New Therapies for Asthma Tracy Bridges, MD Speaker Disclosure: Dr. Bridges participates in speaker bureaus for Teva, Genetech & Astra Zeneca. Objectives: Discuss the use of LAMA s for Asthma Detail the use of biologics to target IgE Describe the use of biologics to target IL5, IL4, IL13 What has happened in Asthma Pharmacology in the last few years? Tracy Bridges, MD Allergy and Asthma Clinics of Georgia Georgia Pollens Clinical Research What s new in Inhaled Therapy for Asthma? In NHLBI Guidelines for treatment of asthma, Inhaled Corticosteroids (ICS) and Inhaled Corticosteroids PLUS Long Acting Beta Agonists (ICS+LABA) are integrally positioned at in the guidelines for treatment of asthma. Inhaled Corticosteroids are Cornerstone Therapies for Asthma in the NHLBI Guidelines 1
Traditional ICS available for years Fluticasone propionate BID (HFA/DISKUS) Mometasone furoate BID/QD(HFA/Twisthaler) Budesonide BID/QD (Flexhaler/Respules) Beclomethasone dipropionate BID (HFA) Ciclesonide BID (HFA) Flunisolide BID (HFA) Recent ICS NEW Flunisolide (80 mcg) HFA in MDI with Built in Spacer to be used BID for maintenance therapy for asthma Age 6 12: 1 2 puffs BID Age >12: 2 4 puffs BID Fluticasone Furoate (100 and 200 mcg) Dry Powder Inhaler Age 12 and above: 1 puff QD Benefits: improved lung function and decreased albuterol use Benefits of ICS Flunisolide HFA Benefits Primary Endpoints: Improvement in FEV1 vs. Placebo at dose of 160 mcg and 320 mcg BID Secondary Endpoints: AM Peak Flow, AM and PM asthma sx., Nocturnal Awakenings, PRN SABA use 2
Fluticasone furoate Fluticasone Furoate Benefits Primary Endpoints: Statistical change in trough FEV1 from baseline to end of study (Weeks 12 or24) [100 mcg 146ml 186ml improvement] & [200 mcg 284 ml improvement] Special Note: Studies including Fluticasone Furoate 200 mcg QD and Fluticasone Propionate 500 mcg BID demonstrate improvements in FEV1 = 328ml and 258ml RESPECTIVELY Implication: Fluticasone furoate 200 mcg is as good or better than Fluticasone propionate 500 mcg BID Warning and Precautions Local Infections Acute Asthma Episodes Immunosupression Transfer from Systemic Corticosteroids Adrenal Supression Reductions in Bone Mineral Density Effects on Growth Glaucoma and Cataracts Traditional ICS + LABA: Fluticasone + Salmeterol BID HFA and DPI Mometasone + Formoterol BID HFA Budesonide + Formoterol BID HFA 3
Recent ICS+LABA Fluticasone Furoate + Vilanterol DPI 100/25 and 200/25 (18 and above) Sig: 1 puff once daily Fluticasone Propionate + Salmeterol Breath Actuated Dry Powder BID Supporting Clinical Information Fluticasone Furoate + Vilanterol RDB 12 week study (n=1039), FF+V 100/25 QD vs FF 100 QD: FEV1: FF+V 100/25 108 ml > FF 100 RESCUE FREE DAYS: FF+V 100/25 12.2% > FF 100 SYMPTOM FREE DAYS: FF+V 100/25 7.8%>FF100 RDB 24 76 week study (n=2019), FF+V 100/25 QD vs FF 100 QD: RISK OF EXACERBATION: : FF+V 100/25 DECREASED 20% VS FF100 Long Acting Muscarinic Antagonist (LAMA) Tiotropium Bromide was approved in 2003 for treatment of COPD Clinical studies in treating asthma has shown efficacy such that Tiotropium Bromide was approved in 2016 for the treatment of asthma in patients aged 12 and above, and in early 2017 6 and above. Tiotropium dosing 1.25 mcg 2 puffs once daily (total dose 2.5 mcg) 4
Differences between Beta Agonists (LABA/SABA) & Muscarinic Antagonists (SAMA/LAMA) Effect of Beta Agonist in Airway: LABA/SABA stimulate bronchodilation Effect of Anti Muscarinic in Airway: SAMA (ipratropium) and LAMA (tiotropium) works via cholinergic pathway to block bronchoconstriction How do LAMAs benefit Asthma? Improve Lung Function (FEV1 and PEF) Improve Quality of Life Reduce Exacerbations Note: All Tiotropium Asthma Trials were conducted on a background of ICS therapy!! Tiotropium may be used with ICS+LABA Tiotropium Warning and Precautions Not for acute use Not a Rescue! Immediate Hypersensitivity Reactions (hives,angioedema, anaphylaxis, itching) Paradoxical Bronchospasm Worsening of Narrow Angle Glaucoma Worsening of Urinary Retention Renal Impairment renal excretion watch for anticholinergic side effects with CrCl <60ml/min 5
