Pediatric Asthma: Pharmacotherapy. Joseph Spahn, MD Children s Hospital Colorado & University of Colorado Medical School Aurora, Colorado

Transcription

1 Pediatric Asthma: Pharmacotherapy Joseph Spahn, MD Children s Hospital Colorado & University of Colorado Medical School Aurora, Colorado

2 Pediatric Asthma: Pharmacotherapy Disclosures/Conflicts of Interest: None Discussion of investigational drugs: Dupilumab in childhood asthma. Focus on: Inhaled steroids: first-line for all levels of persistent asthma Effectiveness and safety Comparative efficacy of inhaled steroid vs. leukotriene receptor antagonists Combination therapy in patients inadequately controlled on low- to moderate dose inhaled steroids What is the best add-on therapy Concerns re: safety of long-acting beta-agonists Biologic agents for use in severe asthma

3 Use of Inhaled Steroids in Children with Asthma 1. Inhaled steroids were approved for use in asthma in 1974! Yet they were reserved for those with severe asthma Theophylline was the preferred drug until the mid-1980 s 2. Inhaled steroids were not recommended for children with mild persistent asthma until the 2002 NHLBI Update on the Diagnosis & Management of Asthma. This recommendation change came from 2 studies. The CAMP study and a long-term safety study from Denmark. Both studies published in the same issue of the N Engl J Med in 2000.

4 Inhaled Glucocorticoid Therapy: Products and Doses for Children Glucocorticoid Low daily dose Medium daily dose Beclomethasone (Qvar ) MDI: 40 or 80 µg/puff (Approved for children 5 y.o.) Budesonide (Pulmicort Flexhaler ) DPI: 90, 180 µg/puff (Approved for children 6 y.o.) Budesonide suspension for nebulization (Pulmicort Respules ); 0.25 mg, 0.5 mg, 1.0 mg/2 ml (Approved for children 1 to 8 y.o.) Ciclesonide (Alvesco ) MDI: 80, 160 µg/puff (Approved for children 12 y.o.) Flunisolide (Aerospan ) MDI: 80 µg/puff (Approved for children 6 y.o.) Fluticasone propionate (Flovent, Flovent Diskus ) MDI: 44, 110, 220 mcg DPI: 50, 100, 250 mcg (44 and 50 mcg approved for children 4 y.o.) Fluticasone furoate (Arnuity Ellipta ) DPI: 100, 200 mcg (Approved for children 12 y.o.) Mometasone Furoate (Asmanex, Asmanex Twisthaler ) MDI: 100, 200 mcg DPI: 110, 220 mcg (Approved for children 4 y.o.) High daily dose mcg mcg >320 mcg 200 mcg mcg >400 mcg 0.5 mg 1.0 mg 2.0 mg 80 mcg mcg 160 mcg 80 mcg mcg 160 mcg mcg mcg mcg 200 to 500 mcg >440 mcg >500 mcg 100 mcg mcg 200 mcg 110 mcg 100 mcg 110 mcg (100 mcg 110 mcg 100 mcg

5 The Efficacy of Inhaled Glucocorticoids in Asthma The Most Extensively Studied & Most Effective Class of Controllers Agents! 1. Decrease asthma symptoms 2. Improve lung function 3. Reduce in asthma morbidity/mortality less need for oral glucocorticoids protection against hospitalization protection against asthma death 4. Reduce bronchial hyperresponsiveness

6 Percentage Placebo History: Dutch Chronic Non-specific Respiratory Disease Study Group 116 children with moderate asthma (mean FEV 1 77% of predicted) received budesonide 200 mcg or placebo three times/day for 2 to 3 yrs. Budesonide 0 Withdrawals Exacerbations Change in FEV 1 (%) 10 Van Essen-Zandvleit et al., Am Rev Respir Dis 1992;146: % -6 Budesonide Placebo PD 20 µg 0 Budesonide Placebo Months 20

7 Childhood Asthma Management Program (CAMP) budesonide 200 mcg BID (n=311) 1041 children 5-12 y.o. nedocromil 8 mcg BID (n=312) placebo (n=418) 5 years to 12 year old children with mild to moderate asthma based on symptom frequency and need for controller therapy were studied. Baseline FEV 1 94%, post-albuterol FEV 1 103% of predicted, moderate AW reactivity (PC 20 1 mg/ml). Primary endpoint: Change in post-albuterol FEV 1 hildhood Asthma Management Program Research Group. N Engl J Med 2000;343:

