Rheumatoid Arthritis and the Changing Canadian Landscape

Transcription

1 Rheumatoid Arthritis and the Changing Canadian Landscape This event is an Accredited Group Learning Activity (Section 1) as defined by the Maintenance of Certification program of The Royal College of Physicians and Surgeons of Canada and approved by Continuing Professional Development, Schulich School of Medicine & Dentistry, Western University (#hours) Each participant should claim only those hours of credit that he/she actually spent participating in the educational program. Preparation date: May

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3 Existing therapies and their limitations: NSAIDs Goals: relief of joint pain and swelling Analgesic effects immediate, 2 3 weeks for optimal reduction in inflammation Limitations Ineffective as sole therapy for RA Do not prevent joint damage Side effects, e.g., dyspepsia (common), gastric bleeding, renal insufficiency Drug interactions ACR Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:

4 Existing therapies and their limitations: corticosteroids Goals: treatment of symptomatic joints, recovery of motion Useful in bridging for the DMARD effect Limitations Temporary benefit/not advisable for long-term therapy Local injections/systemic disease Inappropriate as only treatment Side effects, e.g., osteoporosis, hypertension, hyperglycemia, cataracts, weight gain, hyperlipidemia Increased risk of infection ACR Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:

5 Non-biologic DMARDs Most commonly used DMARDs Methotrexate Sulfasalazine (Salazopyrin ) Hydroxychloroquine (Plaquenil ) Leflunomide (Arava ) Azothiaprine Gold (Myochrisine ) Double and triple combinations regimens are also available Roughly 2/3 of patients initially respond to non-biologic DMARD monotherapy (approximately 60% reduction in pain, swelling and stiffness) Combination DMARDs may offer an advantage for some patients Kiely PDW, et al. Rheumatology 2009;48:675-72; HLA Averns, 5

6 What Traditional DMARDs are Considered Today? First Choice Hydroxychloroquine Sulfasalazine Methotrexate Leflunomide Second Choice Cyclosporine Azathioprine Others: Parenteral/oral gold ACR Subcommittee on RA Guidelines: Arthritis Rheum 2002; 46(2):

7 Why is methotrexate (MTX) so important? Best benefit/side effect ratio of all DMARDs pre-biologics Best drug survival of all DMARDs Massive international data about benefit and safety Side effects usually resolve quickly when stopped Basic to all DMARD combinations, including biologics Improved survival - untreated RA shortens life 7-20 years - studies suggest controlling disease with MTX returns life expectancy to normal

8 Optimizing Methotrexate Dosing To optimize MTX dose: Increase dose to mg/wk Ensure folic acid or folinic acid use is appropriate if toxicity is the limiting factor Switch to parenteral route if patient on oral therapy Pharmacokinetics of MTX: Absorption of MTX after oral administration varies from 20% to 95% (mean 80%) SC absorption similar to IM Mean MTX dose 19 mg/wk Genovese MC, et al. Arthritis Rheum 2002; 46(6):

9 % achieving remission Increased Remission Rates with Intensive versus Conventional Methotrexate Treatment (Utrecht RA Cohort Study) 41 p = Intensive Conventional Verstappen SMM, et al. Presented at ACR 2006, Washington. Abstract #1310.

10 % ACR responders Methotrexate: Efficacy of Oral vs. Subcutaneous Therapy 100 p = 0.02 MTX s.c. (n = 147) MTX oral (n = 147) p = ns p = 0.03 p = ACR20 ACR50 ACR70 EULAR remission* *DAS28 < 2.6 Braun J, et al. Presented at EULAR 2006, Amsterdam. Abstract #OP0111.

11 Optimizing Methotrexate Dosing To optimize MTX dose: Increase dose to mg/wk Ensure folic acid or folinic acid use is appropriate if toxicity is the limiting factor Switch to parenteral route if patient on oral therapy Pharmacokinetics of MTX: Absorption of MTX after oral administration varies from 20% to 95% (mean 80%) SC absorption similar to IM Mean MTX dose 19 mg/wk Genovese MC, et al. Arthritis Rheum 2002; 46(6):

