Asthma Heterogeneity: Endotypes, Phenotypes and Choosing the Right
TreatmentPresenter of Michael Wechsler, MD MMSc Reproduction Director, NJH Cohenfor Family Asthma PropertyInstitute Not Professor of Medicine National Jewish Health [email protected] Disclosures
Dr. Wechsler has received consulting honoraria from AstraZeneca, Boehringer Ingelheim, Glaxosmithkline,Presenter Novartis, of Regeneron, Sanofi, Teva Reproduction for Property Not Asthma Defined
Muscle • Asthma is a heterogeneous disease, characterized by chronic Healthy airway airway inflammation and history of respiratory symptoms Normal such as bronchial tube lining • Wheeze Presenter Tightened Asthma muscle • Shortness of breath of Inflamed • Chest tightness lining Reproduction Severely • Cough that varies over time and in intensity Severe tightened Asthma muscle • Variable airflow limitation for Excess Property mucus Not Inflamed lining
Global strategy for asthma management and prevention. Global Initiative for Asthma website. https://ginasthma.org/wp‐content/uploads/2018/04/wms‐GINA‐2018‐report‐tracked_v1.3.pdf. Updated 2018. Accessed September 2018. Heterogeneity in Asthma—Not a New Concept
Presenter of Reproduction for Property Not
Spector SL, Farr RS. J Allergy Clin Immunol. 1976 May;57(5):499‐511. . Asthma is Not a Clinically Homogeneous Condition
• Multiple areas of difference: • Clinical presentations • Physiological characteristics Presenter • Responses to therapy of • Time of asthma development is a key factor: • Children—relatively homogeneous with a strong personal and family Reproduction allergic history of atopy for • Adults—very mixedProperty group of patients Not Basis for Disease is Present Early and Evolves Throughout Life
Genetics , environment
Presenter Proteins, biochemicalof pathways, cells Reproduction Physiology,for symptoms Property Not Factors That Can Contribute to Uncontrolled Asthma
Disease-Related Factors Patient-Related Factors •Cyclical nature of disease •Increased disease severity •Comorbidities (eg, GERD Environmental Factors •Differing asthma phenotypes rhinosinusitis, depression) Presenter •Smoking •Passive smoking Uncontrolled Asthma •Frequent exposure to of •Obesity •Age traffic or air pollution Physician-Related Factors •Outdoor and indoor •Psychosocial issues allergens •Medication under-prescribingReproduction(eg, lower income, poor •Failure to assess adherence health literacy) •Failure to assessfor inhaler •Poor treatment adherence Propertytechnique •Inadequate inhaler technique •MisdiagnosisNot •Heterogeneity of treatment •Lack of asthma action plan response •Absence of specialty care •Failure to follow self- management plan •Side effects of other medications (eg, NSAIDs) The Asthma Patient Population is Segmented Based on Disease Severity
Asthma Patient Population Presenter of Intermittent Mild Moderate Severe Reproduction for Property Persistent Asthma Not
National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute website. https://www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Published October 2007. Accessed September 2018. Evolution of Asthma Classification
1960’s- 1980’s- Early Late Present 1970’s 1990’s 2000’s 2000’s Presenter of Bronchoconstriction Inflammation Identification of Precision Precision therapy phenotypes and medicine: by endotype clustersReproductionidentification of endotypes and for mechanisms of disease including Property T2 vs. non-T2 Not
Desai M, Oppenheimer J. Ann Allergy Asthma Immunol. 2016;116(5):394-401. Approach to Asthma Mangement 1. Assess adherence and make sure it’s asthma
Presenter 2. Characterizeof the asthma- Reproduction what type offor asthma is it? Property Not 3. Treat the Asthma Asthma Phenotype vs Endotype
