Different kinds of asthma, different kinds of therapies Friday 10 th - - PowerPoint PPT Presentation

Different kinds of asthma, different kinds of therapies Friday 10th 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

Disclousures

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

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

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

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

Asthma diagnosis can be confirmed by excluding other conditions

Congestive heart failure COPD Bronchiectasis/cystic fibrosis Hypereosinophilic syndromes Allergic bronchopulmonary aspergillosis Nasal and sinus complications (e.g. cough due to post-nasal drip) Endobronchial lesion/foreign body (e.g. amyloid, carcinoid, tracheal stricture) Hyperventilation with panic attacks Depression Dysfunctional breathlessness/ vocal cord dysfunction Bronchiolitis obliterans Pulmonary embolus Adverse drug reaction (e.g. ACE inhibitors)

Non-asthmatic conditions misdiagnosed as uncontrolled severe asthma in 12–30% of patients

Chung KF et al. Eur Respir J. 2014;43:343–373.

Prescription filling and health care utilisation

<50% ICT n=63 >50% ICT n=119 p value Sex M/F 16/47 53/66 0.02 Admissions in last 12 months 25%=3 10%=3 0.02 5%=2 9%=2 18%=1 16%=1 52%=0 65%=0 Nebuliser 31(49%) 35(29%) 0.01 Total SABA nebules 99 42 0.03

Prescription filling

Gamble et al AJRCCM 2009

AJRCCM 2012 Dec 1;186(11):1102-8

Baseline FeNO does not identify non-adherence

The utility of fractional exhaled nitric oxide suppression in the identification of non-adherence in difficult asthma

AJRCCM 2012 Dec 1;186(11):1102-8

Directly observed inhaled steroid therapy

– 12 European centres – Age 17-65 years – Diagnosed <45 years – Well documented asthma – <5 pack years smoking – No other chronic lung disease ENFUMOSA study

ERJ 2003;22:470-7

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

ENFUMOSA study treatment Controlled Severe Median dose ICS mcg 666 1773 % on long acting inhaled bronchodilator 24.7 95.5 % on theophyllines 2.5 45.5 Oral steroids 0/158 53/163

ERJ 2003;22:470-7

ENFUMOSA study demographics Controlled Severe Controlled vs severe Subjects 158 163 Age years 40.9 42.4 ns Duration of asthma 20.2 20.8 ns Female :male 1.6:1 4.4:1 p<0.001 Atopy IgE 148 108 p<0.05

ERJ 2003;22:470-7

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

• Identify/exclude

difficult-to-treat asthma

• Treat comorbidities

affecting asthma control: chronic rhinosinusitis, GERD,

• besity, depression,

anxiety, obstructive sleep apnoea syndrome

• Check inhaler

technique/adherence Differentiate severe asthma from milder forms

• f asthma
• 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 Determine if severe asthma is controlled or uncontrolled

• Confirm if severe

asthma is controlled

• r uncontrolled while
• n high-dose therapy

(four aspects of uncontrolled)

• Includes asthma that

worsens on tapering

• f corticosteroids

Chung KF et al. Eur Respir J. 2014;43:343–373.

10 20 30 40 50 60 70 80 90 100

placebo FP 1000mcg bd % patients discontinuing prednisone

Noonan et al, 1995

FP 750mcg bd * p<0.001

Reduction in oral prednisone requirements in patients with severe asthma

* *

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

A controlled trial of methotrexate in severe steroid- dependent asthma

Shiner et al Lancet 1990

Lock et al AJRCCM 1996

Ciclosporin A in steroid-dependent asthma

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

Golimumab tnf-α antagonist in severe asthma

Wenzel et al AJRCCM 2009

Contents – Background – Steroid sparing agents – Biologics in severe asthma – Conclusions

Different asthma phenotypes exist with different pathophysiology

Macrophages NKT cells IL-33 Allergens Goblet cells Pollution, Microbes IL-33 IL-25 TSLP Dendritic cells IL-33 IL-25 TSLP IgE B cells Eosinophils Smooth muscle cells Neutrophils Naive T cells Airway epithelium ILC2 Basophil Mast cells IL-9 IL-13 IL-13 TH2 IL-5 IL-13 IL-4,IL-13 IL-5 IL-13

Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma

CXCL8 GM-CSF Th17 cells IL-17A IL-17R

Brusselle G, Bracke K. Ann Am Thorac Soc. 2014:11;S322–S328.

Effect of anti-IgE on serum IgE

Milgrom et al NEJM 1999

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

– 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

INNOVATE study

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

Anti-IL5 effect on severe exacerbations of asthma

4 14 25 34 47 58 69 79 85 97 108 109 13 21 27 36 40 44 49 55 57 33 7 3 20 40 60 80 100 120 1 2 3 4 5 6 7 8 9 10 11 12

Treatment period (months) Cumulative exacerbation number

Placebo Anti-IL5

P=0.02

Haldar et al. NEJM 2009;360:973-84

DREAM: Study design

Pavord ID et al. Lancet. 2012;380:651–659.

