Different kinds of asthma, different kinds of therapies

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1 Different kinds of asthma, different kinds of therapies Friday 10 th November 2017 XXXIII Congresso Sezione SIAAIC Toscana Professor Neil Barnes Medical Head Global Respiratory Franchise, GSK Brentford, London Symposium sponsored by GSK Prescribing information is available on request

2 Disclousures Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare I am a full time employee of GSK No relevant conflicts of interest to declare I hold stocks and shares in GSK No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare

3 Contents Background Steroid sparing agents Biologics in severe asthma Conclusions

4 Severe Asthma Uncontrolled at step 4 once Co-morbidities Wrong diagnosis Adherence/compliance issues

5 Factors in difficult asthma Other diseases in association with asthma Psychological Adherence/compliance issues Severe asthma

6 Asthma diagnosis can be confirmed by excluding other conditions Non-asthmatic conditions misdiagnosed as uncontrolled severe asthma in 12 30% of patients COPD Depression Nasal and sinus complications (e.g. cough due to post-nasal drip) Hyperventilation with panic attacks Dysfunctional breathlessness/ vocal cord dysfunction Endobronchial lesion/foreign body (e.g.amyloid, carcinoid, tracheal stricture) Allergic bronchopulmonary aspergillosis Bronchiolitis obliterans Congestive heart failure Hypereosinophilic syndromes Adverse drug reaction (e.g. ACE inhibitors) Pulmonary embolus Bronchiectasis/cystic fibrosis Chung KF et al. Eur Respir J. 2014;43:

7 Prescription filling and health care utilisation <50% ICT n=63 >50% ICT n=119 p value Sex M/F 16/47 53/ Admissions in last 12 months 25%=3 10%= %=2 9%=2 18%=1 16%=1 52%=0 65%=0 Nebuliser 31(49%) 35(29%) 0.01 Total SABA nebules Prescription filling Gamble et al AJRCCM 2009

8 Baseline FeNO does not identify non-adherence AJRCCM 2012 Dec 1;186(11):1102-8

9 The utility of fractional exhaled nitric oxide suppression in the identification of non-adherence in difficult asthma Directly observed inhaled steroid therapy AJRCCM 2012 Dec 1;186(11):1102-8

10 ENFUMOSA study 12 European centres Age years Diagnosed <45 years Well documented asthma <5 pack years smoking No other chronic lung disease ERJ 2003;22:470-7

11 ENFUMOSA study design Well defined asthma Mild to moderate <1000mcg ICS No exacerbations in last year Severe asthma >1200mcg ICS At least one exacerbation in last year ERJ 2003;22:470-7

12 ENFUMOSA study treatment Controlled Severe Median dose ICS mcg % on long acting inhaled bronchodilator % on theophyllines Oral steroids 0/158 53/163 ERJ 2003;22:470-7

13 ENFUMOSA study demographics Controlled Severe Controlled vs severe Subjects Age years ns Duration of asthma Female :male ns 1.6:1 4.4:1 p<0.001 Atopy IgE p<0.05 ERJ 2003;22:470-7

14 Many factors must be considered and checked to confirm the diagnosis of severe asthma Guideline recommendations for diagnosis of severe asthma Confirm asthma diagnosis by excluding other conditions Differentiate severe asthma from milder forms of asthma Determine if severe asthma is controlled or uncontrolled Identify/exclude difficult-to-treat asthma Treat comorbidities affecting asthma control: chronic rhinosinusitis, GERD, obesity, depression, anxiety, obstructive sleep apnoea syndrome Check inhaler technique/adherence Check if high-dose ICS plus a second controller agent is needed to prevent attack from becoming uncontrolled or if the attack remains uncontrolled despite high-dose therapy Confirm if severe asthma is controlled or uncontrolled while on high-dose therapy (four aspects of uncontrolled) Includes asthma that worsens on tapering of corticosteroids Chung KF et al. Eur Respir J. 2014;43:

15 Reduction in oral prednisone requirements in patients with severe asthma 100 * % patients discontinuing prednisone * * p< placebo FP 750mcg bd FP 1000mcg bd Noonan et al, 1995

