BIOLOGICAL THERAPY IN ASTHMA MARIO CASTRO, MD, MPH PROFESSOR OF MEDICINE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE ST. LOUIS, MO Dr. Castro received his medical degree from the University of Missouri in 1988 and his Masters in Public Health from the St. Louis University School of Public Health in 1998. He is the Alan A. and Edith L. Professor of Pulmonary and Critical Care Medicine, Professor of Medicine, Pediatrics, and Radiology at the Washington University School of Medicine in St. Louis, Missouri and also serves as an Adjunct Associate Professor of Community Health at the St. Louis University School of Public Health. He is the Director of the Asthma and Airway Translational Research Unit (AATRU) at Washington University School of Medicine. Dr. Castro has served as President of the ALA of Missouri Board, is current Board member of national ALA Board, and is Chair of the ALA Scientific Advisory Committee. Dr. Castro is Chair of the Board of the International Medical Assistance Foundation and past Chair of the St. Louis Regional Asthma Consortium and the Allergy Immunology Inflammation Program Committee for the American Thoracic Society. He also served on the National Asthma Educator Certification Board from 2000-2005. Dr. Castro is following children from very early in life and looking at how their genetic, biologic and immune responses as well as their environment are coming together to cause some of them to develop asthma (NIH RSV Bronchiolitis in Early Life (RBEL) study). Dr. Castro is the lead investigator for two major asthma networks - the NIH AsthmaNet and the ALA Asthma Clinical Research Center (ACRC) network – which are studying better ways to treat asthma. He chairs the Protocol Committee for ACRC. He is also studying what causes asthma through the NIH Asthma and Allergic Disease Clinical Research Center (AADCRC) grant and what makes severe asthma different from milder forms (Severe Asthma Research Program (SARP)). Dr. Castro’s translational work has been complimented by multiple clinical trials evaluating new and existing therapies in the treatment of asthma, especially severe asthma. His major contribution to the treatment of severe asthma has been in the development of bronchial thermoplasty, a novel therapy to reduce airway smooth muscle, and anti-IL5 therapy for severe eosinophilic asthma. OBJECTIVES: Participants should be better able to: 1. Discuss current unmet medical needs in patients with severe asthma; 2. Understand new approaches to phenotyping/endotyping in asthma patients; 3. Review evidence for efficacy and safety with currently available and future biologic therapy for asthma. THURSDAY, MARCH 23, 2017 10:30 AM
Transcript
BIOLOGICAL THERAPY IN ASTHMA MARIO CASTRO, MD, MPH PROFESSOR OF MEDICINE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE ST. LOUIS, MO
Dr. Castro received his medical degree from the University of Missouri in 1988 and his Masters in Public Health from the St. Louis University School of Public Health in 1998. He is the Alan A. and Edith L. Professor of Pulmonary and Critical Care Medicine, Professor of Medicine, Pediatrics, and Radiology at the Washington University School of Medicine in St. Louis, Missouri and also serves as an Adjunct Associate Professor of Community Health at the St. Louis University School of Public Health. He is the Director of the Asthma and Airway Translational Research Unit (AATRU) at Washington University School of Medicine. Dr. Castro has served as President of the ALA of Missouri Board, is current Board member of national ALA Board, and is Chair of the ALA Scientific Advisory Committee. Dr. Castro is Chair of the Board of the International Medical Assistance Foundation and past Chair of the St. Louis Regional Asthma Consortium and the Allergy Immunology Inflammation Program Committee for the American Thoracic Society. He also served on the National Asthma Educator Certification Board from 2000-2005. Dr. Castro is following children from very early in life and looking at how their genetic, biologic and immune responses as well as their environment are coming together to cause some of them to develop asthma (NIH RSV Bronchiolitis in Early Life (RBEL) study). Dr. Castro is the lead investigator for two major asthma networks - the NIH AsthmaNet and the ALA Asthma Clinical Research Center (ACRC) network – which are studying better ways to treat asthma. He chairs the Protocol Committee for ACRC. He is also studying what causes asthma through the NIH Asthma and Allergic Disease Clinical Research Center (AADCRC) grant and what makes severe asthma different from milder forms (Severe Asthma Research Program (SARP)). Dr. Castro’s translational work has been complimented by multiple clinical trials evaluating new and existing therapies in the treatment of asthma, especially severe asthma. His major contribution to the treatment of severe asthma has been in the development of bronchial thermoplasty, a novel therapy to reduce airway smooth muscle, and anti-IL5 therapy for severe eosinophilic asthma.