Phenotype Endotype The set of observable A specific biologic characteristics of an mechanism that explains individual resulting from observable properties of the interaction of its Presenteran organism genotype with the of environment Reproduction for Different asthmaProperty phenotypes and endotypes may respond differentlyNot to targeted therapies Understanding Severe Asthma Heterogeneity Through Phenotyping and Endotyping
Environment: Genes Allergies Gene expression
Environment: Infections/ Presenter Severe Asthma Cytokines Irritants Phenotypeof and Endotype Immune Reproduction cells Meds/ for AdherenceProperty Airway Not Patient epithelium, factors smooth Comorbid muscle disease
1. Chung KF et al. Eur Respir J. 2014;43:343-373. Asthma Phenotypes
Category Phenotype Trigger‐‐inducedinduced asthmaasthma • AllergicAllergic • NonallergicNon‐allergic • AspirinAspirin‐‐exacerbatedexacerbated respiratory respiratory disease disease (AERD) (AERD) • InfectionInfection • ExerciseExercisePresenter‐‐inducedinduced • OccupationalOccupationalof Asthma patientpatient characteristicscharacteristics • Smoking • ObesityReproduction • Elderly •forBlack Clinical presentation of asthmaProperty• Pre‐asthma wheezing in infants Not − Episodic (viral wheeze) − Multi‐trigger wheezing • Exacerbation‐prone asthma • Asthma associated with apparent irreversible airflow limitation
Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48. Separation of Asthma Into Clinical Phenotypes
• Unbiased hierarchical cluster analysis • Clinical characteristics (gender, age of onset, severity) • Physiology (lung function, airwayPresenter hyperresponsiveness) • Triggers (allergens, tobacco, ofoccupation) • Sputum inflammatory cells (eosinophils, neutrophils) • Sum total of characteristics areReproduction segregated into groups, with no single feature playingfor a predominant role in the classification Property Not Asthma Cluster Approaches and Eosinophilic Inflammation1
Discordant Monitoring inflammation Primary Care Secondary Care Symptoms allows down-titration of CS Asthma Asthma
Early Symptom Predominant Early onset, atopic; normal BMI; high Concordant Disease symptom expression Symptom-based approach Obese Presenterto therapy titration may be Noneosinophilic sufficient Later onset, female of preponderance;
Symptoms high symptom expression Reproduction
for Monitoring inflammation Property allows targeted CS to lower exacerbation frequency Discordant Benign Asthma Inflammation Mixed middle-aged Not Inflammation Predominant cohort; well-controlled Late onset, greater proportion of symptoms and males; few daily symptoms but inflammation; benign active eosinophilic inflammation prognosis
Eosinophilic Inflammation 1. Adapted from Haldar P et al. Am J Respir Crit Care Med. 2008;178:218-224. The Transition from Phenotyping and Endotyping to Genotyping Personalized approach to asthma Diagnosis
Refractory asthma?
CharacterizePresenter subtype of Phenotype/Cluster Endotypes (Th2 high vs. low) Genotype approach Blood SputumReproduction Other Gender biomarkers forbiomarkers Age IgEProperty Eosinophils FeNO Obesity Eosinophils Neutrophils Ethnicity/Race Not Periostin Cytokines Smoking Hx Cytokines Early vs. Late Onset
Dunn and Wechsler 2015 TAILORED THERAPY 16 Asthma is Not Just One Disease
Asthma Syndrome Symptoms of asthma, variable airflow obstruction
Airway Wheeze, Lung Exacerbation Allergy inflammatio cough, other function s Presenter n symptoms Asthma Phenotypeof Characteristics Based on observable features with no direct relationship to a disease process (e.g., gender, age, obesity, ethnicity,Reproduction smoking history, early vs. late onset, etc.) Asthma Endotypes Distinct functional or pathophysiologicfor mechanisms that may be present in clusters of phenotypes; identifiedProperty by biomarkers (e.g., blood, sputum, urine, FeNO, exhaled Not breath) Endotype 1 Endotype 2 Endotype 3 Endotype 4 Endotype 5
