CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761070Orig1s000 NON-CLINICAL REVIEW(S) Tertiary Pharmacology/Toxicology Review Date: November 1, 2017 From: Timothy J. McGovern, PhD, ODE Associate Director for Pharmacology and Toxicology, OND IO BLA: 761070 Agency receipt date: November 16, 2016 Drug: FASENRA (benralizumab) injection, for subcutaneous use Sponsor: AstraZeneca Pharmaceuticals LP Indication: Add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Reviewing Division: Division of Pulmonary, Allergy, and Rheumatology Products The primary pharmacology/toxicology reviewer and team leader concluded that the nonclinical data for FASENRA (benralizumab) solution for subcutaneous injection support approval for the indication listed above. Benralizumab is a humanized, afucosylated IgG1 kappa monoclonal antibody that targets interleukin-5 receptor alpha. The recommended dose of benralizumab is 30 mg administered once every 4 weeks for the first 3 doses, and then once every 8 weeks thereafter. The Established Pharmacologic Class (EPC) for benralizumab is “interleukin- 5 receptor alpha-directed cytolytic monoclonal antibody”. Pivotal nonclinical studies were conducted in Cynomolgus monkeys. In toxicology studies up to 39 weeks duration, NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified. The primary finding at a dose of 25 mg/kg IV was a post-dose reaction in one high-dose female that included bruising in the areas of the eyes, face, chest and lower abdomen, a decrease in platelet counts, and abnormal erythrocytes after the fourth dose. The NOAEL doses were associated with systemic exposures (AUC) that provided 153- to 271-fold exposure margins compared to the recommended clinical dose. Genetic toxicity studies were not applicable for this therapeutic biologic protein. Carcinogenicity studies were not conducted since rodents are not pharmacologically relevant species. AstraZeneca submitted a carcinogenicity risk assessment that was evaluated by the CDER Executive Carcinogenicity Assessment Committee. The Committee agreed that a carcinogenicity study was not required. Based on a review of the literature by Dr. Robison, the role of eosinophils in tumor development is unclear. The product label will reflect the outcome of this review. The effects of benralizumab on fertility were evaluated in cynomolgus monkeys in the 39-week toxicity study; no drug-related effects were observed. An enhanced pre- and post-natal development studies were conducted with cynomolgus monkeys to evaluate benralizumab’s effects on development. The NOAEL was the high dose of 30 mg/kg IV; associated with exposure that were ~ 310-times the anticipated clinical exposure. Adult 1 Reference ID: 4175200 females and infants demonstrated reduced eosinophil levels. Placental transfer was demonstrated by measuring benralizumab levels in the serum of infants in utero. Conclusion: I agree with the Division pharmacology/toxicology conclusion that this BLA can be approved from the pharmacology/toxicology perspective. The EPC for benralizumab is appropriate. I have discussed labeling issues with the Division and agree with the proposed text. APPEARS THIS WAY ON ORIGINAL 2 Reference ID: 4175200 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- TIMOTHY J MCGOVERN 11/01/2017 Reference ID: 4175200 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY BLA REVIEW AND EVALUATION OF EXTRACTABLES AND LEACHABLES FROM THE CONTAINER CLOSURE SYSTEM (PREFILLED SYRINGE) Application number: 761070 Supporting document/s: SDN #1 and 22 Applicant’s letter date: November 16, 2016 and July 14, 2017 CDER stamp date: November 16, 2016 and July 14, 2017 Product: Benralizumab [Humanized, afucosylated, immunoglobulin (Ig)G1κ mAb that targets IL-5Rα] Indication: Asthma Applicant: AstraZeneca Pharmaceuticals LP One MedImmune Way Gaithersburg MD 20878 Review Division: Pulmonary, Allergy, and Rheumatology Products Reviewer/Team Leader: Timothy W. Robison, Ph.D., D.A.B.T. Division Director: Badrul Chowdhury, M.D., Ph.D. Project Manager: Colette Jackson Template Version: September 1, 2010 Disclaimer 1 Reference ID: 4131961 BLA #761070 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY...........................................................................................5 1.1 INTRODUCTION .....................................................................................................5 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................5 1.3 RECOMMENDATIONS .............................................................................................6 2 DRUG INFORMATION..............................................................................................6 2.1 DRUG ..................................................................................................................6 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS............................................................7 2.3 DRUG FORMULATION ............................................................................................7 2.4 COMMENTS ON NOVEL EXCIPIENTS......................................................................10 2.5 COMMENTS ON EXTRACTABLES AND LEACHABLES.................................................10 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.....................................11 2.7 REGULATORY BACKGROUND ...............................................................................11 3 STUDIES SUBMITTED...........................................................................................12 3.1 STUDIES REVIEWED ............................................................................................12 3.2 STUDIES NOT REVIEWED.....................................................................................12 3.3 PREVIOUS REVIEWS REFERENCED.......................................................................12 11 INTEGRATED SUMMARY AND SAFETY EVALUATION..................................12 2 Reference ID: 4131961 BLA #761070 Reviewer: Timothy W. Robison, Ph.D., D.A.B.T. Table of Tables Table 1 Composition of the Drug Product ........................................................................8 (b) (4) Table 2 Prefilled syringe (PFS(b) (4) ): primary packaging components .......8 Table 3 Material components of the pre-sterilized syringe barrel.....................................9 Table 4 Material components of the needle safety shield ................................................9 Table 5 Summary of the drug product development ......................................................13 Table 6 Prefilled syringe component surface areas .......................................................16 Table 7 Extraction details for the glass barrel and 29-gauge needle .............................16 (b) (4) Table 8 Extractables profile of the syringe barrel with 29-gauge staked needle (Forced Extraction Study [Stage 1])....................................................................17 Table 9 Extractables profile of the (b) (4)plunger stopper (Forced Extraction Study [Stage 1])..............................................................................................................18 Table 10 Extractables profile of the (b) (4)plunger stopper using isopropanol..19 (b) (4) Table 11 Measurements of isopropanol extractables from the plunger stopper using LC/MS with electrospray positive mode...................................................20 (b) (4) Table 12 Measurements of isopropanol extractables from the plunger stopper using LC/MS with electrospray negative mode .................................................21 (b) (4) Table 13 Extractables profile of the elastomeric needle shield ..........................22 Table 14 Extractables profile of the elastomeric needle shield using isopropanol ........................................................................................................................................22 Table 15 Prefilled syringe buffer simulation study design ..............................................23 Table 16 Prefilled syringe simulation (Stage 2) study: 38-42°C .....................................25 Table 17 Prefilled syringe simulation (Stage 2) study: 23-27°C .....................................26 Table 18 Prefilled syringe simulation (Stage 2) study: 2-8°C .........................................28 Table 19 Elemental impurities limits ..............................................29 (b) (4) Table 20 Sponsor’s Limits for ..............................................29 (b) (4) Table 21 Time points for measurements of elemental impurities, (b) (4) .........................................................................................................................30 (b) (4) Table 22 Leachables results for elemental impurities, from Process 3 commercial lots (Lots 020F15, 021F15, and 004K15) at time points of 0, 6, and 12 months................................................................................................................30