OBJECTIVES: Participants should be better able to:
1. Discuss current unmet medical needs in patients with severe asthma; 2. Understand new approaches to phenotyping/endotyping in asthma patients; 3. Review evidence for efficacy and safety with currently available and future biologic therapy
for asthma.
THURSDAY, MARCH 23, 2017 10:30 AM
4/6/2018
1
DISCLOSURE
Dr. Castro has received grant/research support from Sanofi-Aventis, Boehringer-Ingelheim, Gilead, Invion; serves as a consultant for Aviragen, Genentech, Holaira, Teva, Therabron, Sanofi-Aventis and serves on the speakers’ bureau atBoston Scientific, Genentech, Teva, Boehringer-Ingelheim; receives royalties from Elsevier, but these do not create a conflict related to his presentation.
NAMDRC Educational Conference:
Biological Therapy in Asthma
Mario Castro MD, MPHAsthma & Airway Translational Research Unit
Washington University School of Medicine
St. Louis, Missouri, USA
4/6/2018
2
Disclosures
• Principal Investigator (University Grant Funding): AsthmaNet, American Lung Association, Severe Asthma Research Program
• Principal Investigator (Pharmaceutical Grant Funding): Amgen, BoeringerIngelheim, Genentech, Gilead, GSK, Invion, Johnson&Johnson, Medimmune/AstraZeneca, Novartis, Pfizer, Sanofi Aventis, Teva, Vectura
• Speaker: Boeringer Ingelheim, Boston Scientific, Genentech, Teva
• Royalties: Elsevier
• Stock Options: Sparo Inc.
Educational Objectives
Discuss current unmet medical needs in patients with severe asthma
Understand new approaches to phenotyping/endotyping in asthma patients
Review evidence for efficacy and safety with currently available and future biologic therapy for asthma
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5
Unmet Need in Severe Persistent Asthma
Prevalence of severe asthma 5-20% (NAEPP/NHLBI)
Many patients remain symptomatic despite standard of care medications
Treatments are limited, require adherence, and may have serious side effects
New options are needed
Mild Moderate Severe
$12,800
$4,800
$2,200
Cost/Patient/Year
1. Barnett SBL, et al. Costs of asthma in the United States: 2002–2007. J Allergy Clin Immunol 2011;127:145–52.2. Cisternas M, et al., A comprehensive study of the direct and indirect costs of an adult with asthma. J Allergy Clin
Immunol 2003;111(6):1212-1218.3. American Lung Association, Trends in Asthma Morbidity and Mortality, February 2010 report.
$4,000
$2,000
$6,000
$8,000
$10,000
$12,000Increased healthcare utilization
ER visits
Hospitalizations
Higher Cost of Severe Asthma
Higher healthcare costs with asthma severity2
Patients with exacerbations have higher health care costs than patients without exacerbations3
Est. $56B total cost of asthma1
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Asthma is a Complex Heterogeneous Disease
• Asthma likely encompasses many different disease variants with different etiologies and pathophysiologies
– Many phenotypes exist and are determined by clinical characteristics, physiology, triggers, and inflammatory parameters
– Multiple environmental and genetic factors contribute to the disease
Kim et al. Nat Immunol. 2010;11:577-584.Lotvall et al. J Allergy Clin Immunol. 2011; 127:355
“Old School”
Categorizing Asthma by Endotype
Phenotype:• Observable properties of an organism that are produced by
the interactions of the genotype and the environment• Encompasses the heterogeneity of clinical presentations but
do not provide insight into the underlying pathophysiology
Endotype:• A specific biologic pathway that explains the observable
properties of a phenotype• A subtype of a condition, which is defined by a distinct
functional or pathophysiological mechanism
Lotvall et al. J Allergy Clin Immunol. 2011; 127:355-60.Holgate et al. J Allergy Clin Immunol. 2011
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Classification by Endotype May Identify Appropriately Targeted Treatment
Approaches
• One of the major unmet needs in asthma lies with delivering mechanism-specific treatments that are highly effective in specific endotypes of asthma
• Understanding endotypes can identify those patients most likely to benefit from a particular type of therapy
– This strategy can be advantageous both in clinical study design and for the development of future targeted therapies
Lotvall et al. J Allergy Clin Immunol. 2011; 127:355-60.