Subjects with severe, uncontrolled asthma with evidence of eosinophilic inflammation

Treatment period, N=616

Screening Follow-up 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 Mepolizumab 75 mg IV every 4 weeks (n=153) Mepolizumab 750 mg IV every 4 weeks (n=156) R Placebo IV every 4 weeks (n=155) Mepolizumab 250 mg IV every 4 weeks (n=152)

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

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

• r 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

• ral corticosteroids

Pavord ID et al. Lancet. 2012; 380(9842):651–659.

The cumulative number of exacerbations over time was reduced with mepolizumab versus placebo

300 250 200 150 100 50 1 2 3 4 5 6 7 8 9 10 11 12 Placebo (n=155) Mepolizumab 75 mg (n=153) Mepolizumab 250 mg (n=152) 750 mg mepolizumab (n=156) Time from start of treatment (months) Total number of clinically significant exacerbations

~50% reduction

P<0.001 P<0.001 P<0.001 Pavord ID et al. Lancet. 2012;380:651–659.

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;11:531–536.

DREAM: Modelling Analysis

30% reduction in exacerbation was considered meaningful

• achieved at a baseline blood eosinophil count of 150 cells/μL

3.0 2.5 2.0 1.5 1.0 0.5 0.0 50 100 150 200 400 800 1600 Predicted Rate of Exacerbations/Year Baseline Blood Eosinophil(cells/µL)

30%

{

Placebo Mepolizumab

Katz LE, et al. An Am Thorac Soc. 2014;11:531-536.

Objective: Evaluate the safety, efficacy, and tolerability of 2 doses of mepolizumab (75 mg IV and 100 mg SC) versus placebo.

Placebo IV and placebo SC

Run-in period (1-6 wk before randomisation) Primary efficacy outcome Study drug administered week visit Visit 1 Screen Visit 2 Random assignment 1:1:1

Mepolizumab 75 mg IV and placebo SC Mepolizumab 100 mg SC and placebo IV

32 10 40 Follow-up 2 4 3 8 4 12 5 16 6 20 7 24 8 28 9

Visit 1 Screening Visit 2 Randomisation 1:1:1 Ortega HG, et al. N Engl J Med. 2014;371:1198-1207.

The MENSA study: study design

Mepolizumab 75mg IV is not licensed doses/routes of administration

The MENSA study: Key Inclusion and Randomisation Criteria

Documented requirement for regular treatment with high- dose inhaled corticosteroids and ≥3 months of treatment with additional maintenance treatment(s) History of ≥2 exacerbations requiring treatment with systemic steroids in previous 12 months Subjects on maintenance OCS required two-fold or greater increase

Background Medication

Ortega et al. N Engl J Med. 2014;371(13):1198-1207.

≥150 cells/µL in peripheral blood screening at Visit 1 OR ≥300 cells/µL in the 12 months prior to Visit 1

Eosinophilc airway inflammation (as key randomistaion criteria) OR Evidence of asthma as documented by airway reversibility, airway hyperresponsiveness, or Airflow variability

Exacerbation History Eosinophilic Asthma Key Inclusion Criteria Key Randomisation Criteria – Blood Eosinophil Level

The MENSA study: Significant Reduction in Clinically Significant Exacerbations – Primary Endpoint

Ortega HG, et al. N Engl J Med. 2014; 371: 1198-1207.

aThe between-group difference in this category is the percent reduction as compared with the placebo group.

Frequency of clinically significant exacerbations significantly lower at week 32 in all treatment groups as compared with placebo (Ρ < .001)

Mepolizumab 75mg IV is not licensed doses/routes of administration

The MENSA study: Improvement in SGRQ score compared with placebo

Greater change from baseline in SGRQ scores at week 32 in all treatment groups compared with placebo (P < .001 for both)

Mepolizumab 75 mg IV Mepolizumab 100 mg SC Placebo

Change from baseline in SGRQ score

2 4 6 8 10 12 14 16 20 18 9 15.4 16

6.4 points differencea 7.0 points differencea

Ortega HG, et al. N Engl J Med. 2014;371:1198-1207.

aStatistical significance cannot be inferred due to the hierarchical ‘gatekeeping’ approach used. The p-

values provided are unadjusted for multiple comparison

Mepolizumab 75mg IV is not licensed doses/routes of administration

This is interesting data…

…, but the indicated cut off level for eosinophils of 150 cells/µL is in the normal range!

Blood eosinophil counts in healthy individuals

FH, family history of allergy; PH, past history of allergy; ST, skin test.

