Melissa Whitehouse, PharmD Candidate 7/18/13

TITLE AND BACKGROUND Title Authors/ Journal Background

Dupilumab in Persistent Asthma with Elevated Eosinophil Levels

Physicians with mostly asthma and biochemistry work. Journal impact factor ~53 Asthma rates on the rise What constitutes persistent, moderate-to-severe?

National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138.

Despite therapy with long acting beta agonists (LABA) and inhaled glucocorticoids, 10-20% of patients still uncontrolled. 1 Eosinophils correlate with greater asthma severity. 4 IL-4 and IL-13 signal for inflammation and reactions in asthma and atopic diseases.1

National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis

and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138.

Rationale behind this study?

Options for poorly controlled asthma are limited (see attached. 5). Hospitalizations for exacerbations greatly contribute to the high cost associated with asthma. 1 An antibody that targets the cytokines that are primarily responsible for the inflammation in the Th2 pathway is a novel target for drug therapy in persistent, moderate-to-severe asthma not controlled on a LABA and inhaled glucocorticoids. GENERAL STUDY OVERVIEW Sanofi and Regeneron Pharmaceuticals Randomized, double-blind, placebo controlled, parallel-group phase 2A study To evaluate the safety and efficacy of dupilumab, a human monoclonal antibody for reducing exacerbations of asthma patients with persistent, moderate-to-severe asthma. METHODS 28 sites in the United States 491 patients screened 104 randomized in a 1:1 ratio into two groups, 52 receiving 300 mg SQ weekly of dupilumab, the other receiving a SQ placebo weekly If they received even one dose, they were included in the analysis N= 104 participants (intent to treat) Twelve weeks Three phases: stable phase for 4 weeks, withdrawal phase for 5 weeks, monotherapy for 3 weeks, 8 week follow-up

Funding Trial Design Objectives

Enrollment

Population Size Duration

Inclusion/ Exclusion Criteria

Exclusion criteria Patients <18 years or > 65 years of age Abnormal laboratory values requiring treatment or evaluation COPD or other lung disease Patients requiring beta blockers Current smoker or cessation within last 6 months Previous smoking with a smoking history >10 cigarette pack-years In-patient hospitalization or emergency care

Inclusion criteria Patients with a physician diagnosis of persistent asthma for at least 12 whose airway inflammation was likely to be eosinophilic and whose asthma was partially controlled or uncontrolled on ICS/LABA combination therapy based on the following criteria: On a stable dose of either fluticasone/salmeterol combination therapy or budesonide/formoterol combination therapy or mometasone/formoterol combination for at

visit due to asthma exacerbation in the 2 months prior to screening Planned to begin allergen immunotherapy within the study period Exposure to another investigative antibody within 6 months Previous enrollment into the current study Patient was the Investigator, his/her family member, or employee at the investigational site Known or suspected non-compliance, alcohol or drug abuse Inability to follow the procedures of the study Reversal of sleep pattern Treatment with drugs known to prolong QTc Concomitant severe diseases or diseases for which the use of ICS or LABA, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, prolonged QTc are contraindicated Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening Pre-treatment with variable doses of ICS Patients receiving prohibited concomitant medications Known allergy to doxycycline or related compounds Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception Patient Groups Endpoints

least 1 month prior to screening. Blood eosinophils 300 cells /L or sputum eosinophils 3% during the screening phase. Patients whose initial screening blood eosinophil count was 200 to 299 cells/L were permitted to have 1 additional hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/L. Juniper Asthma Control Questionnaire (ACQ) score 1.5 and 3.0 at screening Forced expiratory volume (FEV1) 50% predicted normal during the screening phase (3 attempts maximum) and on the randomization day Reversibility of at least 12% and 200 ml in FEV1 after 200 g to 400 g (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum, or documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine 8 mg) within 12 months prior to screening Had within the 2 years prior to screening at least 1 asthma exacerbation defined by any of the following events: - Treatment with 1 or more systemic (oral and/or parenteral) steroid bursts for worsening asthma - In-patient hospitalization or an emergency care visit for worsening asthma

Placebo Dupilumab 300 mg SQ weekly Primary endpoint: asthma exacerbation Secondary endpoints: - Time to asthma exacerbation post-randomization - FEV1 change from baseline at Week 12 and change from baseline at each visit - Morning and evening PEF change from baseline at Week 12 and change from baseline at each visit - ACQ score change from baseline at Week 12 and change from baseline at each study visit - Change from baseline at Week 12 and change from baseline at each visit for asthma symptom scores in the morning and evening, and nocturnal awakenings - Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol for symptom relief Safety endpoints: - Adverse events (AE) - Vital signs - Physical exam - Electrocardiogram (ECG) - Clinical laboratory tests

Statistical Analyses

- Anti-drug antibodies 80% power A sample size of 100 (50 per treatment group) were needed to detect a 30% difference in asthma exacerbation Two-sided alpha level of 0.05 Logistic-regression model used to compare study groups for primary endpoint A stratified chi-square test RESULTS Similar characteristics between treatment groups Primary outcome: 95% Confidence interval 0.02 to 0.28 ARR: 0.38 RRR: 0.922 NNT: 100/38= 2.63 = 3 people would need to be treated with dupilumab in order to prevent one exacerbation

Baseline characteristics Outcomes

 Intervention

Endpoints Strengths

Limitations

Clinical Relevance

AUTHORS CONCLUSIONS Limitations of study: short study period, definition of exacerbation may not be real world definition, need to define population, regimen, and long-term efficacy/safety. They concluded more research needs to be done GENERALIZABILITY/CRITIQUE/DISCUSSION Dupilumab dose: 300 mg SQ weekly Duration 12 weeks Rescue inhaler The outcomes were measurable and quantifiable, though some were subjectively measured. MY CONCLUSIONS Preferred study design ITT Protocol Placebo indistinguishable Compliance was high, administered on-site Most statistical details were only in the supplementary materials. Is it ethical to treat severe asthma patients with placebo? Severe bias Place in therapy? Dupilumab compared to placebo was associated with fewer exacerbations induced by medication withdrawal and might be a promising option in persistent, moderate-to-severe asthma but further studies need to be done to evaluate its place in therapy.

Works Cited 1. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. 2. Wenzel S, Ford L, Pearlman D, et al. Supplementary Appendix to: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):S1-40. 3. Wenzel S, Ford L, Pearlman D, et al. Disclosure forms: Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26). 4. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138. 5. Asthma Care Quick Reference: Diagnosing and Managing Asthma.[Internet]. Bethesda (MD): National Institute of Health [June 2012] Available from: http://www.nhlbi.nih.gov/guidelines/asthma/asthma_qrg.pdf