Phenotypes based on TH2 vs non-TH2
Wenzel SE. Nat Med 2012;18:716–25
Se
veri
ty
TH
2
Alle
rgy/
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ratio
n
TH2 Non-TH2
AERD
Allergic asthma
Late-onset,eosinophilic
EIA
Verylate-onset,(women)
Obesity-associated
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Childhood Adult AdultAge at onset
No
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Biomarkers Play an Important Role in Patient Diagnosis and Management
• Biomarkers provide objective evidence for patient diagnosis and management in many disease states1
• Diagnose patients, assess disease severity, identify if additional treatment is required and/or what treatments patients will optimally respond to
• Examples of commonly used biomarkers• Diabetes: A1C
• Dyslipidemia: LDL, HDL, TG
• Cardiac disorders: troponin, CK-MB
• Hepatic disorders: AST, ALT
• Biomarkers may also be used to help assess and manage patients with asthma1,2 ALT = alanine transaminase; AST = aspartate transaminase; CK-MB = creatine kinase myocardial band; HDL = high-density
lipoprotein; LDL = low-density lipoprotein; TG = triglyceride.1. National Asthma Education and Prevention Program. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-138. 2. Chung KF. EurRespir J. 2014;43:343-373.
CONFIDENTIAL – NOT FOR PROMOTION – FOR INTERNAL PURPOSES ONLY – DO NOT DISTRIBUTE11
Potential Biomarkers for Asthma Assessment and Management1
EOS = eosinophil; FeNO = exhaled nitric oxide fraction; Ig = immunoglobulin.1. Chung KF. Eur Respir J. 2014;43:343-373.
Biomarker Characteristics
Sputum EOS
• Severe allergic and eosinophilic asthma• Increased exacerbations and poor lung function
Blood EOS • Severe allergic and eosinophilic asthma• Increased exacerbations and poor lung function
IgE • Severe allergic asthma
FeNO • Indicator of oxidative and nitrative stress• Severe allergic and eosinophilic asthma
Periostin • Potentially allergic and eosinophilic asthma
CONFIDENTIAL – NOT FOR PROMOTION – FOR INTERNAL PURPOSES ONLY – DO NOT DISTRIBUTE12
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Question 1
40 Year Old African American Male was diagnosed with asthma shortly after birth. He has history of allergic rhinitis. Hospitalized 15 times with one additional burst of steroids in the last year. During one hospitalization for asthma was in the ICU, but never intubated. Medications albuterol PRN and fluticasone/salmeterol (Advair) 500/50 1 puff BID. ACQ score today was 2.0. FEV1 1.93 L 50% predicted; post bronchodilator FEV1 increased to 2.50L 64% predicted (29% reversibility). 0.408 K/cu mm absolute blood eosinophils and total serum IgE 66 IU/ml.
The best predictor of a subsequent exacerbation of asthma in this patient is:
A. Bronchodilator reversibility
B. Blood eosinophils
C. African American race
D. ACQ score
E. Atopic history
40 Year Old African American Male was diagnosed with asthma shortly after birth. He has history of allergic rhinitis. Hospitalized 15 times with one additional burst of steroids in the last year. During one hospitalization for asthma was in the ICU, but never intubated. Medications albuterol PRN and fluticasone/salmeterol (Advair) 500/50 1 puff BID. ACQ score today was 2.0. FEV1 1.93 L 50% predicted; post bronchodilator FEV1 increased to 2.50L 64% predicted (29% reversibility). 0.408 K/cu mm absolute blood eosinophils and total serum IgE 66 IU/ml.The best predictor of a subsequent exacerbation of asthma in this patient is:
A. Bronchodilator reversibilityB. Blood eosinophilsC. African American raceD. ACQ scoreE. Atopic history
A. B. C. D. E.
7%
48%
7%
30%
7%
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Adjusted rate ratios (RRs) for severe exacerbations and acute respiratory events, and odds ratios (ORs) for asthma control, forpatients with peripheral blood eosinophil count greater than 400 cells per μL (vs 400 cells per μL or less) during 1 outcome year
Severe Exacerbations are Associated with High EOS Levels1
• Medical record data to identify primary care patients with asthma aged 12–80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after –20,929 (16%) of 130 248 had blood eos >400/μL.
Question 2
40 Year Old African American Male was diagnosed with asthma shortly after birth. He has history of allergic rhinitis. Hospitalized 15 times with one additional burst of steroids in the last year. During one hospitalization for asthma was in the ICU, but never intubated. Medications albuterol PRN and fluticasone/salmeterol (Advair) 500/50 1 puff BID. ACQ score today was 2.0. FEV1 1.93 L 50% predicted; post bronchodilator FEV1 increased to 2.50L 64% predicted (29% reversibility). 0.408 K/cu mm absolute blood eosinophils and total serum IgE 66 IU/ml.
