Treatment of Severe Asthma: Biologics to Bronchial Thermoplasty Monica Kraft, M.D. Robert and Irene Flinn Professor of Medicine Chair, Department of Medicine Deputy Director, Asthma and Airway Disease Research Center University of Arizona Health Sciences Center Tucson, Arizona Disclosures Research (funds paid to U of Arizona): NIH, Roche, Sanofi, Chiesi Consulting: TEVA, Astra-Zeneca, Regeneron (all < $5) Royalties: Elsevier HPI: 38 year old female with severe persistent asthma on chronic oral steroid therapy p/w increasing SOB and worsening wheezing. Asthma history Diagnosed with asthma at age 13 3-4 hospitalizations for asthma throughout her life Endotracheal intubation X 1 for status asthmaticus Chronic steroid dependence since 23 Has been treated for contributing diseases GERD, Allergic rhinitis (h/o nasal polyps) Current status: Daily symptoms of shortness and wheezing, limited activity Use of rescue inhalers 6-8x/day Adherent with her medical regimen
Past Medical History: 1.Severe Persistent Asthma 2. Allergic rhinitis 3. GERD 4. Fibromyalgia 5.Major Depressive Disorder Allergies: ASA- causes rash and wheezing Medications: 1.Methylprednisolone 32 mg daily 2.Fluticasone/Salmeterol 5/5 mcg inhalation b.i.d. 3. Montelukast 1 mg daily 4. DuoNebs as needed 5. Albuterol INH 3-4 times daily 6. Omeprazole 2 mg twice daily 7. Loratadine 1 mg daily 8. Fluticasone Nasal 1 puff twice daily 9.Calcium/Vitamin D 1. Alendronate 7 mg weekly 11. Omalizumab 3 mg q 2 weeks Social History: Married with 3 children and husband, 2 dogs, outside cats, office work with no exposures, non-smoker. Family History: mother with asthma and atopic dermatitis Physical Exam: Pulmonary- prolonged expiration with moderate air movement and diffuse expiratory wheezing.
Pulmonary Function Testing: Ref Best % Pred FVC 3.5 2.4 78% FEV1 2.65 1.27 48% FEV1/FVC 86 53 FEF 25-75% 3.28.58 18% PEF 5.78 2.89 5% MVV 19 45 41% Additional biomarkers FeNO: 25 ppb Peripheral eosinophils: 25 The GINA Report Has A More Updated Treatment Approach for Adults, Adolescents, and Children (ages 6-11) STEP 4 STEP 5 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low-dose ICS STEP 3 Low-dose ICS/LABA Med/high ICS/LABA Refer for add-on treatment e.g. tiotropium, anti-ige, anti-il5 Other controller options RELIEVER Consider lowdose ICS Leukotriene receptor antagonists (LTRA) Low-dose theophylline As-needed short-acting beta 2 -agonist (SABA) Med/high-dose ICS Low-dose ICS+LTRA (or + theoph) Not for children <12 years For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations Add tiotropium High-dose ICS + LTRA (or + theoph) As-needed SABA or low dose ICS/formoterol # Add lowdose OCS
What is Asthma? Asthma Early onset Late onset Symptoms Exacerbations FEV1 T H2 inflammation Eosinophilic No or less T H2 inflammation Non-eosinophilic Phenotype A Phenotype B Phenotype C Phenotype D. Wenzel S. Nature Medicine18, 716 725 (212) Asthma Inflammatory Phenotypes: Early Investigation Wenzel et al. AJRCCM 1999; 16:11
A pathologic comparison of eosinophilic and non-eosinophilic asthma Berry et al. Thorax 27;62:143 Quality of Life after Inhaled Corticosteroids (Berry et al.) Berry et al. Thorax 27;62:143 Airways Hyperresponsiveness After Inhaled Corticosteroids (Berry et al.) Berry et al. Thorax 27;62:143