8 Efficacy of Long-Term Inhaled Steroid Therapy in Children with Asthma Budesonide had no effect on post-albuterol FEV 1 but... - Reduction in level of AHR ( airways twitchiness ) - 43% Fewer hospitalizations - 45% Fewer urgent care visits - 43% Fewer courses of prednisone - Less need for rescue β-agonist - Fewer number of days requiring supplemental inhaled GC therapy 6.6% of budesonide treated patients vs.17.1% of nedocromil and 18.7% of placebo treated patients *CAMP Research Study group. N Engl J Med 2000;343:

9 Safety of Long-Term Budesonide Therapy Growth: - Mean increase in height of budesonide 1.1 cm less than placebo group which occurred in the first year BUD 22.7 cm, NED 23.7 cm, Placebo 23.8 cm - Projected final height for each group was identical* cm for budesonide,,nedocromil, & placebo. Bone Mineral Density (BMD): - Lumbar BMD performed yearly: no difference between groups at any time during the study. *Follow-up growth study found budesonide-treated patients to be 1 cm shorter vs. placebo-treated patients as young adults. CAMP Research Group. N Engl J Med 2000;343: *Kelly W et al. N Engl J Med 2012;

10 Prevention of Early Asthma In Kids (PEAK): Study Design Screening/ Eligibility Run-in Treatment Observation 1 month 1 month Years 1 & 2 Year 3 Randomize Interim Efficacy Primary Outcome 280 children (2 to 3 y.o.) at risk for asthma (+mapi) randomized to receive fluticasone propionate (44µg/puff) or placebo (2 puffs MDI BID) for 2 years with a 3 rd observation year. Sought to determine if early intervention would prevent the development of asthma.

11 Hypothetical Representation of the Natural History of Asthma Inception Early Administration of Inhaled Steroid Rx Chronic Asthma No Asthma Asthma Initial Phase Protection Asthma, Not Chronic Exacerbations No Asthma Modified API: Must have > 4 wheezing episodes in the past year plus One major criteria Two minor criteria or Parent with asthma Food sensitivity Atopic dermatitis Eosinophilia ( 4%) Allergen sensitivity Wheezing without infection

12 Outcomes During Observation Phase (Year 3) Primary Outcome: Episode-free days during the observation-year (off controller for 1 yr) No differences between groups seen for: - Number of exacerbations requiring prednisone bursts - Unscheduled physician visits/ hospitalizations - Bronchodilator use - Montelukast use - Lung function (respiratory system impedance) No differences in adherence, drop-outs, treatment failures or serious adverse events between groups. Guilbert et al., N Engl J Med 2006;354:

13 Was Any Effect Seen During Treatment?

14 PEAK Study: Outcomes During Treatment Phase (Years 1 & 2) Fluticasone superior to placebo in: - Number of episode-free days - Number of acute exacerbations - Need for supplemental controller medications - Time to addition of supplementary asthma controller medications - Improved lung function (respiratory reactance at 5 hz) Fluticasone was associated with modest growth impairment at end of treatment. - Average height percentile for fluticasone 51.5% - Average height percentile for placebo 56.4 % Guilbert et al., N Engl J Med 2006;354:

15 Inhaled Steroids vs. Leukotriene Receptor Antagonists as Single Agent Controller Medications: What s Best?..

16 Characterization of Within-Subject Responses to Fluticasone & Montelukast in Childhood Asthma 44 Participants Randomized Period 1 8 weeks Period 2 8 weeks Treatment Failures Sequence 1 N=73 LTRA 68 completed Period 1 5 treatment failures LTRA 62 completed Period 2 5 treatment failures LTRA *10 treatment failures Sequence 2 N=71 ICS 68 completed Period 1 0 treatment failures ICS 68 completed Period 2 5 treatment failures ICS 2 treatment failures Total 136 completed Period 1 8 dropouts 5 treatment failures 127 completed Period 2 9 dropouts 5 treatment failures 12 total treatment failures