The best description of this patient’s asthma phenotype is:
A. Severe eosinophilic asthma
B. Severe neutrophilic asthma
C. Chronic airflow obstruction asthma
D. Severe allergic asthma
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A. B. C. D.
48%
6% 9%
36%
40 Year Old African American Male was diagnosed with asthma shortly after birth. He has history of allergic rhinitis. Hospitalized 15 times with one additional burst of steroids in the last year. During one hospitalization for asthma was in the ICU, but never intubated. Medications albuterol PRN and fluticasone/salmeterol (Advair) 500/50 1 puff BID. ACQ score today was 2.0. FEV1 1.93 L 50% predicted; post bronchodilator FEV1 increased to 2.50L 64% predicted (29% reversibility). 0.408 K/cu mm absolute blood eosinophils and total serum IgE 66 IU/ml.The best description of this patient’s asthma phenotype is:
A. Severe eosinophilic asthmaB. Severe neutrophilic asthmaC. Chronic airflow obstruction
All mepolizumab doses P<.001 vs placebo at 52 weeks p=0.0082 for mepolizumab 750 mg vs placebo at 52 weeks
Mepolizumab: DREAM trial
Mepolizumab is not currently licensed for the treatment of asthmaPavord ID, et al. Lancet 2012;380:651–9
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Mepolizumab : MENSA study
Ortega H, et al. N Engl J Med. 2014;371:1198–207.
Primary endpoint - asthma exacerbations
Mepolizumab 100 mg SC is licensed for the treatment of severe eosinophilic asthma.
Ortega H, et al. N Engl J Med. 2014;371:1198–207.
IV, intravenous; SC, subcutaneous; SGRQ, St. George's Respiratory Questionnaire.
Mepolizumab 100 mg SC is licensed for the treatment of severe eosinophilic
9
15.416
0
2
4
6
8
10
12
14
16
18
Placebo 75 mg IV 100 mg SC
Change from baseline in SGRQ score
6.4 points difference *
7.0 points difference*
*p<0.001
Changes in SGRQ
Mepolizumab : MENSA study
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Bel EH et al. N Engl J Med 2014;371:1189-1197
Mepolizumab: Oral Steroid Sparing
Mepolizumab summary
Mepolizumab significantly reduces the number of asthma exacerbations in patients with severe eosinophilic asthma compared with placebo
Treatment lowers blood and sputum eosinophil counts (750 mg IV) but SC 100 mg Q4wks variable effects
There were small effects of mepolizumab on FEV1, QOL and ACQ scores, which generally did not differ significantly from those reported with placebo
Safety and tolerability profile for mepolizumab comparable to that for placebo
Pavord ID, et al. Lancet 2012;380:651–9Mepolizumab 100 mg SC is licensed for the treatment of severe eosinophilic asthma.
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Reslizumab 3 mg/kg q 4 weeks over 52 weeks in exacerbation-prone, uncontrolled asthmatics with elevated blood eosinophils
Pooled results (Studies 3082/3083)
PBOn=476
Reslizumab3 mg/kgn=477 RR (95% CI) % reduction
CAE* 1.81 0.84 0.46 (0.37, 0.58) 54%
CAE requiring systemic corticosteroid
1.54 0.66 0.42 (0.33, 0.55) 58%
Change from baseline over 52 weeks Resli-PBO (95% CI)
FEV1, L 0.12 0.22 0.11 (0.07, 0.15)
AQLQ 0.81 1.08 0.27 (0.16, 0.39)
ACQ –0.77 –1.02 –0.250 (–0.34, –0.16)
ASUI 0.12 0.17 0.05 (0.03, 0.07)
*CAE defined as a worsening requiring additional corticosteroid and/or other urgent treatment including ER/hospital
Reslizumab is not currently licensed for the treatment of asthmaCastro M, et al. Lancet Respir Med 2015;3:355–66
Reslizumab effect on lung function
Change from baseline to each visit in FEV1 by treatment group: pooled results for studies 3082/3083
** p<0.01
Reslizumab is not currently licensed for the treatment of asthmaCastro M, et al. Lancet Respir Med 2015;3:355–66
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Influence of background therapy on asthma exacerbations with reslizumab
Reslizumab was efficacious in reducing CAE regardless of the treatments patients were receiving at baseline
0.46 (0.37–0.58) 477 476
0.32 (0.18–0.55) 73 73
0.45 (0.35–0.58) 397 383
0.51 (0.29–0.89) 80 93
nReslizumab Placebo
Rate-Ratio*(95% CI)
Rate ratio
–0.1 0 0.3 0.6 0.90.20.1 0.4 0.5 0.7 0.8 1.0 1.1
*Reslizumab relative to placebo
ICS no LABA
ICS plus LABA
OCS at baseline
All
Reslizumab is not currently licensed for the treatment of asthmaCastro M, et al. Lancet Respir Med 2015;3:355–66