Asthma Phenotypes Phenotype: observable properties of an organism that are produced by the interactions of the genotype and the environment Asthma phenotypes are based on clinical characteristics, triggers or general inflammatory processes have been proposed and do not always suggest an underlying mechanism Endotype: a specific biological pathway is identified that explains the observable properties of a phenotype Th2/T2 asthma T2/Th2-associated asthma linked to: atopy and allergy type I hypersensitivity reactions eosinophilic inflammation and response to corticosteroids Early-onset (preadolescence) mostly atopic and allergic asthma phenotype Strong family history of atopic disease Overlap with other co-morbid atopic conditions: allergic rhinitis and atopic dermatitis Early-onset allergic asthma can present with mild to severe disease; unclear whether mild allergic asthma progresses to severe disease or whether severe allergic asthma arises in childhood and remains severe Can be exacerbated by obesity Overview of Asthma Phenotypes T H 2/T2 Non T H 2/T2 AERD Late-onset eosinophilic Non-T H2 Severity T H2 Allergy/duration Allergic asthma EIA Very Late onset, (women) Obesityassociated Smoking-associated neutrophilic Smooth-muscle mediated, neutrophilic Pollutants/exposures Infection (viral, bacterial) Childhood Adult Age at onset Adult Adaptedfrom Wenzel S. Nature Medicine18, 716 725 (212)
Biomarkers to identify the Th2 phenotype Sputum eosinophils Exhaled nitric oxide Circulating eosinophils Periostin -? Future DPP4 IgE Allergen skin testing Eosinophil Peroxidase? EPX is increased in eosinophilic asthma and correlates with sputum eosinopils Rank et al. Allergy 216;7:567
CC16 Club (formerly Clara) cell secretory protein Pneumoprotein: produced mainly by non-ciliated airway epithelial cells (including club cells) Possible protective effects from noxious exposures and against obstructive lung diseases (asthma and COPD) Serum levels substantially reduced in smokers Cross-sectional associations with asthma and COPD Currently being investigated in longitudinal studies CC16 levels in childhood and lung function decline Guerra et al, Lancet Resp Med 215 Airway epithelial CC16 gene expression and asthma outcomes Table 1 Association Test (BEC CC16 mrna levels) P-value (n=17) Healthy Control vs Asthma.388 Mild vs Moderate vs Severe Asthma.263 Healthy Control vs Mild vs Moderate vs Severe Asthma.6 Kraft, Ledford, Li Bleecker & SARP ATS 218 Table 2 Association Test (BEC CC16 mrna levels) P-value (n=17) Baseline FEV 1 (% predicted).97 Baseline FVC (% predicted).196 Baseline FEV 1 /FVC.6 Maximal FEV 1 (% predicted).361 Maximal change in FEV 1 (reversibility).228 Table 3 Association Test (BEC CC16 mrna levels) P-value (n=17) ER/urgent care visit for asthma in last year no (n=61) yes (n=43).499 Oral or infected corticosteroid use no (n=82) yes (n=22).42
What Are Treatment Options for the T2/Eosinophilic Phenotype Beyond Combination Therapy? Treatments approved or under development Jak/stat Inh Omalizumab Muraro et al. JACI 216 137, 1347-1358 Omalizumab Significantly Reduces Submucosal Eosinophils Eosinophils (cells/mm 2 ) 8 P=.33 P=.81 8 6 6 4 P<.1 2 8. 1.5 Baseline Posttreatment Omalizumab (n=14) Djukanovic et al. AJRCCM 24 4 2 6.3 6.4 Baseline Posttreatment Placebo (n=14)
Seasonal Variation in Days with Symptoms, Frequency of Exacerbations, and Dose of Inhaled Glucocorticoids. Busse WW et al. N Engl J Med 211; 364:15-115 How Does Omalizumab Compare With New Biologics In Similar Patients? Reduction in protocol-defined Asthma exacerbation rate (Mean %, 95% CI) 4 2 Effect of omalizumab based on Th2 biomarkers 2 4 6 8 FeN Eosinophils Periostin <19.5 ppb 19.5 ppb <26/µL 26/µL <5 ng/ml 5 ng/ml 16 n = 193 P=.45 53 n = 21 P=.1 9 n = 383 P=.54 32 3 n = 414 P=.5 n = 279 P=.94 3 n = 255 P=.7 Exacerbation reduction P-values; omalizumab versus placebo in each biomarker subgroup. Hanania NA et al. Am J Respir Crit Care Med. 213;187:84-811. 29 Mepolizumab (anti-il-5) in Severe, Eosinophilic Asthma (Pavord et al. Lancet 212;38:651)