Howard R, Rattray M, Prosperi M, Custovic A. Curr Allergy Asthma Rep. 2015;15(7):38. Lötvall J, Akdis CA, Bacharier LB, et al. J Allergy Clin Immunol. 2011;127(2):355‐60. Why Endotype? Presenter of To personalize therapyReproduction and maximize drug responsefor Property Not Biomarkers to Identify Asthma Phenotype Current • Sputum eosinophils • Circulating blood eosinophils • Exhaled nitric oxide • IgE Presenter of • Allergen skin testing ? Future Reproduction for • Periostin Property • Dipeptidyl peptidaseNot‐4 (DPP ‐4) • Eosinophil peroxidase • Urinary bromotyrosine IgE = Immunoglobulin E. Asthma Endotypes
• Type 2 asthma • Non‐type 2 asthma – Eosinophilic Presenter– Neutrophilic – High nitric oxide of – Mediated by IL‐1, IL‐6, IL‐ – 17, and TNF High IgE Reproduction – Mediated by IL‐4, IL‐5, and IL‐13 for Property Not
IL, interleukin; TNF, tumor necrosis factor. Chung KF, et al. Eur Respir J. 2014;43(2):343‐373; Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48. Inflammatory, Immunologic, and Pathobiologic Features Leading to Severe Asthma
Presenter of Reproduction for Property Not
Israel E, Reddel HK. N Engl J Med 2017;377:965-976 Inflammation, Endotypes, and Phenotypes in Severe Asthma are Heterogeneous
Severe Asthma
Disease burden: Exacerbations, symptoms, airflow obstruction/FEV1 impairment
Type 2‐high Type 2‐low Endotype IL‐4, IL‐13, IL‐5‐ mediated IL‐6, IL‐17, TNF mediated
Eosinophilia (eosinophilic asthma) Neutrophilia
Biomarker Elevated IgE Presenter Paucigranulocytic
Elevated FeNO of
Early age of onset Later age of onset Phenotype Reproduction Allergic sensitization Obesity, infections, smokers for Chronic rhinosinusitis ± nasal polyps Comorbidities Property AtopicNot dermatitis Type 2 inflammation is prevalent in patients with uncontrolled persistent asthma, and these patients have the highest disease burden
Gauthier M, et al. Am J Respir Crit Care Med. 2015;192:660–668; Fahy JV. Nat Rev Immunol. 2015;15:57–65; Wenzel SE. Nat Med. 2012;18:716‒725; Woodruff PG, et al. Am J Respir Crit Care. 2009;180:388–395; Dunican EM, Fahy JV. Ann Am Thorac Soc. 2015;12 Suppl 2:S144–S149; Peters MC, et al. J Allergy Clin Immunol. 2014;133:388–394; Volbeda F, et al. Thorax. 2013;68:19–24. Targeted Pathways for Biologic Therapies Targeted Pathways IgE Inhaled allergens stimulate production of IgE by B lymphocytes and bind to mast cellsdegranualation IL-5 Pro-eosinophilic cytokine; cytokine that regulates proliferation, maturation, migration, and effector functions of eosinophils IL-4 Cytokine found in increased levels in airways and sputum of asthma patients and involved in eosinophil trafficking and B cell production of IgEPresenter IL-13 Cytokine associated with eosinophil traffickingof and production of eNO from epithelial cells TSLP Novel target; epithelial-cell-derived cytokine; drives allergic inflammatory responses by activating dendritic cells and mast cells Reproduction Non-Type 2 Inflammatory Pathwaysfor IL-17 Cytokine produced by Th17Property cells; plays important role in the immunologic responses seen in asthma CXCR2 Potent chemoattractant for neutrophils;Not under investigation in asthma and COPD Wechsler ME. Respir Care. 2018 ;63:699-707.
CXCR2, Chemokine receptor 2; IgE, Immunoglobulin E; Th2, T helper 2 cells; TSLP, Thymic stromal lymphopoietin Novel Asthma Therapies . Anti IL5: mepolizumab, reslizumab, benralizumab . Anti IL4- R alpha/Anti IL13: dupilumab . Anti IL13 lebrikizumab, tralokinumab . Other Novel therapies: • Anti TSLP Presenter • Anti IL33 of • Anti IL17 Reproduction • Anti IL6 for • Anti M1’ Property • Anti Gata3 DNAzymeNot • TLR9 agonists • CRTH2 Antagonists • Antibiotics • Vitamin D What is your approach to treating patients with severe asthma?
. Treat with personalized approach . Identify asthma type by phenotype or endotype Presenter . Treat with the most appropriateof therapeutic strategy based on underlying asthmatic mechanism of inflammationReproduction for Property Not What can we achieve with biologics?
