Are Biologicals Safe Enough?

Transcription

1 Are Biologicals Safe Enough? Dr Anne Duggan Director of Gastroenterology, John Hunter Hospital, Hunter New England Area Health Service (HNEAHS) Conjoint A/Professor, University of Newcastle, Australia

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3 Outline Are biologicals of enough benefit in IBD? Is IBD safe enough (without biologicals)? Safety experience with biologicals A safety strategy to improve benefit : risk profile Future prospects

4 Hazard Ratios for Death by IBD type * Age at entry Deaths among Hazard 95% Confidence cases ratio interval Ulcerative Colitis All ages Under Crohn s Disease All ages Under * Corrected for smoking and gender Card 2003

5 Biologicals Investigated in IBD TNFα Inhibitors infliximab CDP 571 adalimumab certolizumab pegol (CDP870) etenercept onercept thalidomide CNI-1493 Inhibitors of lymphocyte trafficking natalizumab alicaforsen (ISIS 2302) MLN 02 Inhibitors of T-cell activation antihuman CD40 Mab ch5d12 visilizumab Inhibitors of T lymphocyte polarization recombinant human IL-10, IL-11 Anti IL-12 Ab, anti IL-2recepter antibodies Growth factors human growth factor, EGF, KeratinocyteGF2 Immune stimulators Interferon α and β

6 Biologicals Investigated in IBD Inhibitors of lymphocyte trafficking natalizumab alicaforsen (n=416) MLN 02 (n=366) well tolerated. *PML well tolerated - infection, headache well tolerated - nausea, antibodies Inhibitors of T-cell activation antihuman CD40 (n=18) visilizumab (n=26) Inhibitors of T lymphocyte polarization recombinant human IL-10 (5 RCTs) recombinant human IL-11 (n=224) anti IL-12 Antibodies (n= 79) anti IL-2 recepter antibodies (n=20) pyrexia, myalgia, arthralgia, headache nausea, arthralgia, no infections well tolerated,lymphopenia,thrombocytopenia well tolerated, injection site reactions well tolerated, injection site reactions *labs Growth factors well tolerated, oedema, headache human growth factor (n=37) EGF (n=85) Keratinocyte GF2 (n=12) Immune stimulators Interferon α and β (n=120) flu like symptoms

7 Comparison of TNFα Inhibitors

8 Infliximab versus placebo Remission Clinical response Akobeng 2003

9 Etenercept versus placebo Remission Clinical response Akobeng 2003

10 TNFα Inhibitors: Worldwide Experience to date Worldwide > 1,000,000 patients have been treated with TNFα inhibitors - Rheumatoid arthritis - Psoriatic arthritis -Psoriasis - Ankylosing spondilitis - Crohn s disease

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14 Data available Data available Strengths Weaknesses Clinical trials control group select population high quality data short duration sample size Postmarketing surveillance long follow-up under reporting no comparator Clinical audit long follow-up no control group Case reports rare associations no frequency data

15 Safety Considerations: Infectious complications Lymphoma Antibody development Other TNFα Inhibitors infusion/infusion site reactions Autoimmunity and autoantibodies Demyelination Congestive cardiac failure Haematological disorders Liver toxicity

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17 Infections in crohn s maintenance trials 1,2 Infliximab Placebo Infections 30-34% 27-37% (with antibiotics) Serious infections 3-4% 6-7% 1 Hanauer 2002; 2 Sands 2004

18 Cumulative probability of infection relative to total infusions Colombel 2004

19 Pre-operative safety of Infliximab Complications Infliximab Controls p value (n=40) (n=39) Minor Early (to 10 days) 6 (15) 5 (12.8) NS Late (to 3 mths) 1 (2.5) 2 (5.1) NS Major Early (to 10 days) 5 (12.5) 3 (7.7) NS Late (to 3 mths) 7 (17.5) 5 (12.8) NS Marchal 2004

20 Opportunistic infections seen with infliximab and etenercept Infections Infliximab Etenercept (n=365,000) (n=150,000) Aspergillosis 26 7 Candidiasis Cryptococcosis 13 1 Cytomegalovirus 20 8 Histoplasmosis 37 2 Infectious mononucleosis 12 5 Listeria moncytogenes 29 2 Nocardiosis 8 2 Pneumocystis carinii 44 5 Tuberculosis Atypical mycobacteria Khanna 2004

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22 TB and TNFα Inhibitors Class effect 91% of cases were from countries with a low incidence 1 Median (range) time to diagnosis 12 weeks (1-52) 1 in 2 extrapulmonary 1 in 4 disseminated Reduced with screening protocols and education Khanna 2004

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24 TNFα Inhibitors and Lymphoma 310 reports in 634,191 patients Rheumatoid Arthritis increased risk of lymphoma OR 2-26 U.S National Databank for rheumatic diseases - 18,572 Standard Incidence Ratio (SIR) = 3 (95% CI 1-5) Infliximab = 2 (95% CI 2-5) overall