Predicting response to reslizumab
2.16
1.73 1.72
0.63 0.67 0.7
0
0.5
1
1.5
2
2.5
FEV1Responder
ACQ6Responder
FEV1 or ACQ6Responder
An
nu
al C
AE
rat
e
Placebo Reslizumab
–60%
–71%
–61%
Pooled studies 3082 and 3083: Percentage CAE reduction
1.57
1.972.12
1.171.27
1.57
0
0.5
1
1.5
2
2.5
FEV1Non-Responder
ACQNon-Responder
FEV1 or ACQNon-Responder
–26%
–25%
–36%
Bateman ED, et al. Abstract A7782. Presented at ATS 2016
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Reslizumab summary
Patients receiving reslizumab (3 mg/kg IV Q 4wks) showed significantly greater reductions in sputum eosinophils, asthma exacerbations, improvements in airway function, and greater asthma control than those receiving placebo
Reslizumab can be targeted to the patients most likely to benefit by applying fairly simple blood eosinophil, asthma control, lung function, and disease severity criteria
Reslizumab was generally well-tolerated
Reslizumab is not currently licensed for the treatment of asthma
Benralizumab (anti-IL-5Rα)
A targeted, anti-eosinophil therapy under investigation for asthma
• Eosinophils are thought to play a critical role in the pathogenesis and severity of asthma2
• ~40–60% of people with severe asthma have eosinophilic inflammation3
• Increased eosinophil count is associated with an increased frequency of exacerbations2
• IL-5R is important in mediating the differentiation, proliferation, and activation of eosinophils by IL-54
Benralizumab is a humanized, afucosylated monoclonal antibody (IgG1k) that binds with high affinity to IL-5Rα and efficiently depletes eosinophils through antibody-dependent cell-mediated cytotoxicity (ADCC)1
1. Kolbeck R, et al. J Allergy Clin Immunol 2010;125:1344–53; 2. Green RH, et al. Lancet 2002;360:1715–213. Douwes J, et al. Thorax 2002;57:643–8; 4. Long AA. mAbs 2009;1:237–46
Benralizumab is not currently licensed for the treatment of asthma
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Benralizumab
ACQ-6; Asthma Control Questionnaire-6; AER, annual exacerbation rate (total observed exacerbations to week 52 divided by total duration of person-year follow-up); CBC, complete blood count with differential; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroids; ppb, parts per billion
• Primary endpoint: AER
• Secondary endpoints: FEV1, ACQ-6
Eosinophilic phenotype
• ELEN Index positive and/or
• FeNO ≥50 ppb
Non-eosinophilic phenotype
• ELEN Index negative and
• FeNO <50 ppb
ELEN Index: mathematical algorithm to
predict sputum eosinophils from CBC data1
Castro M, et al. Lancet Resp Med 2014,2:879–90
Benralizumab is not currently licensed for the treatment of asthma
*Statistically significant (p<0.169)†Data are expressed as mean (80% CI)
• Benralizumab 20 mg significantly reduced AER relative to placebo in patients with baseline blood eosinophils ≥300 cells/µL
• Benralizumab 100 mg significantly reduced AER relative to placebo in eosinophilic patients and in patients with baseline blood eosinophils ≥300 and ≥400 cells/µL
AERR, annual exacerbation rate reduction; RR, rate reduction Castro M, et al. Lancet Resp Med 2014,2:879–90
Benralizumab is not currently licensed for the treatment of asthma
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Benralizumab (anti-IL-5Rα)
Placebo(n=248)
Benralizumab30 mg Q4W
(n=241)
Benralizumab30 mg Q8W
(n=239)
Ann
ual a
sthm
a ex
acer
bati
on ra
te (
95%
CI)
0ꞏ2
0ꞏ4
0ꞏ6
0ꞏ8
1ꞏ2
1ꞏ4
(0ꞏ48–0ꞏ74)* (0ꞏ54–0ꞏ82)
–36% –28% –36% –40%
Placebo(n=122)
Benralizumab30 mg Q4W
(n=116)
Benralizumab30 mg Q8W
(n=125)
B. Eosinophils <300 cells/µL
0ꞏ2
0ꞏ4
0ꞏ6
0ꞏ8
1ꞏ2
1ꞏ4
†
(0ꞏ77–1ꞏ12)
(0ꞏ59–1ꞏ02)(0ꞏ55–0ꞏ95)
(0ꞏ96–1ꞏ52)
Ann
ual a
sthm
a ex
acer
bati
on ra
te (
95%
CI)
Percentage reduction relative to placebo Percentage reduction relative to placebo
A. Eosinophils ≥300 cells/µL
‡ §
0ꞏ0
1ꞏ0
0ꞏ0
1ꞏ0
Sirocco Calima
Fitgerald M, et al. Lancet 2016Bleecker E, et al. Lancet 2016
Estimates calculated using a negative binomial model, with adjustment for treatment, region, oral corticosteroid use, and prior exacerbations. Sirocco: *p <0·0001. †p =0·0471. Calima: *p=0·0018. †p=0·0188. ‡p=0·0150. §p=0·0048.CI=confidence interval. Q4W=once every 4 weeks; Q8W=once every 8 weeks.
