilizumab (Actemra TM ): anti-il-6r Ab Rationale: IL-6 originally described as B-cell differentiating/stimulating factor inducer of acute phase reactants activator of neoangiogenesis, lymphocytes, synovial fibroblasts, osteoclasts, causes fever and fatigue required for many experimental autoimmune diseases, while anti-inflammatory in acute inflammation anti-il-6 mab causes accumulation of IL-6 immune complexes anti-il-6r-ab does not and also inhibits the effects of IL-6/sIL-6R complexes 21

22 Inhibition of Cytokines Tocilizumab (Actemra TM ): anti-il-6r Ab Clinical data: very effective in phase IV trials in RA; approval expected next year adverse effects: leukopenia, LFT elevation, lipid elevation TOWARD study, Genovese et al., A&R

23 Novel Therapeutics: Targets Cytokines: IL-15 IL-15 RANKL 23

24 Inhibition of Cytokines AMG714: human IgG1 anti-il-15 Ab Rationale: IL-15 signals via common γ-chain: recruitment and activation of T-cells, maintenance of T memory slowing of apoptosis of RASF and EC promotion of synovial cytokine and chemokine release Pre-clinical data: amelioration of inflammation and articular destrution in CIA using sil-15rα Clinical data: 1 phase I-II RCT low no. of patients, but promising no further trials in progress Baslund et al., A&R

25 Novel Therapeutics: Targets Cytokines: Inhibition of intracellular signalling IL-15 RANKL 25

26 Inhibition of Cytokines Pamapimod (RO ): p38 MAPK inhibitor Rationale: intracellular signaling via p38 MAPK: cell growth apoptosis pro-inflammatory cytokines orally bioavailable small molecule

27 Inhibition of Cytokines Pamapimod (RO ): p38 MAPK inhibitor Pre-clinical data: specific inhibition of p38α and β inhibition of TNF, IL-1 and IL-6 production reduced inflammation/bone loss in CIA analgesic in animal models inhibition of renal disease in MRL/lpr mice

28 Inhibition of Cytokines Pamapimod (RO ): p38 MAPK inhibitor Clinical data: 2 phase II RCT PA18604: MTX monotherapy vs. pamapimod monotherapy PA18439: pamapimod vs. placebo as add-on in MTX failures PA18439 prematurely discontinued due to lack of efficacy (acceptable safety) PA18604 MTX (n=53) Percentage of patients 5= mg QD (n=52) 150 mg QD (n=51) 300 mg QD (n=48) ACR ACR PA18439 Placebo (n=53) 25 mg BID (n=57) Percentage of patients 75 mg BID (n=57) 50 mg QD (n=53) 150 mg QD (n=54) 300 mg QD (n=54) Roche Investigator Web Conference October 2007 ACR ACR

29 Inhibition of Cytokines Le roi est mort, vive le roi: p38 MAPK inhibitor SCIO-469 Clinical data: 2 phase II RCT n = 302 stable dose of (hydroxy-)chloroquine, minocycline, doxycycline Tolerability: skin rash; 60 mg TID: dose-limiting liver toxicity Parameter at week 12 Placebo SCIO mg ER QD 30 mg IR TID 60 mg IR TID ACR 20 24% 23% 26% 33% ACR 50 9% 8% 4% 3% SJC -27% -18% -18% -25% TJC -38% -22% -32% -39% CRP 8% -3% -10%* -1%* Geneovese et al., ACR 2008 HAQ

30 Novel Therapeutics: Targets APC - T-Cell interaction: Inhibition of costimulation CD20 CD22 BCR MHCII TCR CD80/86 CD40 CD28 CD40L TACI BLyS 30

31 Inhibition of Costimulation Inhibition of CD40/CD40L interaction: Rationale: CD40/CD40L costimulation induces differentiation of B-cells CD40L serum levels correlate with anti-dsdna-ab titers in SLE increased CD40 u. CD40L in renal parenchyma in LN Preclinical data in SLE: anti-cd40l Ab: prevention or improvement of nephritis Clinical Data in SLE: Ruplizumab: effective, but thromboembolic complications of unclear cause IDEC 131: insuffcient effectiveness vs. placebo in phase II - No data on RA 31