12 Mechanisms of action of traditional DMARDs in RA 1-7 MTX Leflunomide Sulfasalazine Hydroxychloroq uine Reduction of cell proliferation, increase of apoptosis of T cells, increase of endogenous adenosine release, alteration of expression of cellular adhesion molecules, and influence on production of cytokines, humoral responses, and bone formation An isoxazole immunomodulatory agent that inhibits de novo pyrimidine synthesis and has anti-proliferative activity. Also exhibits anti-inflammatory activity Unclear but is suggested as being anti-inflammatory, immunosuppressive and bacteriostatic Interferes with antigen processing in macrophages and other antigen-presenting cells to stimulate CD4+ T cells and down-regulate the immune response 1. Bykerk VP, et al. J Rheumatol 2012;39: Methotrexate (Pfizer) Product Monograph. April 21, Arava (sanofi-aventis) Product Monograph. December 6, Salazopyrin (Pfizer Health AB) Product Monograph. March 21, Plaquenil (sanofi-aventis) Product Monograph. September 10, Brauna J, Rau R. Curr Opin Rheumatol 2009;21(3): Fox RI. Sem Arth Rheum 1993;23(2 Suppl 1):

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15 Leflunomide- Adverse effects Diarrhea, nausea, dyspepsia 10-20% Headache 11% Rash 11% Elevated Liver Function Tests 14% Serious Adverse Effects- 104,000 Pt. Years 129 Serious Liver- 15 cases of Liver failure, 2 cases of Liver cirrhosis.

16 Rheumatoid Arthritis Module 2 Current and upcoming agents: Get ready for a broader horizon 17

17 Non-biologic DMARDs PRODUCT Dose Time to onset Methotrexate (po or sc) Up to 25 mg per week 4 to 6 weeks Hydroxychloroquine 200 to 400 mg QD 4 to 12 weeks Sulfasalazine 1 g BID to QID 5 to 10 weeks Leflunomide 10 to 20 mg daily 4 to 12 weeks Cyclosporine 2.5 to 5 mg/kg/d 2 intakes 6 to 12 weeks Azathioprine 50 to 150 mg QD 6 to 12 weeks Gold salts(i.m.) mg q2-4 weeks 3 to 6 months Tofacitinib 5 mg twice daily 2 to 12 weeks 18

18 Biologics: Possible Side Effects Increased risk of infection Colds or sinus infections Injection site reactions Infusion reactions Headaches/dizziness Nausea or diarrhea Reactivation of infections like hepatitis or tuberculosis Risk of skin cancer

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20 Biologic Options for RA Mechanism of action Name Trade name Administration Route Frequency* Adalimumab 1 Humira SC Every other week Certolizumab pegol 1 Cimzia SC Every 2 to 4 weeks Inhibits tumour necrosis factor Etanercept 1 Enbrel SC 1X or 2X/week Golimumab 1 Simponi SC Once a month Golimumab 1 Simponi IV IV Infliximab 1,2 Remicade Inflectra IV Weeks 0 and 4, and every 8 weeks thereafter Every 8 weeks Inhibits interleukin-6 Tocilizumab 2 Actemra Inhibits interleukin-1 Anakinra Kineret SC Daily Inhibits T cell activation Abatacept 1 Orencia Depletes B cells Rituximab 2 Rituxan IV IV SC IV SC Every 4 weeks Every other week (weight < 100 kg) Weekly (weight > 100 kg) Every 4 weeks Weekly 2 courses 2 weeks apart; can be repeated after 16 weeks 21 *Maintenance frequency except fo

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22 DC IL12, IL23 chemokines, ECM, Co-stimulation IL17, IL22 IFNγ ± Macrophage peptidoglycan lipopolysaccharide heat shock proteins Th1/Th17 IL17 IL22 Cell contact, co-stimulation immune complexes acute phase reactants complement TNFα IL1 IL15 IL18 IL6 IL20 IL32 IL33 RANKL GM-CSF IL10 IL1Ra IL18BP sil1r stnfr IL27 IL35 TGFβ Synoviocytes B cell Neutrophil Mast cell Tissue cell Endothelial cell C H R O N I C I N F L A M M A T I O N