Presenter of Reproduction for Property Not What can we achieve with biologics?
. Reduced exacerbation . Reduced steroid dose and side effects . Improved symptoms andPresenter quality of life . Disease modification toof prevent asthma over long term Reproduction for Property Not Which therapy is best for a specific patient? How do you choose between biologics?
Presenter of Reproduction for Property Not
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51. Which therapy is best for a specific patient? How do you choose between biologics?
• Biomarkers help predict therapeutic responses . Phenotype patients and choose most appropriate therapy . Goal of personalized or “precisionPresenter medicine” . Potential need to measure ofdifferent biomarkers to determine endotype/phenotype Reproduction for Property Not
George L, et al. Ther Adv Chronic Dis. 2016;7:34-51. BLOCKING EOSINOPHILS WITH ANTI IL5
Presenter of Reproduction for Property Not Eosinophilic asthma
• Asthma can be classified phenotypically as eosinophilic (40–60% of cases) or non-eosinophilic • Symptom severity is increased in eosinophilic asthma Presenter of • Interleukin-5 (IL-5) regulates proliferation, maturation, migration and effector functionsReproduction of eosinophils • IL-5 mRNA is increasedfor in patients with asthma, Property correlates with asthmaNot severity, and is inducible by allergen exposure
Corren J. Discov Med 2012;13:305–12 Kouro T & Takatsu K. Int Immunol 2009;21:1303–9 Miranda C, et al. J Allergy Clin Immunol 2004;113:101–8 Wenzel SE. Lancet 2006;368:804–13 Eosinophilic cytokines contribute to the chronic inflammatory process allergen/ IL-3, IL-6 macrophage irritant IL-8, ECP RANTES monocyte MBP dendritic epithelial cell RANTES cell IL-8 IL-3, IL-5 GM-CSF GM-CSF Presenter neutrophil eosinophil TH1 basophil of TH0 IL-4 IL-1 ReproductionTNF- IL-2 endothelial IL-4 IL-3 for IL-10 TH2 IL-6 cell IL-16 IL-8 IL-4Property IL-4 LT GM-CSF RANTES ECP TNF-Not IL-4 smooth IL-5 muscle mast cell myofibroblast cell B cell neuron The targets: IL‐5 or eosinophils (IL‐5Rα)
Mepolizumab Benralizumab Reslizumab
Presenter of Reproduction for Eosinophil Property IL‐5 Not
IL, interleukin Total exacerbations over time are reduced with mepolizumab vs. placebo
Inclusion criteria • sputum eos >3%, • FeNO>50, • blood eos >300, Presenter • deterioration of of asthma after <25% reduction in ICS or Reproduction OCS for Property • AND Not
>2 asthma exacerbations in previous year Pavord I, et al. Lancet 2012;380:651–9 MEPOLIZUMAB NEJM 2014
Presenter of Reproduction for Property Not
ORTEGA NEJM 2014 BEL NEJM 2014 Reslizumab Effects on Exacerbations and Lung Function
Placebo; n=244 (L) 1 Placebo 100 Reslizumab 3.0 mg/kg; n=245 0.40 Reslizumab 3.0 mg/kg 90 HR 0.575 (95% CI 0.440–0.750) 80 p<0.0001 0.30 † 70 † † † † † † † † 60 Presenter * † † 50 of 0.20 * 40 30 0.10 20 Placebo Reproduction Reslizumab 10
Probability of not having CAE of not having Probability (%) for 0 0 0 1020304050607080Property 0 4 8 1216202428323640444852 Endpoin LS mean change from baseline in FEV Number at risk t Not Visit (week) Placebo 244 169 138 112 107 97 0 0 0 Reslizumab 245 207 177 158 146 136 1 0 0
Castro et al. Lancet Respir Med 2015; Epub ahead of print 36 Benralizumab and Exacerbations
Presenter of Reproduction for Property Not Reduction in Exacerbation Eosinophils ≥300 cells per μL
(1.12‐1.58) CI) CI)
(95% (95%
Percentage reduction relative to placebo Percentage reduction relative to ‐45% ‐51% placebo ratio ratio
Presenter(0.77‐1.12) ‐36% ‐28% rate rate
p<0.0001 (0.60‐0.89) of p=0.0188 p=0.0018 (0.54‐0.82) (0.48‐0.74) Reproduction exacerbation exacerbation
for asthma asthma Property Not Annual Annual
Bleecker ER, et al. FitzGerald JM, et al. Bleecker E et al. Lancet Online Publishing, thelancet.com. September 2016. FitzGerald J et al. Lancet Online Publishing, thelancet.com. September 2016. Presenter of Reproduction for Property Not
P NAIR ET AL, NEJM MAY 2017 Presenter of Reproduction for Property Not Does Broader Blockade of Type 2 Cytokines Improve Outcomes?