25 Observed and expected cases of lymphoma in clinical trials Population n Median follow-up Observed /Expected SIR* (95%) (yrs) Adalimumab / (2.6-10) Etenercept / ( ) Infliximab / ( ) Infliximab / (0) (Aspire) *SIR=Standard Incidence Rate Khanna 2004

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27 Antibodies to TNFα Inhibitors Rheumatoid patients - 8% Infliximab 1; 5% Adalimumab 2 Crohn s patients % episodic; 7-10% maintenance 3,4 Presence of antibodies (>8µg/ml): 2 fold rate of infusion reactions (16-30% v placebo 8-16%) 3 Reduced drug efficacy 4 Management: Reduced with concomitant immunomodulators 3 Reduced with systematic (v episodic) treatment 3 1 Remicade SPC, Centocor,2005; 2 Humira SPC Abbott Laboratories, Hanauer 2004 ;4 Baert 2003

28 Injection/infusion reactions Injection site reactions Adalimumab 1 (20%) v placebo (14%) Infusion reactions Infliximab 2 (20%) v placebo (10%) Usually mild, requiring infusion rate reduction or pretreatment with hydrocortisone 1 Humira SPC Abbott Laboratories, 2005; 2 Remicade SPC,Centocor,2005

29 Congestive cardiac failure: the ATTACH Trial NYHA class III, IV CHF Placebo, infliximab 5mg and 10mg 0, 2 and 6 weeks 150 patients 1 year mortality Placebo 4 (8%) Infliximab (5mg/kg) 4 (8%) Infliximab (10mg/kg) 8 (15.7%) (p<0.05) Coletta 2002

30 Other Autoimmunity and autoantibodies Increased incidence of developing positive double stranded DNA and ANA Maintenance trials: Infliximab Placebo 1,2 Anti-dsDNA 23-34% 6-11% ANA 46-56% 18-35% Lupus-like syndrome is rare with TNFα inhibitors Demyelinating disorders Reported with all TNFα inhibitors 3,4,5 1 Hanauer 2002; Sands 2004; 3 Khanna 2004; 4 Remicade SPC, Centocor,2005; 5 Humira SPC Abbott Laboratories, 2005

31 Other Haematological disorders Pancytopenia, leukopenia, neutropenia, thrombocytopenia rare No clear association Liver toxicity Asymptomatic elevation in up to 10% of patients 1 35 cases of liver failure in 576,000 patients treated 1 Different drug indications Co-morbidities Concurrent medications No clear association 1 Data on file Centocor, 2005

32 Adverse events with Infliximab Clinical trials Stockholm 1 Mayo 2 (n=1081) (n=217) (n=500) (%) (%) (%) Serious infections Opportunistic infections Serum sickness Drug induced lupus Crude deaths p.a NHL Ljung 2004; 2 Colombel 2004

33 Pregnancy and TNFα Inhibitors Few data / small studies Large antibodies don t pass through the placenta (T1, T2) No reported congenital abnormalities No data on lactation Category B classification Katz 2004; Mahadevan 2005

34 Smoking cessation and Crohn s Cosnes 2001

35 Effect of smoking on duration of response to Infliximab Arnott 2002

36 Outline How safe is IBD? Biologicals of clinical benefit in IBD Safety experience with biologicals Infections Malignancy Antibody development Other A risk:benefit strategy Future prospects for improved risk:benefit

37 Practical Safety Steps - 1 Patient selection Active inflammatory disease (raised CRP) (non-stricturing disease, colonic Crohn s) 1 Early onset disease (? in children) 1 Short duration of disease Concomitant immunosuppression 2 Non-smokers 3 1 Vermiere 2002; Hanauer 2004; Arnott 2002

38 Practical Safety Steps - 2 Precautions TB testing/pre-treatment and, suspicion re:opportunistic infection If listeriosis risk - avoid non-pasteurized dairy/soft cheese For infliximab: Systematic treatment (not episodic) After >3/12 lapse in treatment: pre-treatment with hydrocortisone If no response after 14 week regimen - discontinue

39 Practical Safety Steps - 3 Contraindications Absolute CHF III/IV Active /latent TB Infection/sepsis Malignancy MS/Optic neuritis Lymphoma history Known anaphylaxis Precautionary CHF I/II Hepatitis B/C HIV Chronic Infection Pregnancy Lactation Malignancy in remission

40 Conclusions Severe IBD is associated with reduced quantity (and quality) of life These patients benefit most from biologicals TNFα inhibitors are associated with a small increased risk, particularly of opportunistic infections; possibly of lymphoma Risk:benefit profiles should be optimised using current safety data Smokers with crohn s have a worse risk:benefit profile (smoking cessation is a therapeutic strategy) The efficacy and safety of other biologicals is yet to be determined

41 The Future Genetic predictors of responders Humanized biologicals Large surveillance databases Europe ENCORE USA TREAT

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