Reslizumab for Poorly Controlled Eosinophilic Asthma 16 patients randomized to reslizumab 3 mg/kg vs. placebo (IV dosing at weeks, 4, 8, and 12). Sputum eosinophil count reduced by 95.4% in -.2 reslizumab group vs. 38.7% -.4 in placebo group (P=.68) -.6 Mean change in FEV1 was p=ns.8 in the placebo group -.8 versus +.18 in reslizumab -1. group (P=.23) p=.7-1.2 Exacerbations reduced (P=.8) Week Greater change from baseline in patients with nasal polyps 1. vs..1 with placebo (P=.12) Percent Change in ACQ Score p=ns Resli zum ab Placebo p=ns 2 4 6 8 1 12 14 16 Castro M et al. Am J Respir Crit Care Med. 211;184:1125-1132. 31 Reslizumab Effects on Exacerbations and Lung Function Probability of not having CAE (%) 1 9 8 7 6 5 4 3 2 1 Placebo; n = 244 Reslizumab 3. mg/kg; n = 245 HR =.575 (95% CI.44.75) P<.1 Placebo Reslizumab 1 2 3 4 5 6 7 8 Visit (week) No. at risk Placebo 244 169 138 112 17 97 Reslizumab 245 27 177 158 146 136 1 LS mean change from baseline in FEV 1 (L).4.3.2.1 Placebo Reslizumab 3. mg/kg 4 8 12 16 2 24 28 32 36 4 44 48 52 Endpoint Visit (week) HR = hazard ratio; CI = confidence interval; LS = least square (mean). Castro M et al. Lancet Respir Med. 215;3:355-366. 32 Benralizumab (anti-il-5rα) Benralizumab is a humanised, afucosylated monoclonal antibody (IgG1k) that binds with high affinity to IL-5Rα and efficiently depletes eosinophils by inducing apoptosis through ADCC
Benralizumab Phase III (Sirocco) Bleecker et al. Lancet 216;388:2115-2127 Benralizumab Phase III (CALIMA) Fitzgerald et al. Lancet 216;388:2128-2141 Lung Function: % Change in FEV 1 Placebo Dup 2q4w Dup 3q4w Dup 2q2w Dup 3q2w LS mean % change (± SE) LS mean % change (± SE) 3 2 1 3 2 1 HEos population 2 4 8 12 Week Overall population 2 4 6 8 1 12 Week LS mean % change (± SE) 3 2 1 LEos population 2 4 8 12 Week In the overall population, significant improvement was observed for all dupilumab dose regimens versus placebo In the LEos population, significant improvement was observed for the q2w regimens versus placebo, but not for the q4w regimens Wenzel et al. Lancet 216 ; P <.5, P <.1, P <.1 vs placebo; Dup, dupilumab; LS, least squares; SE, standard error
Adjusted annualized severe exacerbation rate - estimate (95% CI) Adjusted Annual Severe Exacerbation Event Rate 1.8 1.6 1.4 1.2 1..8.6.4.2. Placebo (N = 68) HEos population 1.8 26% 74% 64% 75% 51% 46% 68% 62% 1.6 2 mg q4w (N = 59) 3 mg q4w (N = 66) 2 mg q2w (N = 64) 3 mg q2w (N = 64) Adjusted annualized severe exacerbation rate - estimate (95% CI) 1.4 1.2 1..8.6.4.2. Placebo (N = 9) LEos population 2 mg q4w (N = 91) 3 mg q4w (N = 91) 2 mg q2w (N = 84) 3 mg q2w (N = 92) Adjusted annualized severe exacerbation rate - estimate (95% CI) 1.8 1.6 1.4 1.2 1..8.6.4.2. Placebo (N = 158) Overall population 57% 38% 67% 68% 2 mg q4w3 mg q4w2 mg q2w3 mg q2w (N = 15) (N = 157) (N = 148) (N = 156) In the HEos and overall populations, significant decreases in severe asthma exacerbation rates were observed for all dupilumab regimens versus placebo, except the 3 mg q4w In the LEos population, significant decreases in severe asthma exacerbation rates were observed for the dupilumab q2w regimens versus placebo Wenzel et al. Lancet 216 The annualized rate of asthma exacerbation events (eg, LOAC, severe exacerbation) was analyzed using a negative binomial regression model. The model included the total number of events occurring during the double-blind treatment period as the response variable, with treatment group, pooled countries/regions, and number of asthma events prior to the study as covariates. Arrows represent percent change compared to placebo.p <.5, P <.1, P <.1 vs placebo; CI, confidence interval. Treatments under development Non T2 imatinib Macrolides IL-17 IL-1 IL-6 Bacterial products Bronchial Thermoplasty Adapted from Muraro et al. JACI 216 137, 1347-1358 Asthma Phenotypes and Macrolides Brusselle et al. recruited 19 subjects with asthma, on combination therapy (Thorax 213;177:148) Subjects were exacerbation prone as they were required to have had two exacerbations requiring oral corticosteroids or LRTI requiring antibiotics in the previous 12 months Azithromycin vs. placebo added to combination therapy for 6 months in a double-blind fashion Primary outcome was the rate of exacerbations and LRTI requiring antibiotics