17 Characterization of Within-Subject Responses to Fluticasone & Montelukast in Childhood Asthma 144 children (6-17 y.o.) with mild to moderate asthma enrolled in a 16 wk cross-over study of fluticasone 100 mcg bid and montelukast. Sought to determine a phenotype for response. A positive response was considered an increase in FEV 1 7.5% Baseline values: FEV 1 96% FeNO 27 ppb PC mg/ml. Effect Noted for both medications 17% Effect seen only with Fluticasone: 23% Effect seen only with Montelukast: 5% No Effect with either Medication: 55% Adapted from: Szefler et al., J Allergy Clin Immunol 2005;115:

18 Many More Children had a Favorable Response to Fluticasone & had Far Fewer Treatment Failures Compared to Those Treated with Montelukast Treatment Failures (n) *p=0.019 Participants Better Response to Fluticasone (n=75) 2 Better Response to Montelukast (n=24) 0 Fluticasone Montelukast Szefler SJ, JACI 2005;115: Difference in FEV 1 Response, % of baseline (Fluticasone-Montelukast) 45

19 Fluticasone was associated >2 times the number of ACDs per week vs. Montelukast A 1 day increase in asthma control days (ACD) per week was considered a clinically significant improvement. 30% had a better response while on montelukast therapy 70% had a better response while on fluticasone therapy. Zeiger et al., J Allergy Clin Immunol 2006;117: Participants Better Response to Montelukast (n=15) Better Response to Fluticasone (n=36) Difference in ACDs per wk FP-Mt

20 Predictors of Response Baseline Characteristic ( %) Fluticasone Propionate Montelukast Pre-bronchodilator FEV 1 % predicted <90% (40%) ** 4.2 Pre-bronchodilator FEV 1 /FVC <80% ( 40%) ** 4.3 * 2.4 Methacholine PC 20 1 mg/ml (44%) Exhaled Nitric Oxide >25 ppb (55%) Circulating Eosinophil Count >350 cells/mm 3 (41%) Serum Eosinophil cationic protein >15 ng/ml (54%) ** * * ** Serum IgE >200 ku/ml (44%) ** 2.9 Urinary Leukotriene E4 >100 pg/ml (50%) * 3.2 Age <10 yrs (67%) * 2.5 **p<0.01 *p< Odds Ratio Odds Ratio Szefler et al., J Allergy Clin Immunol 2005;115:

21 Montelukast is Effective in Preschool-Aged Children with Viral-Induced Wheeze 549 children 2 to 5 y.o. with intermittent asthma received placebo or montelukast x 1yr. Montelukast vs. Placebo Exacerbations (episodes) GC courses Inhaled GCs Oral GCs Montelukast (n=265) 1.60 ( ) 1.19 (0.94, 1.51) 0.66 (0.46, 0.94) 0.53 (0.40, 0.70) Placebo (n=257) 2.34 ( ) 1.74 (1.39, 2.18) 1.10 (0.83, 1.45) 0.64 (0.47, 0.88) Bisgaard et al., Am J Respir Crit Care Med 2005;171: Relative Rate 0.68 (0.56, 0.83) 0.68 (0.49, 0.95) 0.60 ( ) 0.82 (0.54, 1.25) Rate Reduction 31.9% 31.6% 39.8% 17.5% p value <

22 Time to First Exacerbation and Seasonal Variability in Exacerbations Proportion Surviving Without an Exacerbation Episode Placebo Montelukast Percentage of Patients with an Exacerbation Episode Winter Spring Summer Autumn log-rank test: p= Time in Months Bisgaard et al., Am J Respir Crit Care Med 2005;171: Placebo Montelukast January April July October Month January

23 Summary: Inhaled Steroids Remain the most effective class of agents to treat asthma. Inhaled steroids more effective than leukotriene modifying agents in: - In atopic children of all ages - Improving baseline lung function (10-15% gain vs %) - Reducing symptoms - Reducing exacerbations Leukotriene modifying agents - Considered alternative agents to inhaled steroids - Are as effective as inhaled steroids in non-atopic viral-induced wheezers and non-atopic grade school-aged asthmatics

24 Combination Therapy for Moderate Persistent Asthma or for Asthmatics Sub-optimally Controlled on Low Dose Inhaled Steroid therapy 2002 Update to the NHLBI Asthma guidelines recommended combination inhaled steroid plus long-acting beta-agonist (LABA) therapy. The recommendations changed when the 2007 NHLBI Asthma guidelines were released due to concerns about the safety of LABA therapy treatment guidelines for 5 to12 y.o. children- 4 choices: (1) 2x inhaled steroid; (2) 1x inhaled steroid plus LTRA; (3) 1x inhaled steroid plus LABA; (4) 1x inhaled steroid plus theophylline