32 Inhibition of Costimulation Inhibition of CD28/CD80 interaction: Abatacept (CTLA4-Ig; Orencia TM ) Clinical data: approved for treatment of RA second line after DMARD failure not to be combined with TNF blockers b/o increase in serious infections several trials ongoing for other autoimmune diseases Abatacept Treg Kremer et al., A&R

33 Novel Therapeutics: Targets Depletion of B-cells CD20 CD22 BCR MHCII TCR CD80/86 CD40 CD28 CD40L TACI BLyS; APRIL 33

34 Depletion of B-Cells Rituximab (MabThera TM ): anti-cd20 mab Rationale: CD20: unknown function, but B-cell specific (except plasma cells) effective B-cell depletion in B cell lymphoma Clinical data: approved for RA, effective in cases refractory to TNF blockers effective also in RF- RA, though less than in RF+ RA generally well tolerated; rate of infections comparable to other DMARDs case reports of progressive multifocal leukencephalopathy (JC-Virus): prevalence of latent JC infection: 80% 76 documented cases of PML in 1.5 million rituximab patients 5 cases in autoimmune disease (2 SLE, 2 vasculitis, 1 RA) 37 cases in autoimmune disease w/o rituximab (40% SLE) all had extensive immunosuppression 34

35 Depletion of B-Cells Rituximab (MabThera TM ): anti-cd20 mab Clinical data: depletion of peripheral, BM and synovial B-cells synovial B-cells and ACPA predict response Teng et al., A&R

36 Depletion of B-Cells Ocrelizumab: anti-cd20 mab Rationale: humanized, not chimeric antibody Clinical data: Phase I/II RCT: well tolerated, effective, low immunogenicity ACTION study, Genovese et al., A&R

37 Depletion of B-Cells Epratuzumab: anti-cd22 mab Rationale: CD22 expressed specifically on B-cells immune-mediated B-cell lysis humanized antibody (vs. rituximab = chimeric) Clinical data: open label studies: "moderately active" lupus (n=14): well tolerated, no formation of HACA, reduction of activity score by >50% in all patients primary Sjögren s (n=15): 67% achieved >20% improvement by week 32 (at least 2 parameters: ocular/oral sicca, fatigue, ESR) ongoing in SLE: 1 non-randomized phase III study, 1 RCT phase IIb 2 phase III RCT were discontinued no trials in RA 37

38 Novel Therapeutics: Targets Inhibition of B-cells CD20 CD22 BCR MHCII TCR CD80/86 CD40 CD28 CD40L TACI BLyS 38

39 Inhibition of B-Cells Belimumab (LymphoStat-B TM ): anti-blys (BAFF) mab Rationale: BLyS/BAFF stimulates proliferation, differentiation and Ab-production, inhibits apoptosis serum levels correlate with IgM-RF, anti-ccp and SJC in early RA increased levels in RA synovium Clinical data: Phase II RCT, only published in abstract form (ACR 2005): included anti-tnf non-responders add-on to stable 0-2 DMARDs (w/o biologics) + NSAID/steroids ACR20 (week 24): 29% in all dosing groups vs. 16% in placebo significant reduction of RF and CD20+ B-cells (p<0.001) McKay et al., ACR

40 Inhibition of B-Cells Belimumab (LymphoStat-B TM ): anti-blys (BAFF) mab Clinical data: Phase II RCT, subgroup analysis: ACR20 response at week 24 subgroup placebo all dosages combined Belimumab dosage 1 mg/kg 4 mg/kg 10 mg/kg RF+ 7/58 (12%) 53/180 (29%) N/A N/A N/A RF- no significant difference between belimumab and placebo groups anti-tnf naive 5/40 (13%) 48/135 (36%) 18/45 (40%) 15/45 (33%) 15/45 (33%) anti-tnf experienced no significant difference between belimumab and placebo groups Genovese et al., ACR 2005 New: LY , fully human Ab, binds soluble and membrane-bound BAFF 40