DupilumabPresenter of Reproduction for Property Not Anti IL4/13 and Asthma
Presenter of Reproduction for Property Not Dupilumab in Asthma
Presenter of Reproduction for Property Not Improvement in Lung Function, On Top of Combination Rx
Presenter of Reproduction P < 0.001 for Property Not Dupilumab Significantly Lowers Rates of Severe Exacerbation in a Phase 3 Trial
• Phase 3, randomized, double‐blind, Risk of Severe Asthma Exacerbations placebo‐controlled trial A Dupilumab, 200 mg Every 2 Wk, vs. Matched Placebo Subgroup No. of Patients Relative Risk vs. Placebo (95% Cl) Placebo Dupilumab Overall 317 631 0.52 (0.41‐0.66) • n=1902 patients ≥12 years of age with Eosinophil count ≥300 cells/mm3 148 264 0.34 (0.24‐0.48) uncontrolled asthma stratified by ≥150 to <300 cells/mm3 84 173 0.64 (0.41‐1.02) <150 cells/mm3 85 193 0.93 (0.58‐1.47) baseline blood eosinophil level FENO Presenter ≥50 ppb 71 119 0.31 (0.18‐0.52) ≥25 to <50 ppb 91 180 0.39 (0.24‐0.62) • Randomized to receive add‐on SC of<25 ppb 149 32 0.75 (0.54‐1.05) 5 0.1 0.25 0.50.751 1.5 2 dupilumab at a dose of 200 or 300 mg Dupilumab Placebo every 2 weeks or placebo for 52 weeks Better Better B ReproductionDupilumab, 300 mg Every 2 Wk, vs. Matched Placebo • Primary outcomes: Annualized rate of Subgroup No. of Patients Placebo Dupilumab Relative Risk vs. Placebo (95%Cl) severe asthma exacerbations and the Overall 321 633 0.54 (0.43‐0.68) Eosinophil count absolute change from baseline to week for ≥300 cells/mm3 142 277 0.33 (0.23‐0.45) ≥150 to <300 cells/mm3 95 175 0.56 (0.35‐0.89) 12 in FEV1 before bronchodilatorProperty use <150 cells/mm3 83 181 1.15 (0.75‐1.77) FENO ≥50 ppb 75 124 0.31 (0.19‐0.49) Not ≥25 to <50 ppb 97 186 0.44 (0.28‐0.69) <25 ppb 144 317 0.79 (0.57‐1.10) 0.1 0.25 0.50.751 1.5 2 Dupilumab Placebo Better Better Castro M, Corren J, Pavord ID, et al. N Engl J Med. 2018;378(26):2486‐2496. Dupilumab Significantly Improved Lung Function
Change in the Prebronchodilator FEV1 from Baseline over 52‐Weeks
0.4 (liters)
Change 1 0.3 FEV
Mean in 0.2 Presenter Dupilumab, 300 mg
Squares 0.1 Dupilumab, 200 mg Baseline ‐ of Placebo, 2.00 ml Placebo, 1.14 ml from Least 0.0 024 6 8 10 12 16 20 24 28 32 36 40 44 48 52 ReproductionWeek No. at Risk Dupilumab, 300 mg 633 625 614 612 609598610 611 593 596 586 579 584 584 570 562 488 Dupilumab, 200 mg 631 610 613 615 604607611 605 601 599 589 585 590 577 581 570 477 Placebo, 2.00 ml 321 313 311 313 311309313for310 304 296 304 301 301 297 292 290 250 Placebo, 1.14 ml 317 315Property307 301 305301307 300 303 300 290 286 289 287 288 281 240
The benefit of dupilumabNot on FEV 1 was greatest among patients with a blood eosinophil count of ≥300 eos/cc at baseline
Castro M, Corren J, Pavord ID, et al. N Engl J Med. 2018;378(26):2486‐2496. BLOCKING IGE WITHPresenter OMALIZUMAB of Reproduction for Property Not Omalizumab Blocks IgE Binding to Mast Cells IgE molecule
Omalizumab Omalizumab Presenter of FcRI receptor Reproduction for Property Not Mast cell Omalizumab Mechanism of Action
Reduces Allergic B lymphocyte mediator inflammation: release eosinophils and lymphocytes -switch Allergic mediators
Plasma cell Presenter