Tiotropium Clinical Trials :PI all asthma TIO trials done on background of ICS Dose Selection Trials 4 8 weeks: 256 adults/105 adolescents/101 peds 0 3 hour post dose improvement in FEV1 vs placebo ADULTS 2.5 mcg QD 128 ml improvement ADOLESCENTS 2.5 mcg QD 57 ml improvement PEDIATRICS 2.5 mcg QD 104 ml improvement Trial #2 Tiotropium PI Asthma:Effects on FEV1 Medium Dose ICS+TIO, ICS+Salmeterol, ICS+PBO ICS + Tx Peak FEV1 change Mean Trough FEV1 change Mean Tiotropium 2.5 mcg 290 ml 240 ml 150 ml 190 ml Salmeterol 100 mcg 270 ml 210 ml 90 ml 120 ml Placebo 50 ml 30 ml Package Insert Tiotropium Bromide Inhalation Spray for Oral Inhalation Tiotropium PI: Effect on Asthma Exacerbations # of patients with at least 1 event, n (%) Tiotropium 2.5 mcg N=259 Placebo N=256 Tiotropium 2.5 mcg N=256 Placebo N=253 9 (3.5%) 24 (9.1% 13 (5.1%) 19 (7.5%) Rate of asthma exacerbations per patient yr. Mean rate of events 0.08 0.24 0.13 0.18 Comparison to 0.32 0.70 68% Placebo, RR (0.20, 0.51) (0.46,1.08) 30% Time to first asthma exacerbation Comparison to Placebo, RR 0.37 (0.17,0.80) TRIAL 2 TRIAL 3 0.66 (0.33,1.34) 6
Tiotropium Adolescent Patients 12 17: Effects of LAMA vs. PBO added to ICS+LABA Peak FEV1 (0 3 hr) @ Week 12 Change from Baseline ICS+LABA+ LAMA= 550 ml ICS+LABA+ Placebo= 438 ml Difference = 110 ml (p=0.0457,[95% CI: 2,220 ml) NOTE: 83% of patients in trial were on medium to high dose ICS+LABA Biologic Therapy for Asthma! Until 2015, no Biologic Therapy had been approved for treatment of asthma in over a decade. Omalizumab, a monoclonal antibody directed against IgE the allergy antibody was approved in the early 2000 s for individuals > 12 year of age based on the primary endpoint of FDA mandated clinical trials of REDUCTION in ASTHMA EXACERBATIONS In 2015, Omalizumab was approved for treatment of children age 6 and above Why block IgE? IgE or the allergy antibody is present in low levels in the blood as compared to IgG,A,M If one is allergic, they have specific IgE antibodies to allergens such as Dust Mites, Weeds, Trees, Grasses, Molds, etc. The tendency to be allergic is common in patients with Asthma such that 70 80% of asthmatics are allergic to something. 7
Role of IgE in Asthma Studies have clearly shown that the higher the serum IgE level, the greater the probability of asthma Therefore, if elevated IgE levels are common in asthma patients and a large % of asthmatics are allergic, blocking the allergy antibody (IgE) leads to improvement in asthma. Omalizumab: Pediatric Indication Age 6 12 52 Weeks while maintaining ICS for 24 weeks, and allowing adjustment of ICS for the next 28 weeks Omalizumab 0.78 rate of asthma attacks vs 1.36 rate of asthma attacks control 43% reduction in asthma exacerabations Enter IL5 Inhibitors Since late 2015, 3 monoclonal antibody therapies that block IL5 have been approved to treat Severe Persistent Asthmatics with Eosinophilic Phenotypes 8
To understand role of IL 5 inhibitors..knowledge of Eosinophils critical! Eosinophils are WBC s that comprise a small % of WBC #. Along with other circumstances (parasites/malignancy), eosinophils are commonly seen in respiratory tissues that are inflammed e.g.allergy Eosinophils can be found in large numbers in nasal secretions, nasal polyps, sputum and bronchial biopsies from asthmatics, inflammed skin, etc. IL5 eosinophils IL5 is a cytokine that is produced by key inflammatory cells that has a variety of effects on eosinophils Maturation and expulsion of eos from BM Recruitment of eos from blood into sites of inflammation Prolongation of survival and activation of eos in tissues IL 5 is the major cytokine responsible for growth and differentiation, 1-5* recruitment, activation, and survival of eosinophils 2 6* *Multiple cell types, including eosinophils, and chemical mediators are involved in inflammation 6 9
IL5 Inhibitors Approved IL5 inhibitors for Subcutaneous or IV administration: Mepolizumab 100 mg SC q 4 weeks age 12 and up approved 2015 Reslizumab 3mg/kg IV q 4 weeks age 18 and up approved 2016 Benralizumab 8 mg SC q 4 weeks x 3 months, and then q 8 weeks thereafter approved late 2017 Eosinophil effects in tissue Eos co migrate with other inflammatory cells into the lung tissue Eos degranulate releasing cytotoxic granules locally including the following: Major Basic Protein Eosinophilic Cationic Protein Eosinophil Peroxidase Eos richly produce a litany of cytokines and chemokines that perpetuate airway inflammation What do IL5 inhibitors do? By blocking either IL5 (mepolizumab and reslizumab) or the IL5 receptor, eosinophil levels in the blood drop dramatically to largely undetectable levels within hours of administration and remain low for many days after the last infusion.. Tissue eosinophil levels drop to low levels as well presumably reducing the toxic effects of eosinophils on surrounding tissues. 10