16 Contents Background Steroid sparing agents Biologics in severe asthma Conclusions

17 A controlled trial of methotrexate in severe steroiddependent asthma Shiner et al Lancet 1990

18 Ciclosporin A in steroid-dependent asthma Lock et al AJRCCM 1996

19 Immunosuppressive agents evidence of lack of efficacy Troleandomycin Colchicine Hydroxychloroquine Gamma-globulin

20 Golimumab tnf-α antagonist in severe asthma Wenzel et al AJRCCM 2009

21 Contents Background Steroid sparing agents Biologics in severe asthma Conclusions

22 Different asthma phenotypes exist with different pathophysiology Allergens Pollution, Microbes Airway epithelium Goblet cells Basophil IgE IL-33 IL-25 TSLP Mast cells IL-9 Dendritic cells Naive T cells T H 2 IL-13 IL-13 IL-33 IL-25 TSLP Macrophages ILC2 IL-33 NKT cells CXCL8 GM-CSF IL-17R IL-17A Th17 cells IL-4,IL-13 IL-5 IL-5 IL-13 Eosinophils IL-13 Neutrophils B cells Smooth muscle cells Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma Brusselle G, Bracke K. Ann Am Thorac Soc. 2014:11;S322 S328.

23 Effect of anti-ige on serum IgE Milgrom et al NEJM 1999

24 INNOVATE study 419 patients FEV1 61% predicted 28 weeks treatment 19% reduction in exacerbations NS 26% reduction when corrected for imbalance of exacerbation history Allergy 2005;60:309

25 INNOVATE study FEV1 2.8% predicted better 0.5 puffs/day less NS 60.8% vs 47.8% significant 0.5 change in AQLQ Allergy 2005;60:309

26 Novel therapies Anti-IL5 Mepolizumab/Resiluzumab/ Benraluzimab Anti-IL2 Daciluzimab Anti-IL13 Lebrikizumab Anti-IL4/13 Dupilimab Anti TSLP

27 Anti-IL5 effect on severe exacerbations of asthma 120 Placebo Cumulative exacerbation number Anti-IL P= Treatment period (months) Haldar et al. NEJM 2009;360:973-84

28 DREAM: Study design Subjects with severe, uncontrolled asthma with evidence of eosinophilic inflammation Treatment period, N=616 Mepolizumab 750 mg IV every 4 weeks (n=156) Screening Mepolizumab 250 mg IV every 4 weeks (n=152) Follow-up R Mepolizumab 75 mg IV every 4 weeks (n=153) Placebo IV every 4 weeks (n=155) 2 weeks 4 weeks 52 weeks (+/ 5 days) Visits at week 0, week 1, week 4, and at 4-weekly intervals thereafter Visit 1 Visit 2 Randomisation Visit 16 Visit 17 Objective: to evaluate the efficacy, safety and pharmacodynamics of three doses of mepolizumab versus placebo in patients with severe refractory eosinophilic asthma Primary end point: rate of clinically significant asthma exacerbations Pavord ID et al. Lancet. 2012;380:

29 DREAM: Key inclusion criteria Background medication Requirement for the following in the previous 12 months: Regular treatment with high-dose ICS (i.e. 880 µg/day FP or equivalent) Controller therapy (e.g. LABA, LTRA) With or without maintenance OCS Exacerbation history History of 2 exacerbations requiring treatment with systemic steroids in previous year Subjects on maintenance OCS required 2-fold increase in the dose of OCS Eosinophilic inflammation Requirement for 1 of the following in the previous 12 months: Blood eosinophil level of 300/µL Sputum eosinophils 3% FeNO 50 ppb Deterioration of asthma control following a 25% reduction in regular maintenance inhaled or oral corticosteroids Pavord ID et al. Lancet. 2012; 380(9842):

30 The cumulative number of exacerbations over time was reduced with mepolizumab versus placebo Placebo (n=155) Mepolizumab 75 mg (n=153) Mepolizumab 250 mg (n=152) 750 mg mepolizumab (n=156) ~50% reduction Total number of clinically significant exacerbations P<0.001 P<0.001 P< Time from start of treatment (months) Pavord ID et al. Lancet. 2012;380:

31 Blood eosinophil count is a key biomarker of response to mepolizumab therapy DREAM: subjects with markers of eosinophilic disease Blood Eos 300 cells/µl, or Sputum Eos 3%, or Exhaled nitric oxide concentration 50 ppb, or Prompt deterioration of asthma control following a 25% reduction in regular maintenance dose of ICS or OCS Modelling of covariates which predict response to mepolizumab Selection of blood eosinophils as biomarker with best prediction Subgroup Analysis of DREAM data Blood Eos 150 cells/µl at screening (from modelling data) Blood Eos 300 cells/µl in last 12 months (from inclusion criteria) Katz LE et al. Ann Am Thorac Soc. 2014;11:

32 DREAM: Modelling Analysis 30% reduction in exacerbation was considered meaningful - achieved at a baseline blood eosinophil count of 150 cells/μl 3.0 Placebo 2.5 Predicted Rate of Exacerbations/Year { 30% Mepolizumab Baseline Blood Eosinophil(cells/µL) Katz LE, et al. An Am Thorac Soc. 2014;11:

33 The MENSA study: study design Objective: Evaluate the safety, efficacy, and tolerability of 2 doses of mepolizumab (75 mg IV and 100 mg SC) versus placebo. Primary efficacy outcome Run-in period (1-6 wk before randomisation) week visit Study drug administered Follow-up Visit 1 Screening Visit 2 Visit 2 Random assignment 1:1:1 Randomisation 1:1:1 Mepolizumab 75 mg IV and placebo SC Mepolizumab 100 mg SC and placebo IV Placebo IV and placebo SC Mepolizumab 75mg IV is not licensed doses/routes of administration Ortega HG, et al. N Engl J Med. 2014;371:

34 The MENSA study: Key Inclusion and Randomisation Criteria Key Inclusion Criteria Background Medication Documented requirement for regular treatment with highdose inhaled corticosteroids and 3 months of treatment with additional maintenance treatment(s) Exacerbation History History of 2 exacerbations requiring treatment with systemic steroids in previous 12 months Subjects on maintenance OCS required two-fold or greater increase Eosinophilic Asthma Eosinophilc airway inflammation (as key randomistaion criteria) OR Evidence of asthma as documented by airway reversibility, airway hyperresponsiveness, or Airflow variability Key Randomisation Criteria Blood Eosinophil Level 150 cells/µl in peripheral blood screening at Visit 1 OR 300 cells/µl in the 12 months prior to Visit 1 Ortega et al. N Engl J Med. 2014;371(13):

35 The MENSA study: Significant Reduction in Clinically Significant Exacerbations Primary Endpoint Frequency of clinically significant exacerbations significantly lower at week 32 in all treatment groups as compared with placebo (Ρ <.001) a The between-group difference in this category is the percent reduction as compared with the placebo group. Ortega HG, et al. N Engl J Med. 2014; 371: Mepolizumab 75mg IV is not licensed doses/routes of administration

36 The MENSA study: Improvement in SGRQ score compared with placebo 0 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC Change from baseline in SGRQ score points difference a 7.0 points difference a 16 Greater change from baseline in SGRQ scores at week 32 in all treatment groups compared with placebo (P <.001 for both) a Statistical significance cannot be inferred due to the hierarchical gatekeeping approach used. The p- values provided are unadjusted for multiple comparison Ortega HG, et al. N Engl J Med. 2014;371: Mepolizumab 75mg IV is not licensed doses/routes of administration

37 This is interesting data, but the indicated cut off level for eosinophils of 150 cells/µl is in the normal range!

38 Blood eosinophil counts in healthy individuals symptomfree, healthy volunteers, categorised by allergy status were studied Mean blood eosinophil counts in Group A (negative for ST, FH, and PH): 97 cells/µl 1 Eosinophils/mm A B C D E F ST FH PH + + In a separate study, 78 volunteers with no self-reported history of allergic disease, with a mean age of 38.8 years, had a mean blood eosinophil count of 150 cells/µl 2 FH, family history of allergy; PH, past history of allergy; ST, skin test. 1. Felarca AB, Lowell FC. J Allergy. 1967;40:16 20; 2. Anand et al. Abstract presented at BTS 2015.