41 Novel Therapeutics: Targets Inhibition of B-cells CD20 CD22 BCR MHCII TCR CD80/86 CD40 CD28 CD40L TACI BLyS; APRIL 41

42 Inhibition of B-Cells Atacicept: TACI-Ig fusion protein binding BLyS and APRIL Rationale: inhibition of BLyS or APRIL binding to TACI on B-cells reduces Ig levels and B-cells numbers in SLE Clinical data: Phase Ib RCT, only published in abstract form (ACR 2008): dose-dependent reduction of total Ig, RF and anti-ccp Ab levels dose-dependent redution of B-cell numbers good tolerabilty not powered for clinical efficacy, yet trends in high-dose group: mean DAS28 reduction from 6.4 ± 1.3 to 5.1 ± 1.4 ACR20 at week 12 in 6/19 (32%) vs. none in the placebo group Tak et al., A&R

43 Novel Therapeutics: Targets Inhibition of T-cells RANKL 43

44 Inhibition of B-Cells Efalizumab (Raptiva TM ): humanized anti-cd11a mab Rationale: blocks interaction of LFA-1 with ICAM-1 blocks activation, adhesion and trafficking of T-cells Clinical data: approved for the treatment of psoriasis Phase II RCT in PsA: ACR20 in 28% of treatment group at week 12 ACR20 in 19% of placebo group at week 12 Retrospective case series of new-onset PsA within a mean of 15 weeks after efalizumab; also single case report no data on RA 44

45 Novel Therapeutics: Targets Bone destruction: RANKL RANKL 45

46 Inhibition of RANKL Denosumab: anti-rankl antibody Rationale: RANKL induces differentiation, maturation and activation of osteoclasts high expression of RANKL in RA vs. normal synovium Clinical data: Phase II RCT (n=218) in MTX-treated RA less erosion, reduced bone turnover no effect on inflammation good tolerability Cohen et al., A&R

47 Novel Therapeutics: Targets Inhibition of multiple cell types RANKL 47

48 Inhibition of multiple cell types Imatinib Rationale: inhibits tyrosine kinases (abl, c-kit, c-fms, PDGFR) thus reducing cytokine production by macrophages and mast cells proliferation of RASF Preclinical data: effective in CIA: reduction/inhibition of synovitis, pannus and erosions cytokine production by synovial mast cells epitope spreading of autoreactive B-cells anti-cii T-cell proliferation/cytokine production days after initial treatment Clinical data: 3 case reports on successful RA treatment with imatinib Phase II trial of imatinib + MTX: completed but not published yet Paniagua et al., JCI

49 Summary C5 inhibition: eculizumab? PMX53 anti-il-1: Anakinra anti-tnf: Infliximab anti-tnf: Adalimumab anti-tnf: Etanercept p38-mapk inhibition: SCIO-469 co-stimulation: Ruplizumab; IDEC 131 co-stimulation: Abatacept B-cell depletion: Rituximab B-cell depletion: Ocrelizumab anti-tnf: Certolizumab B-cell depletion: Epratuzumab? anti-tnf: Golimumab B-cell inhibition: Belimumab; Atacicept? anti-il-6r: Tocilizumab anti-il-15: AMG 714? p38-mapk inhibition: Pamapimod T-cell depletion: Efalizumab /? anti-rankl: Denosumab anti-everything: Imatinib 49

50 Conclusion Rheumatology research has (re-)discovered the B-cells Rituximab thus far most promising Many interesting new targets Clinical relevance remains to be proven Not all good ideas work e.g. p38 MAPK Still a long way to go... 50

51 ...but worth the effort Thank you for your attention! Merry Christmas! 51