25 BADGER Protocol: Overview In children not satisfactorily controlled on low dose ICS therapy, what is the next best treatment approach? Increase the inhaled steroid dose? Add a LABA? Add a LTRA? Double-blind, 3 way cross-over, 3 Treatment Periods with treatment 6 Sequences Run-in period on 1x ICS to demonstrate lack of control Run-in Period 2-8 weeks Period 1 Period 2 Period 3 2.5x ICS or 1 x ICS + LABA or 1 x ICS + LTRA 2x ICS or 1x ICS + LABA or 1 x ICS + LTRA 2x ICS or 1x ICS + LABA or 1 x ICS + LTRA 16 weeks 16 weeks 16 weeks Randomization Lemanske et al., N Engl J Med 2010;362:975-85

26 Results: Differential Response A Differential response occurred in 161/165 participants (98%); p< Meaning that all patients had a favorable response to step-up therapy. Was one step-up therapy found to be more effective than the other step-up therapies? Lemanske et et al., al., N Engl N Engl J Med J Med 2010;362: ;362:975-85

27 Primary Outcome: Probability of BEST Response Based on Composite Score* LABA step-up was >1.5 times more likely to produce the best response. LABA 2.5 x igc LTRA *Composite score: 1 st exacerbations 2 nd asthma control days LABA 1.7 times better (95% CI ; p=0.002) 1.6 LABA times better (95% CI ; p=0.004) Probability of Best Response 3 rd FEV 1 emanske et al., N Engl J Med 2010;362:975-85

28 LABA Step-up was most effective in reducing exacerbations and treatment failures Type of Exacerbation Number of Treatment Failures (TF) Number of TF s due to Hospitalization for Asthma Number of TF s due to 2 nd Prednisone Burst Number of Prednisone Bursts LABA Step-up ICS Step-up LTRA Step-up Total Lemanske et et al., al., N N Engl Engl J Med J Med 2010;362:975-85

29 SMART Study

30 SMART Study Design 28-week, multicenter, RZ, DB, PC, observational Target enrollment: ~60,000 patients. Only 26,000 enrolled. Included patients >12 years with asthma currently using a prescription asthma medication (inhaled steroid use not an entry requirement) Salmeterol MDI 42 mcg BID + Usual Care (n=13,176) No inhaled long-acting beta 2 -agonist 12 years of age R 28-week treatment period Phone contact every 4 weeks Placebo MDI BID + Usual Care (n=13,179) Single Clinic Visit Nelson HS et al. Chest. 2006;129: Nelson HS et al. Chest. 2006;129: week supply of study medication provided

31 Salmeterol was associated with increased risk of death vs. placebo b-agonists, (13 vs. 3). bthere 2 ADR 9 polymorphisms deaths with salmeterol and vs. 0 deaths asthma: with placebo part therapy 2- the in patients SMART not Study treated with inhaled steroid therapy. White Black Inhaled steroids at baseline (%) ER visit past 12 months hospitalization past 12 months intubation for asthma lifetime (%) 4 8 Number of deaths (%) 6 (46) 7 (54) Effect of inhaled steroid on risk of death Inhaled steroid at randomization Salmeterol Placebo Yes 4 3 No 9 0 Nelson et al., Chest 2006;129:15-26.

32 FDA Black Box LABA warning Monotherapy with LABA in asthma is contraindicated LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled GCs. LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA). Pediatric and adolescent patients who require the addition of a LABA to an inhaled corticosteroid should use a combination product containing both an inhaled corticosteroid and a LABA, to ensure adherence with both medications. FDA Drug Safety Communication June 2, 2010

33 Serious Asthma Events with Fluticasone Plus Salmeterol versus Fluticasone Alone: (VESTRI Study) 2008 FDA meta-analysis showed an increased risk of asthma-related death, intubation or hospitalization in patients on LABA vs. those not on a LABA. Another meta-analysis showed an increased risk even when used with igc in a separate inhaler than salmeterol. Safety of LABA in children is limited. The FDA metaanalysis found an increased risk of hospitalization which was mitigated when used concomitantly with igc. To address these questions, the FDA mandated GSK to perform a large safety trial. Stemple DA et al., N Engl J Med 2016;365:840-9