Benralizumab: conclusions
In patients with uncontrolled asthma, benralizumab 30 mg SC Q 4 and 8 wks moderately reduced exacerbations
In patients with high eosinophils (≥300/L), benralizumab Q 8 wksimproved lung function and asthma control compared with placebo
Benralizumab had an acceptable safety profile at all doses
Attractive every other month dosing option
Benralizumab is not currently licensed for the treatment of asthma
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Question 3
42 Year old female (BMI 33), diagnosed asthma age 32, has severe uncontrolled persistent asthma despite high dose fluticasone (1,000 mcg/day), salmeterol, and tiotropium. She has had 4 courses of corticosteroids in the past year and one hospitalization for asthma resulting in BiPAPtherapy. Baseline FEV1 of 1.60 L 65% of predicted, post-bronchodilator FEV1 increased to 2.02L. 0.440 K/cu mm absolute blood eosinophils and total serum IgE 660.
Which of the following currently available biologic therapy would be most appropriate for this patient?
A. Omalizumab
B. Mepolizumab
C. Dupilumab
D. Reslizumab
E. Epinephrine pen
A. B. C. D. E.
16%
41%
0%
41%
3%
42 Year old female (BMI 33), diagnosed asthma age 32, has severe uncontrolled persistent asthma despite high dose fluticasone (1,000 mcg/day), salmeterol, and tiotropium. She has had 4 courses of corticosteroids in the past year and one hospitalization for asthma resulting in BiPAP therapy. Baseline FEV1 of 1.60 L 65% of predicted, post-bronchodilator FEV1 increased to 2.02L. 0.440 K/cu mm absolute blood eosinophils and total serum IgE 660.Which of the following currently available biologic therapy would be most appropriate for this patient?
A. OmalizumabB. MepolizumabC. DupilumabD. ReslizumabE. Epinephrine pen
Dupilumab, a fully human monoclonal antibody against the IL-4 receptor alpha subunit, inhibits IL-4 and IL-13 signaling
Multinational, 24-week, randomized, double-blind, placebo-controlled, dose-ranging study in patients with persistent, uncontrolled asthma despite use of medium-to-high dose ICS/LABA
To ensure a balanced distribution of blood eosinophil (Eos) counts in patients across treatment regimens, randomization was stratified by blood Eos count at screening: ≥ 300 cells/µL, 200–299 cells/µL, and < 200 cells/µL
Randomization(1:1:1:1:1)
n = 150 Dupilumab 300 mg q4w with loading dose (600 mg)n = 150 Dupilumab 300 mg q4w with loading dose (600 mg)
n = 150 Dupilumab 200 mg q2w with loading dose (400 mg)n = 150 Dupilumab 200 mg q2w with loading dose (400 mg)
n = 150 Dupilumab 200 mg q4w with loading dose (400 mg)n = 150 Dupilumab 200 mg q4w with loading dose (400 mg)
n = 150 Placebon = 150 Placebo
n = 150 Dupilumab 300 mg q2w with loading dose (600 mg)n = 150 Dupilumab 300 mg q2w with loading dose (600 mg)
24-week treatment period
q2w, every 2 weeks; q4w, every 4 weeks.