ST – – + + + + FH – + – + – + PH – – – – + +

Eosinophils/mm3 100 200 300 400 A B C D E F

↑427

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/µL2

• 77 symptom-

free, healthy volunteers, categorised by allergy status were studied

• Mean blood

eosinophil counts in Group A (negative for ST, FH, and PH): 97 cells/µL1

• 1. Felarca AB, Lowell FC. J Allergy. 1967;40:16–20; 2. Anand et al. Abstract presented at BTS 2015.

Integrated Safety Information

Nucala SmPC 2017

Systemic reactions including hypersensitivity have been reported at an overall incidence comparable to that of placebo. 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 19 18 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

Benefit and Risk of Mepolizumab

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary- AllergyDrugsAdvisoryCommittee/UCM452856.pdf (accessed on 07/11/2017)

Primary endpoint: Mepolizumab significantly and clinically meaningfully improved mean SGRQ total score at week 24 versus placebo

CI, confidence interval; LS, least squares; SC, subcutaneous; SE, standard error; SGRQ, St. George’s Respiratory Questionnaire

4 12 Time (weeks) Adjusted mean change in SGRQ score from baseline –20 –16 –12 –8 –4 20 24

Treatment LS mean change (SE) at week 24 Treatment difference (mepolizumab–placebo) 95% CI; P value Placebo (n=260) –7.9 (1.01) –7.7 (–10.5, –4.9) <0.001 Mepolizumab (n=265) –15.6 (1.00) Mepolizumab 100 mg SC Placebo A decrease in SGRQ score indicates improvement.

Chupp et al. Lancet Respir Med. 2017;5:390-400

Treatment 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) 0.001 Mepolizumab (n=264) 176 (26.1)

Secondary endpoint: Significant increase in pre- bronchodilator FEV1 with mepolizumab versus placebo

CI, confidence interval; FEV1, forced expiratory volume in 1 second; LS, least squares; SC, subcutaneous; SE, standard error

4 12 Time (weeks) Adjusted mean change from baseline (mL) –50 50 100 300 150 20 24 16 8 200 250 Mepolizumab 100 mg SC Placebo Chupp et al. Lancet Respir Med. 2017;5:390-400

Mepolizumab delayed time to first clinically significant exacerbation versus placebo

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.

4 8 12 Time to event (weeks) Probability of event (%) 10 20 30 50 40 16 20 24 Mepolizumab 100 mg SC Placebo

235 213 192 277 172 160 116 262 251 236 274 225 221 179 Placebo Mepolizumab Number at risk

Chupp et al. Lancet Respir Med. 2017;5:390-400

Inflammatory pathways in asthma

Brusselle et al. Ann Am Thorac Soc 2014:11(5);322-8

Prior OMA use Prior OMA use 161

MENSA SIRIUS

↓57%

RR: 0.43 (0.21,0.89)

↓47%

RR: 0.53 (0.41,0.70)

↓33%

RR: 0.67 (0.36,1.23)

↓ 29%

RR: 0.71 (0.45,1.14)

In MENSA and SIRIUS, mepolizumab reduced rate of exacerbations irrespective of prior omalizumab use

95% confidence intervals in brackets. OMA, omalizumab; RR, rate ratio. The numbers inside the bars represent number of patients (n). No prior OMA use No prior OMA use

21 54 170 331 22 23 44 46

Placebo Mepolizumab Magnan A et al. Allergy. 2016;71:1335–1344

Corren J et al. N Engl J Med 2011;365:1088-1098

Anti IL13 Lebrikizumab

Corren J et al. N Engl J Med 2011;365:1088-1098

Effect of periostin on response

Effect on clinical measures

Other options in severe eosinophilic airway disease

FEV1 Symptoms Exac PC20 OCS sparing Bl eos Sp eos FeNO IgE

Oral steroids

+ + ++ ++ NA

• Anti-IL-5

+ + ++ ++

• 
• 
• Anti-IL-13

+ + + (?) 0 (?) ?

• Anti-IL-4 / 13

+ + ++ 0 (?) ?

• ?
• Anti-IgE

+ + ++ 0 (?)



• Effect on biomarkers

Bl, blood; eos, eosinophils; Exac, exacerbations; Sp, sputum

Different asthma phenotypes exist with different pathophysiology

Macrophages NKT cells IL-33 Allergens Goblet cells Pollution, Microbes IL-33 IL-25 TSLP Dendritic cells IL-33 IL-25 TSLP IgE B cells Eosinophils Smooth muscle cells Neutrophils Naive T cells Airway epithelium ILC2 Basophil Mast cells IL-9 IL-13 IL-13 TH2 IL-5 IL-13 IL-4,IL-13 IL-5 IL-13

Atopic eosinophilic asthma Non-atopic eosinophilic asthma Neutrophilic asthma

CXCL8 GM-CSF Th17 cells IL-17A IL-17R

Brusselle G, Bracke K. Ann Am Thorac Soc. 2014:11;S322–S328.