34 VESTRI Study To determine if fluticasone/salmeterol was non-inferior to fluticasone alone regarding risk of a serious asthmarelated event: death, intubation or hospitalization. International trial: Over 6,000 children 4 to 11 y.o. enrolled from 11/2011 to 11/2015. Randomized 1:1 on basis pre-trial medications, cact, & exacerbation history to receive either fluticasone or fluticasone/salmeterol 100 or 250 µg bid for 26 weeks. If resulting upper CI for hazard ratio for time to first serious asthma-related event (fluticasone or fluticasone/salmeterol) was <2.675, non-inferiority was demonstrated. Stemple DA et al., N Engl J Med 2016;365:840-9

35 Serious Asthma Exacerbations: Fluticasone Plus Salmeterol versus Fluticasone Alone Adherence 94% Safety Primary: - No deaths, No intubations - Hospitalizations: 27 FP/Salm and 21 FP alone. Risk for a serious asthma-related event was 1.28 for fluticasone/salmeterol vs. fluticasone. As the HR was <2.675, non-inferiority was demonstrated. Safety 2 o : 34 (1.1%) of fluticasone/salmeterol vs. 35 fluticasone treated (1.1%) patients withdrew 2 o asthma exacerbation. Stemple DA et al., N Engl J Med 2016;365:840-9

36 Efficacy of Fluticasone Plus Salmeterol 8.5% of FP/Salm vs. 10% of FP treated children had 1 severe exacerbation (HR to event 0.86). Among blacks: 6.7% FP/Salm vs. 8.4% FP (HR 0.80). Subgroups. versus Fluticasone Alone #1. Controlled on FP/Salm who remained on FP/Salm had fewer severe exacerbations vs. those whose LABA withdrawn. #2. Uncontrolled on low dose igc had fewer exacerbations when treated with FP/Salm vs. those whose igc increased. #3. Uncontrolled asthma on dose mid-fp alone. Addition of LABA to FP 250 µg resulted in fewer exacerbations. #4. Controlled on FP alone. More exacerbations when LABA added vs. FP alone 12.5% vs FP/Salm superior to FP alone in 3 of 4 subgroups. Findings contradict FDA warning stating that LABA should be discontinued once a patient s asthma is controlled on combination therapy.

37 Summary: Combination Inhaled Steroid LABA Therapy The most effective treatment for patients with moderate to severe asthma in both adults and children. They are not associated with increased risk for severe asthma attacks, or deaths from acute asthma. All 3 companies that manufacture combination products have shown similar safety results in >25,000 adults and >6,000 children. Blacks are not at increased risk of having a severe asthma attack while on combination therapy. What will happen to the Black-Box warning?

38 Biologic Agents to Treat Severe Asthma Omalizumab - Anti-IgE antibody. Available for >10 years in adults with allergic asthma, recently approved for use in children. Mepolizumab - Anti-IL-5 antibody. Available since 2016 for severe eosinophilic asthmatics 12 years old. Dupilumab - IL-4 Receptor α antibody (blocks IL-4 and IL-13) - Approved for use in adults with severe atopic dermatitis. - Undergoing Phase 3 studies in adults and children with severe asthma.

39 Omalizumab in Severe Allergic Asthma 850 patients years old with inadequately controlled asthma on high dose inhaled GC plus LABA were treated with omalizumab or placebo for 48 wks. 1 o endpoint: rate of exacerbations. 2 o endpoints: number of albuterol puffs/d, asthma symptoms score, AQLQ. Characteris*cs Omalizumab Placebo Age (yrs) Male (%) Asthma Dura;on (yr) BMI (kg/m 2 ) Serum IgE (IU/ml) FeNO (ppb) FEV 1 (% pred) Puffs rescue albuterol/d prednisone past yr Hanania et al., Ann Int Med 2011;154: Participants Without Protocol-Defined Asthma Exacerbation (%) Placebo (n=421) Omalizumab (n=427) Time Since Day 0, week