Screening period
(14–21 days)
Screening period
(14–21 days)
Dupilumab or placebo was added on to therapy
with ICS/LABA
Wenzel S, Castro M, et al Lancet 2016; 388: 31–44
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Overall population
Ad
just
ed a
nn
ual
ized
sev
ere
exac
erb
atio
n r
ate,
est
imat
e (9
5% C
I)
1.4
0.2
0
1.0
1.2
0.4
0.8
0.6
Placebo(n = 158)
200 mgq4w
(n = 150)
300 mgq4w
(n = 157)
200 mgq2w
(n = 148)
300 mgq2w
(n = 156)
95% CI0.16, 0.45
95% CI0.16, 0.46
95% CI0.40, 0.9195% CI
0.26, 0.66
95% CI0.62, 1.30
********
–70%–70%–33%–54%
Eos < 300 cells/µL
Ad
just
ed a
nn
ual
ized
sev
ere
exac
erb
atio
n r
ate,
est
imat
e (9
5% C
I)
1.4
0.2
0
1.0
1.2
0.4
0.8
0.6
Placebo(n = 90)
200 mgq4w
(n = 91)
300 mgq4w
(n = 91)
200 mgq2w
(n = 84)
300 mgq2w
(n = 92)
95% CI0.17, 0.58
95% CI0.12, 0.52
95% CI0.29, 0.84
95% CI0.25, 0.79
95% CI0.49, 1.23
***
–60%–68%–37%–43%
Dupilumab: Severe Exacerbation RateEos ≥ 300 cells/µL
Ad
just
ed a
nn
ual
ized
sev
ere
exac
erb
atio
n r
ate,
est
imat
e (9
5% C
I)1.4
0.2
0
1.0
1.2
0.4
0.8
0.6
Placebo(n = 68)
200 mgq4w
(n = 59)
300 mgq4w
(n = 66)
200 mgq2w
(n = 64)
300 mgq2w
(n = 64)
95% CI0.08, 0.52
95% CI0.13, 0.68
95% CI0.36, 1.29
95% CI0.16, 0.81
95% CI0.57, 1.90
****
–81%–71%–35%–66%
The annualized exacerbation rate was adjusted for treatment duration in patients who discontinued prematurely. Arrows represent percent change relative to placebo.*P < 0.05, **P < 0.01, ***P < 0.001 vs placebo.CI, confidence interval.
• At Week 24, the q2w regimens showed a significant decrease in severe asthma exacerbation rates in patients with Eos ≥ 300 cells/µL, patients with Eos < 300 cells/µL, and the overall population
Wenzel S, Castro M, et al Lancet 2016; 388: 31–44
Anti-IL-13: lebrikizumab in moderate asthma
IL-13 induces bronchial epithelial cells to secrete periostin1,2
Patients with high pretreatment levels of serum periostin had greater improvement in lung function with anti-IL-13 therapy than patients with low periostin levels3
FEV1, forced expiratory volume in 1 second; IL, interleukin.1. Woodruff PG, et al. Proc Natl Acad Sci USA 2007;104:15858-63; 2. Sidhu SS, et al. Proc Natl Acad Sci USA 2010;107:14170-5; 3. Corren J, et al. N Engl J Med 2011;365:1088–98. Lebrikizumab is not currently licensed for the treatment of asthma.
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Anti-IL-13: lebrikizumab in severe asthma
Hanania N, et al Lancet Resp Med 2016; 2016 4, 781-79
Anti-IL-13: lebrikizumab in severe asthma
Hanania N, et al Lancet Resp Med 2016; 2016 4, 781-79
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Anti-IL13: tralokinumab in severe asthma
RCT phase 2b study of 452 patients with severe asthma (2–6 exacerbations in previous year) treated with placebo or tralokinumab Q2W or Q2W for 12 weeks then Q4W– Neither tralokinumab regimens significantly reduced asthma exacerbation rates:
• Annual asthma exacerbation rate at week 52 was similar with tralokinumab Q2W (0.91 per patient per year [0.76–1.08]), Q4W (0.97 [0.81–1.14]) and placebo (0.90 [0.75–1.08])
In patients with high biomarkers (greater than the median):– Serum dipeptidyl peptidase-4 (DPP-4) - improvements in pre-bronchodilator FEV1, ACQ-6, and
AQLQ(S)
– Periostin concentrations - improvements in asthma exacerbation rate, pre-bronchodilator FEV1, and ACQ-6
Brightling CE, et al. Lancet Respir Med. 2015;3:692–701.
ACQ-6; Asthma Control Questionnaire-6; FEV1, forced expiratory volume in 1 second;IL, interleukin; Q2W, every 2 weeks; Q4W, every 4 weeks.