Release of of IgE Allergens Omalizumab Reproduction Exacerbation for Reduces asthma PropertyReduces exacerbations and Binds to free IgE, Not high-affinity symptoms reducing receptors cell-bound IgE Mast cells Basophils Summary of Reduction in Asthma Exacerbations in Pivotal Studies 1 and 2
Stable Steroid Phase Steroid Reduction Phase 16 weeks 12 weeks
0.5 P = 0.005 P <0.001 0.5 P = 0.004 P <0.001 0.4 0.4 0.4 Presenter0.4 0.3 0.3 0.3 of 0.3 0.2 0.2 0.2 0.2 Reproduction0.2 0.1 for 0.1 Property 0.1 Mean exacerbations per patient Mean exacerbations per patient Mean exacerbations Not 0 0 Study 1 Study 2 Study 1 Study 2
Omalizumab Placebo Different biomarkers and omalizumab response
Effect of omalizumab based on Th2 biomarkers FeN0 Eosinophils Periostin 40 <19.5 ppb ≥19.5 ppb <260/µL ≥260/µL <50 ng/mL ≥50 ng/mL CI)
Asthma 20 95% Presenter %, 0 of defined –9 –30 ‐ –16 –32 –3 (Mean –20 Reproduction rate
–53 protocol for
in –40 Property –60 Not exacerbation
Reduction n = 193 n = 201 n = 383 n = 414 n = 279 n = 255 –80 P=0.45* P=0.001* P=0.54* P=0.005* P=0.94* P=0.07*
*Exacerbation reduction P‐values; omalizumab versus placebo in each biomarker subgroup. Hanania NA et al. Am J Respir Crit Care Med. 2013;187:804‐811. Presenter of Reproduction for Property Not Tezepelumab treatment reduced the annualised AER vs placebo at Week 52
• Significant reduction in annualised AER for all tezepelumab treatment groups compared with placebo; P<0.001
Placebo (N=148) Tezepelumab 210 mg Q4W (medium dose) (N=145) Tezepelumab 70 mg Q4W (low dose) (N=145) Tezepelumab 280 mg Q2W (high dose) (N=146)
0.6 0.67 Presenter rate
61%***of 71%*** 66%*** ‐year) 0.4 Percentage AER reduction vs placebo patient exacerbation Reproduction 0.2 (per 0.26 0.19 0.22 Asthma for 0.0 Property N=148 N=145 N=145 N=146 Not Treatment group ***P<0.001, compared with placebo group. Sequential testing approach was used to adjust for the multiplicity caused by the multiple dose‐placebo comparisons. The hierarchy was tezepelumab 280 mg, 210 mg, and 70 mg vs placebo
53 Anti TSLP in Asthma (Corren 2017)
Presenter of Reproduction for Property Not Individualizing Asthma Therapy: Conclusions • Response to asthma therapies is variable Presenter • Need to understandof who responds to what Reproduction • We now have multiplefor novel biologic therapies thatProperty may treat patients with Not severe eosinophilic asthma • How will we decide which therapies work best in which patients? Treating Severe Asthmatics Now • Do extensive workup • Endotype your patients Presenter of Reproduction for Property Not Asthma Biomarkers
•IGE •FENO Presenter •EOS of – Sputum Reproduction – Blood for Property • Periostin Not • DPP4 (Dipeptidyl Peptidase 4 / CD26; an adipokine) Selecting Treatment for Severe Asthma: Anti-IgE Versus Anti‒IL-5
Patients with allergic Anti-IgE or Anti‒IL-5 or Anti IL4/13 eosinophilic asthma
Patients with allergic Anti-IgE noneosinophilic asthma or Anti IL4/13 if eNO high
Patients with eosinophilic asthma who: Presenter • Are nonallergic OR of • Do not respond to anti-IgE treatment Anti‒IL-5 or Anti iL4/13 OR Reproduction • Are out of range of dosing for anti-IgE treatment for Property • Other factors influencing the decision:Not patient comfort with a new agent vs older treatment with more experience
Head-to-head studies are needed