40 Omalizumab in Severe Allergic Asthma Mean Puffs of Rescue Medication Per Day Mean FeNO (ppb) Omalizumab Placebo 0.27 puff/d reduction in albuterol Omalizumab Weeks Time, week Placebo Weeks Hanania et al., Ann Int Med 2011;154: ppb reduction Not all patients respond to omalizumab. Baseline TH 2 biomarkers (FeNO, circulating eosinophils, serum periostin) were measured to determine if they could predict response. Divided into biomarker high or low groups based whether values above or below the median. Exacerbations were significantly lower in the high vs. low biomarker groups, with the greatest reduction in high FeNO group (53% reduction) vs. 32% reduction high eosinophil group and 30% reduction high periostin group. In patients in the low biomarker group, omalizumab was no more effective than placebo in reducing exacerbations. Hanania et al. Am J Respir Crit Care Med 2013;187: Fall Omalizumab vs. igc boost in inner city asthmatic children found omalizumab to be effective in reducing fall exacerbations in children with 1 exacerbation during the run-in period. Those who exacerbated had elevated FeNO levels at baseline. Teach et al. JACI 2015;136:

41 Mepolizumab For Severe Eosinophilic Asthma (DREAM): A Multicentre, Double- Blind, Placebo-Controlled Study Mepolizumab is an anti-il-5 antibody. IL-5 is the pivotal cytokine involved in eosinophil survival and activation. Eosinophils are thought to play an important role in asthma pathogenesis. 13-month study of mepolizumab in 621 severe asthmatics with frequent exacerbations and eosinophilic inflammation inadequately controlled on high-dose inhaled glucocorticoid therapy. Primary efficacy outcome: Asthma exacerbations (prednisone course, admission, or ED visit). Patients had to have evidence for eosinophilic inflammation: - 1. Sputum eosinophil 3% - 2. FeNO 50 ppb - 3. Circulating eosinophil count 300 cells/ml Pavord et al., Lancet 2012;380:

42 Baseline Characteristics Characteristic Placebo (n=155) 75 mg IV Mep 250 mg IV Mepo 750 mg IV Mepo Age (years) Asthma duration (y) Sex (female %) Atopy (%) /Nasal Polyps (%) 52 /10 51 /7 50 /14 49 /8 Sputum EOS (%) FeNO (ppb) FEV 1 (% predicted) FEV 1 reversibility LABA use (%) Severe exacerbations past yr (n) Severe asthma (<10%), several phenotypes have been identified. Severe asthma is: often adult onset, have female predominance, is less likely to be atopic, and more likely to have irreversible airflow limitation. The cohort studied consisted of adult onset asthmatics. Disease onset 33 years. 50% were atopic, & 10% had nasal polyps. Pavord et al., Lancet 2012;380:

43 Mepolizumab Resulted in a Significant Reduction in Asthma Exacerbations and.. *Total number of clinically significant exacerbations *No clear dose response was noted suggesting the lowest study dose was at the peak of the dose response curve Placebo 75 mg mepolizumab 250 mg mepolizumab 750 mg mepolizumab % -48% -52% Time from start of treatment (mo) Proportion of patients Placebo 75 mg mepolizumab 250 mg mepolizumab 750 mg mepolizumab Number of exacerbations Exacerbations Requiring Hospital Admission: Placebo: 27; 75 mg: 15; 250 mg: 17; 750 mg: 10 Pavord et al., Lancet 2012;380:

44 .And Inhibiting Eosinophils, But it Had No Effect on FEV 1, Quality of Life, Symptom Scores. Ratio of geometric mean blood eosinophil count Mean change in asthma QOL questionnaire score placebo 75 mg 250 mg 750 mg Mean change in prebronchodilator FEV 1 (ml) placebo 75 mg 250 mg 750 mg Time (weeks) Time (weeks) Pavord et al., Lancet 2012;380:

45 Efficacy Associated with Increasing Eosinophil Counts & With Number Of Exacerbations In the Previous Year A multivariate analysis identified 2 variables associated with mepolizumab efficacy: Baseline eosinophil count Exacerbation frequency in the past year. FeNO, IgE concentration and atopic status at baseline were not associated with its effectiveness. effectiveness. FeNO levels were not affected by mepolizumab therapy. Thus eosinophils, & not FeNO, predict response and are significantly reduced during mepolizumab therapy. Traditional markers of asthma such as FEV 1 and beta-agonist response were not associated with mepolizumab effectiveness. Pavord et al., Lancet 2012;380: Online supplementary material.