Asthma Phenotypes and Macrolides- Results in the Entire Cohort Brusselle et al. Thorax 213;177:148 Results in Nonoesinophilic Asthma Only (defined as blood eos < 2/µl) Brusselle et al. Thorax 213;177:148 Phenotype agonistic: Macrolides? Gibson PG et al. Lancet 217: 39:659-668
Tiotropium in Severe Asthma Kerstjens et al. NEJM 212 Predictors of Response to Tiotropium (JACI 213;132:168 ) Bronchodilator response to albuterol Reduced FEV1/FVC ratio Higher cholinergic tone (lower resting HR) What did not predict response: Ethnicity, gender, atopy, IgE, sputum eos, FeNO, BMI, asthma duration Airway Smooth Muscle Airway Smooth Muscle Normal Airway Asthmatic Airway
Bronchial Thermoplasty 9 AIR2 Trial 1. 8 Net Benefit = 19% PPS (Alair - Sham) = 1.% 79 76 Sham Alair 7 64.8 32% Percent of Subjects 6 5 4 3 2 1 57 29 18 7 3 ² -.5 > -.5 to <.5 ³.5 Net Bene fit Sham Alair Events/ Subject/ Year.6.4.2..7.48 Severe Exacerbations 23%.36.28 Unsched. Office Visits.43 84%.7 ER Visits.13.14 73%.4.4 Hospitalizations PPS = 95.6%, PPS= 95.6% Castro M et al. Am J Respir Crit Care Med. 21;181(2):116-24 Five Year Safety Data AIR2 Study Wechsler M et al. J All Clin Immunol 213;132:1295 Comparison of two BT trials AIR2 and PAS2 Exacerbations # subj & rate Emergency Dept # subjects & rate Hospitalizations # subjects & rate Chupp et al ERJ 217; 5: 1717
New Concept: How Can Early Immune Development Lead to Protection from Asthma? Bacterial Extracts Bacterial extracts (OM-85BV) are extracts of bacteria such as H. influenzae, D. pneumonia, K. ozaenae, K. pneumoniae, S. aureus, S. pyogenes, S. viridans, and N. catarrhalis It is a mixture of acidic proteins, peptides and amino acids, with minor components of detoxified LPS and lipoteichoic acids
Clinical Use of Bacterial Extracts Bacterial extracts have been widely used in Europe for the last 2-3 decades in children and adults as oral medicines to reduce the frequency and duration of upper respiratory infections. They have also been used in the prevention of acute symptoms in cystic fibrosis and chronic obstructive pulmonary disease (COPD). Studies with OM85-BV in Asthma OM58-BV reduced the frequency and duration of wheezing episides in children with asthma. (Razi et al. J Allergy and Clinical Immunology 21) The overall incidence of adverse effects in clinical trials was between 3 and 4%. Gastrointestinal troubles and respiratory disorders were the most frequent complaints reported. OM85-BV was also studied in an animal model of asthma and found to be protective through the development of an important type of cell in the lungs that stops inflammation, the T regulatory cell. ORBEX Trial Schemata WLRI outcome Asthma outcome OM-85BV Usual Rx Run-in Placebo Usual Rx 162 6-18 mo olds at high risk for asthma 2 yrs 1 yr
Our Approach to Asthma is Changing Our understanding of the biology of asthma heterogeneity has improved dramatically. The use of clinical characteristics, biomarkers and response to treatment will further hone our ability to deliver personalized/precision therapy. We need readily available point-of-care biomarkers to make real time decisions regarding therapies for our patients.