1. Papathanassiou E et al. Eur Clin Resp J. 2016;3:31813. 2. Magnan A et al. Allergy. 2016;71:1335-1344. Conclusions
• Asthma is a spectrum of diseases, with different pathologic and clinical phenotypes • There has been an increased understanding of the immunology of asthma, leading to new therapeutic options • Defining phenotypes and endotypesPresenter in asthma is a young field, but it is making progress of • Tailoring treatment to phenotypesReproduction and endotypes is the ultimate goal for Property Not Conclusions
• Patients with severe asthma may require additional evaluation and referral • Patients with allergic asthma not well controlled with high‐dose ICS and an additional controller can be considered for treatment withPresenter omalizumab of • Patients with severe eosinophilic asthma not controlled Reproduction with ICS/LABA may benefit from an inhibitor of IL‐5 for (mepolizumab, reslizumab,Property or benralizumab) • Consider DupilumabNot with eosinophilic or type 2 moderate severe asthma or on systemic steroids Understanding Disease Mechanisms May Guide Therapy to a More Personalized Approach
One Size Fits All Stratified Medicine Personalized Medicine
Presenter of Reproduction for Property • Evidence‐based •NotEvidence ‐based • Evidence‐based • One treatment for all • Different treatments • Individualized treatment for groups of patients for each patient
Willis JC, Lord GM. Nat Rev Immunol. 2015;15(5):323‐329. Providing Asthma Care is a Team Sport
Allergist Pediatrician Immunologist Primary care Presenter physician Pulmonologist of School Patient Otolaryngologist personnel Reproduction Case Pharmacist for Manager PulmonaryProperty Nurse Rehabilitation Not Practitioner Specialist Nurse/APN
Your Asthma Care Team. University of Rochester Medical Center website. https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid= 134&contentid=253. Accessed September 2018. FUTURE QUESTIONS
• How will clinicians and payers decide between different biologics based on existing biomarkers? • Can we use combinations of Presenterbiologics? • Are there biomarkers that ofshould be studied other than blood eosinophils, IgE, FeNO? Reproduction • What are best therapies for nontype 2 severe asthma? for • What about AsthmaProperty COPD overlap Syndrome??? Not
63 Drug Phase Dosing Frequency Route Exacerbation Increased FEV1 Reduction Rate (vs. Placebo) (vs. Placebo) Reslizumab Approve 2016 3.0 mg/kg Q4W IV 50-59% 110-126 ml Anti IL5 Mepolizumab Approved 100 mg Q4W Sub-Q 53% 98 ml Anti IL5 asthma 2015; Phase 3 COPD Benralizumab Approved 30 mg Q8W (first 3 Sub-Q 36-55% (Q4W 0-125 ml Anti IL5 Receptor asthma 2017; doses every frequency) Phase 3 COPD 4 weeks)Presenter28-70% (Q8W of frequency) Omalizumab Approved 125mg – Q2W or Sub-Q 33-75% NS Anti IgE asthma 2003; 375mg (based Q4W Approved on weight/ IgE (dependingReproduction urticaria level) on weight/ forIgE level) Dupilumab Approved 2017 Property200-300 mg Q2W Sub-Q 59.9-80.7% 390-430ml Anti IL4 Receptor for Atopic Dermatitis; Not 2018 for Asthma
Tezepelumab Phase III for 70‐280 mg Q2‐4 WSub‐Q61‐71% 110‐150 ml Anti TSLP asthma Thank You! [email protected]
Presenter of Reproduction for Property Not
65 Confidential – Not for Distribution DUP-14387