23 Cytokines in the pathogenesis of RA In RA, abnormal interactions between immune cells lead to a cytokine-mediated inflammatory response 1-5 Several cytokines are active in synovial tissues, including pro- and anti-inflammatory cytokines 1-5 The cytokine network can be disrupted, leading to chronic inflammation and tissue damage 1-5 Joint damage Cytokines Key cytokines in the pathogenesis of RA 1 IFNα and IFNß IL-6 IL-7 IL-10 IL-12 IL-15 IL-23 IL-1 IL-17 IL-18 TGF-ß TNF 1. Brennan FM, McInnes IB. J Clin Invest 2008;118: McInnes IB, Schett G. Nat Rev Immunol 2007;7: Murray PJ. J Immunol 2007;178: Smolen JS, Steiner G. Nat Rev Drug Discov 2003;2: Arend WP. Arthritis Care Res 2001;45:

24 Biologic Agents Used in RA and their Mechanisms of Action Biologics are large, complex proteins grown through biological processes using living cells (from mice, humans, or microorganisms) They reduce inflammation by blocking key molecules involved in the pathogenesis of RA Woodrick RS, Ruderman EM. Nat Rev Rheumatol 25

25 Balancing the disequilibrium of cytokines in rheumatoid arthritis Antigenpresenting cells ACTIVATION T-cells Mediators & modulators of inflammation Anti-inflammatory IL-1R antagonist Soluble IL-1R Soluble TNFR IL-10 IL-4 Pro-inflammatory TNF IL-1 IL-1R = interleukin-1 receptor TNFR = tumour necrosis factor receptor Rheumatoid arthritis

26 Biologics for the management of RA 1-7 Anti-TNFs etanercept, infliximab, adalimumab, golimumab, certolizumab B lymphocytedepleting agent rituximab T cell co-stimulatory inhibitor abatacept IL-6 antagonist tocilizumab IL-1 antagonist anakinra 1. Bykerk VP, et al. J Rheumatol 2012;39: Enbrel (Amgen) Product Monograph. September 13, Remicade (Janssen) Product Monograph. August 6, Orencia (BMS) Product Monograph. October 7, Actemra (Hoffman-La Roche Ltd) Product Monograph. December 5, Kineret (Swedish Orphan BioVitrum AB) Product Monograph. May 28, Rituxan (Hoffman-La Roche) Product Monograph. October 17,

27 Rationale for targeting TNF

28 Involvement of TNF in rheumatoid arthritis Activated macrophage TNF

29 Etanercept (ENBREL TM ): structurally designed to inhibit TNF S S S S S S S S S S S S C H 3 C H 2 Fc portion of human immunoglobulin G1 Human p75 TNF receptor

30 INFLIXIMAB- (Remicade) A chimeric monoclonal antibody to TNF-alpha. Affects soluble and membrane bound forms. Given weeks 0, 2, 6, 14, 22 etc. Given with methotrexate. Caution with infections, especially TB.. Significant improvement clinically and radiologically, (sharp scores), over MTX.

31 Certiluzimab (Cimzia) Pegylated Fab fragment of a humanized anti- TNF antibody. Lacks the Fc region, and therefore may avoid complement mediated adverse effects or antibody dependent cell mediated adverse effects. Effective in RA, may be effective in Crohn s disease. Effective in Psoriatic Arthritis, and AS.

32 Latest Advances in Treatment of RA Small molecules New ways of administration of known Biologics New Biologics

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34 B lymphocyte-depleting agent rituximab Binds to CD20 on B cells, resulting in depletion

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38 Actemra- tozilizumab IL-6 receptor blocker. Particularly helps the anemia of chronic disease and Wt. loss. Effective very fast. Effective as monotherapy.

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42 Tofacitinib: Experience in RA trials Tofacitinib has been studied in an expansive clinical program the largest clinical development program of any therapy currently approved to treat RA 1 Five randomized, double-blind, multicentre Phase 3 clinical trials 1 More than 3,000 patients studied in Phase 3 1 Longest exposure to tofacitinib 5 years 2 Approximately 4,800 patients, with nearly 7,000 patient-years of exposure 3 1. Tofacitinib Product Monograph. 2. Wollenhaupt J, et al. Arthritis Rheum 2013:65(Suppl 10):S Tofacitinib for Rheumatoid Arthritis FDA Advisory Committee Meeting, 9 May 2012 (304200) [Accessed May 2014] 43