Mepolizumab Humanized monoclonal antibody (IgG1) Binds IL5 cytokine blocking the binding of IL5 to receptor but does not block receptor SC one size fits all dosing 100 mg SC Eosinophil requirement > 300 Mepolizumab: Rate of Exacerbations Treatment Rate Difference Rate Ratio Trial 1 Mepolizumab 75 mg IV (n=153) Placebo (n=155) 2.40 1.24 1.16 0.52 (0.39,0.69) 48% Trial 2 Mepolizumab 100 mg SC (n=194) Placebo (n=191) 0.83 0.91 0.47 (0.35 0.64) 1.74 53% Reslizumab Monoclonal antibody that binds IL 5 Similar in MOA to Mepolizumab Dosing is IV and weight based 3 mg/kgoffering tailored dosing Eosinophil requirement >400 11
Reslizumab Reduced Overall Exacerbations (Including Those Requiring OCS or Hospitalization 1,2 ) Reslizumab Reduced Asthma Exacerbations a (Primary Endpoint) by More than Half Asthma Exacerbation Rate 2.5 2 1.5 1 0.5 0 59% fewer events 0.86 Study II 2.11 12. Castro M, Zangrilli J, Wechsler ME, et al. Lancet Respir Med. 2015. May;3(5):355 66. Study I (3082; n=245) results showed 50% fewer exacerbations in patients taking Reslizumab (P<.0001) Study II (3083; n=232) results showed 59% fewer exacerbations in patients taking Reslizumab (P<.0001) Reslizumab reduced exacerbations requiring corticosteroids by 55% and 61% (Study I, II respectively) Reslizumab reduced exacerbations requiring hospitalization or ER visit by 34% and 31% (Study I, II respectively) a Rate Ratio (95% CI): Study I: 0.5 (0.37, 0.67); Study II: 0.41 (0.28, 0.59). 34 Lung Function Improved Significantly Over 16 Weeks 1,2 160 ml Change in FEV 1 Over 16 Weeks (Study III/3081) Reslizumab 160 ml 1. CINQAIR Prescribing Information. Horsham, PA: Teva Pharmaceuticals, LLC; May 2016. 2. Bjermer L, Lemiere C, Maspero J, et al. Chest. 2016 Oct;150(4):789 798. 35 Benralizumab Humanized monoclonal antibody (IgG1) Binds to alpha subunit of IL5 receptor (IL 5Ra) blocking the effects of IL5 IL5 receptor is expressed on surface of eosinophils & basophils Binding of Benralizumab to IL5 receptors leads to apoptosis or programmed cell death of eosinophils and basophils 12
Benralizumab : Clinical Data Reduction in Eosinophils: Noted within 24 hours after dosing In Trials 1&2, SC Benra reduced blood eosinophils to a median absolute blood eos count of 0 cells/ul noted at 4 weeks of treatment & maintained throughout treatment Benralizumab: Rate of Exacerbations Treatment Rate Difference Rate Ratio Trial 1 Benralizumab (n=267) Placebo (n=267) 1.52 0.74 0.78 0.49 Trial 2 Benralizumab (n=239) Placebo (n=248) 0.73 0.29 0.72 1.01 Benralizumab : Daily Oral Steroid Reduction Median percent REDUCTION in daily OCS in clinical trials was as follows 75% Benralizumb (95% CI 60 88) 25% Placebo (95% CI 0 33) 13
Benralizumab: Change in FEV1 Trial Difference from Placebo in Mean Change from Pre Bronchodilator Baseline FEV1, ml (95% CI) 1 159 ml (68 249) 2 116 ml (28 204) 3 112 ml (33 258) Bronchial Thermoplasty A procedure done through a bronchoscope in which a specially designed catheter delivers thermal energy to the airway wall in a controlled manner to reduce excessive airway smooth muscle Reducing excessive Airway Smooth Muscle (ASM) decreases the ability of airways to constrict thereby reducing the frequency of asthma attacks BT Logistics BT is a non drug procedure for Severe Persistent Asthma in patients 18 yo and greater not controlled with ICS+LABA Procedure performed in 3 outpatient procedure visits each treating a different area of the lungs approx. 3 weeks apart 14
BT Benefits and Risks One year follow up 32% reduction in asthma attacks 84% reduction in ER visits 73% reduction in hospitalizations 66% reduction in days lost from work/school Risks of BT In the peri procedure period, expected increase /worsening of asthma sx Increased symptoms last for 1 7 days after procedure 3.4% possibility (per procedure) of hospitalization for management of asthma sx 15