46 Dupilumab (Fully Humanized Monoclonal Antibody to the α-subunit of the IL-4 Receptor) in Persistent Asthma with Elevated Eosinophil Levels 104 moderate/severe eosinophilic asthmatics [circulating ( 300 cells/µl) or sputum eosinophils ( 3%)] on igc/laba therapy received dupilumab (300 mg) or placebo SQ weekly for 12 weeks. LABA discontinued at week 4, igc tapered/discontinued during weeks 6 through 9. 1 o outcome: Reduction in asthma exacerbations Screening/ Run-In Period Intervention Period ~65 patients: dupilumab, 300 mg, subcutaneously, weekly ~65 patients: placebo, subcutaneously, weekly After Intervention Period Randomization Day 29 wk 4 Day 43 wk 6 Day 50 wk 7 Day 57 wk 8 Day 64 wk 9 Day 71 wk 10 Day 78 wk 11 Day 85 wk 12 Day 127 wk 18 Day 141 wk 20 Baseline therapy Stable phase Long-acting β-agonist Inhaled Steroid Baseline therapy Withdrawal phase Dupilumab Monotherapy Wenzel S et al. N Engl J Med 2013;368:

47 Dupilumab resulted in significant reductions in exacerbations, improved lung function, & reduced symptoms vs. placebo Characteristic Placebo n=52 Age Male gender % Asthma duration (yr) # exacerbations past year Eosinophils (cells/ml) FEV 1 (% predicted) FeNO (ppb) IgE (IU/ml) Eotaxin (pg/ml) Dupilumab n=52 enzel S et al. N Engl J Med 2013;368: % with an Exacerbation % Placebo 87% reduction P< % Dupilumab Primary Outcome: Acute Exacerbations FEV 1 (% predicted) Stable on therapy LABA Withdrawal Dupilumab Placebo igc taper Dupilumab or placebo mono-therapy Weeks

48 Dupilumab Therapy Resulted in Significant Reductions in FeNO Levels, and Need for Rescue Albuterol Mean FeNO (ppb) Mean # of albuterol inhalations/d for symptom relief Mean ± SE 50 Placebo Dupilumab LABA Withdrawn igc Therapy Withdrawal No Controller Therapy Mean ± SE Placebo Dupilumab LABA Withdrawn igc Therapy Withdrawal No Controller Therapy Week 8 12 Although eosinophilia was an entry requirement, dupilumab therapy had no effect on circulating eosinophils. enzel S et al. N Engl J Med 2013;368: Online Supplementary Data Week

49 Dupilumab Efficacy & Safety: A Randomized DB, PC Pivotal Phase 2b Dose-Ranging Trial Larger study: 769 adult asthmatics on medium-to-high dose ICS/LABA therapy received subcutaneous dupilumab 200 or 300 mg q 2 to 4 week or placebo for 24 wks. Primary endpoint: Change in FEV 1 at 12 wks. Dupilumab resulted in significant improvements in FEV1, reductions in exacerbations and symptoms and improved quality of life measures/ - The effect was best with 300 mg administered q 2wks - Effect noted independent of eosinophilia, although those with eosinophils >300/µl had a greater effect. Dupilumab resulted in a rapid & significant reduction in FeNO but had no effect on eosinophils. Wenzel S et al. Lancet 2016;388;31-44.

50 Dupilumab Efficacy & Safety In Adults With Uncontrolled Asthma Despite Medium/High Dose ICS Plus LABA: Conclusions. Dupilumab is effective in 2 other atopic conditions: eczema and chronic rhinosinusitis with polyposis. Inhibition of both IL-4 and IL-13 may be an effective strategy in conditions driven by type 2 inflammation. Additionally multiple co-morbid conditions (AD, AR, sinusitis with polyposis) often exist in the same patient reflecting a systemic condition and by blocking IL-4 and IL-13 might allow a systemic solution. Inhibition of IL-4 & -13 appears to be crucial in improving lung function, reducing exacerbations, and QOL in patients with uncontrolled asthma on combination ICS/LABA therapy. Dupilumab resulted in a rapid and sustained reduction in FeNOshowing suppression of type 2 inflammation beyond which is available with combination therapy. Wenzel S et al. Lancet 2016;388;31-44.

51 Role of IL5, IL-4 & IL-13 in Asthma pathogenesis Spahn JD et al. J Allergy Clin Immunol 2016;138;