Tralokinumab is not currently licensed for the treatment of asthma.
Question 4
22 Year old female (BMI 33) diagnosed with asthma at age 2 has severe uncontrolled persistent asthma despite high dose fluticasone (1,000 mcg/day), salmeterol, and tiotropium with history of allergic rhinitis and urticaria. She has had 4 courses of corticosteroids in the past year and one hospitalization for asthma resulting in BiPAP therapy. Baseline FEV1 2.70 L 95% of predicted, post-bronchodilator FEV1 increased to 3.02L (107% predicted, 12% reversibility), 0.240 K/cu mm absolute blood eosinophils, FeNO 55 ppb and total serum IgE 660.
Which of the following currently available biologic therapy would be most appropriate for this patient?
A. Omalizumab
B. Mepolizumab
C. Dupilumab
D. Reslizumab
E. Epinephrine pen
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A. B. C. D. E.
33%
18%
36%
12%0%
22 Year old female (BMI 33) diagnosed with asthma at age 2 has severe uncontrolled persistent asthma despite high dose fluticasone (1,000 mcg/day), salmeterol, and tiotropium with history of allergic rhinitis and urticaria. She has had 4 courses of corticosteroids in the past year and one hospitalization for asthma resulting in BiPAP therapy. Baseline FEV1 2.70 L 95% of predicted, post-bronchodilator FEV1 increased to 3.02L (107% predicted, 12% reversibility), 0.240 K/cu mm absolute blood eosinophils, FeNO 55 ppb and total serum IgE 660.Which of the following currently available biologic therapy would be most appropriate for this patient?
A. OmalizumabB. MepolizumabC. DupilumabD. ReslizumabE. Epinephrine pen
Rodrigo GJ, et al. Chest. 2011;139:28-35.
Omalizumab: anti-IgE therapy for severe eosinophilic asthma?
Exploratory analysis revealed greatest effect in high biomarker subsets (median FeNO, Blood EOS, Periostin)2
EXTRA study: exacerbations reduced in severe asthma patients treated with high dose ICS+LABA: omalizumab vs. placebo RR 0.75 [0.61-0.92]1
1. Hanania N, et al. Ann Int Med 2011,154:573–82; 2. Hanania N, et al Am J Respir Crit Care Med 2012; 187:804–11.
Anti-IL-8CXCR2 antagonistsAnti-LTB4 (adults and children)Macrolides (adults and children)
Chronic airflow obstruction
Airway wall remodelling as increased airway wall thickness
Anti-IL13Bronchial thermoplasty
Recurrent exacerbations
Eosinophils in sputumReduced response to ICS ±OCS
Anti-IL5Anti-IgE (adults and children)
Corticosteroid insensitivity
High neutrophils in sputum2 p38 MAPK inhibitorsTheophylline (adults and children)Macrolides (adults and children)
Potential phenotype-targeted therapiesin severe asthma
International ERS/ATS GUIDELINES Eur Respir J, 2014; 43(2):343-373
B cell
TH2
APC
Eosinophil
Smooth muscle hypertrophy
Mast cell
IL‐5
IL‐4IL‐13
IL‐4IL‐13
IgE
MepolizumabReslizumab
Benralizumab
Omalizumab
DupilumabLebrikizumab Bronchial
thermoplasty
DupilumabLebrikizumab
Airway LumenAllergen
Site of action of targeted therapies for severe asthma.
*Trivedi A et al Lancet Resp 2016 In press
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Phenotype-guided approach in severe asthma with biologics
Many phenotypes exist in asthma though the biologic pathway (endotype) is unclear for most
Ongoing studies of large-scale, molecularly and genetically focused and extensively clinically characterized cohorts of asthma should enhance our ability to molecularly understand these phenotypes
Biologic therapy with anti-IL 5 for the eosinophilicuncontrolled asthma is a well established endotype but likely represents less 40% of uncontrolled asthma
Promising evidence for anti-IL4 R for uncontrolled asthma, especially the non-eosinophilic patient
Phenotype-guided approachin severe asthma with biologics
Targeted phenotype therapy can lead to personalized medical therapy for asthma
Many questions remain:
– Are there better biomarkers than the blood EOS?
– Is anti-IL-4/13 therapy as effective as anti-IL-5?
– Will other biologic targets work?• Anti-IL-17, -23, -33, anti-TSLP, -CRTH2, and more
– Is chronic airflow obstruction and airway remodeling responsive to biologics?
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