39 Integrated Safety Information Systemic reactions including hypersensitivity have been reported at an overall incidence comparable to that of placebo. Nucala SmPC 2017 Adverse reactions with mepolizumab 100 mg SC with 3% incidence and more common than placebo in MENSA and SIRIUS studies. Adverse Reaction Mepolizumab 100 mg SC (n=263) % Placebo (n=257) % Headache Injection site reaction 8 3 Back pain 5 4 Fatigue 5 4 Influenza 3 2 Urinary tract infection 3 2 Abdominal pain upper 3 2 Pruritus 3 2 Eczema 3 <1 Muscle spasms 3 <1

40 Benefit and Risk of Mepolizumab AllergyDrugsAdvisoryCommittee/UCM pdf(accessed on 07/11/2017)

41 Primary endpoint: Mepolizumab significantly and clinically meaningfully improved mean SGRQ total score at week 24 versus placebo 0 Adjusted mean change in SGRQ score from baseline Mepolizumab 100 mg SC Placebo 20 Treatment Time (weeks) A decrease in SGRQ score indicates improvement. LS mean change (SE) at week 24 Placebo (n=260) 7.9 (1.01) Mepolizumab (n=265) 15.6 (1.00) Treatment difference (mepolizumab placebo) 95% CI; P value 7.7 ( 10.5, 4.9) <0.001 CI, confidence interval; LS, least squares; SC, subcutaneous; SE, standard error; SGRQ, St. George s Respiratory Questionnaire Chupp et al. Lancet Respir Med. 2017;5:

42 Secondary endpoint: Significant increase in prebronchodilator FEV 1 with mepolizumab versus placebo Mepolizumab 100 mg SC Placebo Adjusted mean change from baseline (ml) Treatment Time (weeks) LS mean change (SE) at week 24, ml Treatment difference, mepolizumab placebo, ml (95% CI); P value Placebo (n=259) 56 (26.2) 120 (47, 192) Mepolizumab (n=264) 176 (26.1) CI, confidence interval; FEV 1, forced expiratory volume in 1 second; LS, least squares; SC, subcutaneous; SE, standard error Chupp et al. Lancet Respir Med. 2017;5:

43 Mepolizumab delayed time to first clinically significant exacerbation versus placebo Probability of event (%) Mepolizumab 100 mg SC Placebo 0 Number at risk Placebo Mepolizumab Time to event (weeks) Clinically significant exacerbation defined as worsening of asthma that requires use of systemic corticosteroids and/or hospitalisation and/or emergency department visits. Shaded areas represent 95% CIs. SC, subcutaneous. Chupp et al. Lancet Respir Med. 2017;5:

44 Inflammatory pathways in asthma Brusselle et al. Ann Am Thorac Soc 2014:11(5);322-8

45 In MENSA and SIRIUS, mepolizumab reduced rate of exacerbations irrespective of prior omalizumab use Placebo Mepolizumab MENSA SIRIUS 21 57% RR: 0.43 (0.21,0.89) 47% 170 RR: 0.53 (0.41,0.70) 22 33% RR: 0.67 (0.36,1.23) % RR: 0.71 (0.45,1.14) Prior OMA use No prior OMA use Prior OMA use No prior OMA use 95% confidence intervals in brackets. OMA, omalizumab; RR, rate ratio. The numbers inside the bars represent number of patients (n). Magnan A et al. Allergy. 2016;71:

46 Anti IL13 Lebrikizumab Corren J et al. N Engl J Med 2011;365:

47 Effect of periostin on response Corren J et al. N Engl J Med 2011;365:

48 Other options in severe eosinophilic airway disease Effect on clinical measures FEV 1 Symptoms Exac PC 20 OCS sparing Bl eos Effect on biomarkers Sp eos FeNO IgE Oral steroids NA Anti-IL Anti-IL (?) 0 (?)? Anti-IL-4 / (?)?? Anti-IgE (?) Bl, blood; eos, eosinophils; Exac, exacerbations; Sp, sputum

49 Different asthma phenotypes exist with different pathophysiology Allergens Pollution, Microbes Airway epithelium Goblet cells Basophil IgE IL-33 IL-25 TSLP Mast cells IL-9 Dendritic cells Naive T cells T H 2 IL-13 IL-13 IL-33 IL-25 TSLP Macrophages ILC2 IL-33 NKT cells CXCL8 GM-CSF IL-17R IL-17A Th17 cells IL-4,IL-13 IL-5 IL-5 IL-13 Eosinophils IL-13 Neutrophils B cells Smooth muscle cells Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma Brusselle G, Bracke K. Ann Am Thorac Soc. 2014:11;S322 S328.