43 Significance of RA-associated cytokines that activate JAKs Cytokines are involved in each phase of RA pathogenesis: autoimmunity, recruitment of immune cells, immunologic organization and activation and tissue damage 1,2 The cytokine-driven inflammation of synovial tissue results in angiogenesis, hyperplasia and infiltration of immune cells 1,2 Cytokine Role in RA Effect on joint IL-6 IL-10, IL-12, IL-15, IL-23 IFN α/ß, IL-15 IL-6, IL-7, IL-15 Cellular recruitment Immunologic activation and organization Cellular retention and survival Innate and adaptive immune cells Mast cell Dendritic cell Macrophage T cell B cell Extensive angiogenesis RA Normal Neutrophil Neutrophil Plasma cell Plasma cell Synoviocytes Tissue response Synovial hyperpasia 1. Chizzolini C, et al. Arthritis Res Ther 2009;11: McInnes, IB, Schett G. Nat Rev Immunol 2007;7:

44 Tofacitinib modulates cytokines involved in RA 1-4 tofacitinib Cytokines in the pathogenesis of RA Cytokines modulated by tofacitinib Cytokines IL-2 IL-4 JAKs JAK1/JAK3 JAK1/JAK3 IL-7 JAK1/JAK3 Cytokine IL-15 JAK1/JAK3 IL-21 JAK1/JAK3 IL-6 JAK1/JAK2/Tyk2 IFNα and IFNβ JAK1/Tyk2 IFNg JAK1/JAK2 Cytoplasm JAK JAK IL-10 IL-12 IL-23 IL-1 IL-17 IL-18 TGF-β TNF JAK1/Tyk2 JAK2/Tyk2 JAK2/Tyk2 JAK-independent * The relevance of specific JAK combinations to therapeutic effectiveness is not known. 1. Shuai K, Liu B. Nat Rev Immunol 2003;3(11): Jiang JK, et al. J Med Chem 2008;51(24): Meyer DM, et al. J Inflamm (Lond) 2010;7:4. 4. Flanagan ME et al. J Med Chem 2010;53:

45 Dosage of 5 mg.bid and 10 mg. bid response curves are very close. Not much difference in efficacy. Conforms generally to rule. Study head to head with adaliumab showed similar efficicacy- Taso 52% vs. Ada 47%. ACR 20. Infection rate- higher in Taso group vs. Ada. 3.5% vs 2%. TB.

46 Key pharmacokinetic properties PK data Rapid absorption with T max peaking at ~1.1 hr after oral administration 1 Terminal half-life ~3.2 hr 1 Linear, dose proportional oral pharmacokinetics 1 Primary clearance mechanisms include renal clearance (~30%) and CYPmediated oxidation [70%; CYP3A4 (~53%), CYP2C19 (~17%)] 1 Dowty M, et al. Drug Metab Dispos 2014, Jan 24, as doi: /dmd

47 Tofacitinib and special populations No clinically relevant effect of age, gender, weight, race, mild renal or hepatic impairment 1 No clinically relevant food effect no dosage adjustment required when co-administered with MTX 1 The pharmacodynamic effects of tofacitinib are reversible within ~2 weeks (range <1 to 4 weeks) for the majority of markers 2 1. Tofacitinib Product Monograph. 2. Genovese MC, et al. Arthritis Rheum 2013;65(Suppl 10):S193;Abstract

48 Baricitinib Oral JAK inhibitor, affecting preferentially JAK 1 and 2. Double-blind phase 3 studies, comparing 2mg. and 4 mg. daily. Studying monotherapy, with DMARDs and Biologic failures.

49 Sarilumab Fully humanized IL-6 cytokine inhibitor. ACR 70 at 22 weeks, 20, 25 %. Inhibits radiological change. Increased cholesterol, neutropenia, abn. LFT s.

50 Subsequent entry biologics in RA: What s next? Health Canada defines a SEB as "a biologic product that is similar to and would enter the market subsequent to an approved innovator biologic product 1 Both the CRA and the ORA have released position statements on SEBs. Issues tackled include: 1,2 Cost and accessibility to safe and effective drugs Traceability and clear nomenclature No automatic interchangeability or substitution with innovator molecules Ongoing assessment and post-marketing surveillance Health Canada approved two infliximab SEBs in January, Ontario Rheumatology Association. Position paper on subsequent entry biologics in Canada. November Available at: 2. Canadian Rheumatology Association. Position paper on the establishment of a Common Drug Review Procedure and Process for reviewing subsequent entry biologics (SEBs). October 4, Available at: 3. GaBI. Subsequent entry biologics approved in Canada. Available at: 54

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