CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761125Orig1s000 NON-CLINICAL REVIEW(S) 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 Application number: 761125 Supporting document/s: SD 4 (new BLA, submitted 2/07/2019) SD 8 (Response to Information Request, submitted 4/30/2019) SD 26 (Response to Information Request, submitted 8/12/2019) Applicant’s letter date: February 7, 2019 CDER stamp date: February 7, 2019 Product: BeovuTM (Brolucizumab) Indication: Treatment of neovascular age-related macular degeneration (AMD) Applicant: Novartis Pharmaceuticals Corporation East Hanover, New Jersey, 0736-1080 Review Division: Division of Transplant and Ophthalmology Products (DTOP), Office of Antimicrobial Products (OAP), CDER, HFD-590 Reviewer: Andrew J. McDougal, PhD, DABT, DTOP Supervisor: Lori E. Kotch, PhD, DABT, DTOP Acting Division Director: Ozlem Belen, MD, DTOP Project Manager: Judit R. Milstein, DTOP 1 Reference ID: 4477547 BLA # 761125 Reviewer: Dr. Andrew J. McDougal TABLE OF CONTENTS 1 EXECUTIVE SUMMARY...........................................................................................5 1.1 INTRODUCTION .....................................................................................................5 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................6 1.3 RECOMMENDATIONS .............................................................................................8 2 DRUG INFORMATION............................................................................................13 2.1 DRUG ................................................................................................................13 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS..........................................................13 2.3 DRUG FORMULATION ..........................................................................................14 2.4 COMMENTS ON NOVEL EXCIPIENTS......................................................................15 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ........................................16 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.....................................16 2.7 REGULATORY BACKGROUND ...............................................................................16 3 STUDIES SUBMITTED...........................................................................................17 3.1 STUDIES REVIEWED ............................................................................................17 3.2 STUDIES NOT REVIEWED.....................................................................................18 3.3 PREVIOUS REVIEWS REFERENCED.......................................................................19 4 PHARMACOLOGY .................................................................................................19 4.1 PRIMARY PHARMACOLOGY ..................................................................................19 4.2 SECONDARY PHARMACOLOGY .............................................................................33 4.3 SAFETY PHARMACOLOGY ....................................................................................36 5 PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................36 5.1 PK/ADME .........................................................................................................36 6 GENERAL TOXICOLOGY......................................................................................43 6.1 SINGLE-DOSE TOXICITY ......................................................................................43 6.2 REPEAT-DOSE TOXICITY .....................................................................................49 7 GENETIC TOXICOLOGY........................................................................................83 8 CARCINOGENICITY...............................................................................................83 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................83 11 INTEGRATED SUMMARY AND SAFETY EVALUATION..................................85 11.1 OCULAR SAFETY ....................................................................................................85 11.2 CLINICAL PK: BENCHMARK FOR P/T COMPARISONS ..................................................86 11.3 PD RESULTS: COMPARISON TO CLINICAL PK BENCHMARK VALUES .............................87 11.4 SYSTEMIC SAFETY .................................................................................................89 2 Reference ID: 4477547 BLA # 761125 Reviewer: Dr. Andrew J. McDougal Table of Tables Table 1: Brolucizumab drug product formulation............................................................14 Table 2: History of drug product formulation ..................................................................14 Table 3: Primary pharmacology study reports................................................................17 Table 4: Secondary pharmacology study reports ...........................................................17 Table 5: Pharmacokinetic study reports (absorption and distribution)............................17 Table 6: Single-dose toxicology study reports................................................................18 Table 7: Repeat-dose toxicology study reports ..............................................................18 Table 8: PK analytical methods and validation reports...................................................18 Table 9: KD values for brolucizumab and ranibizumab binding to huVEGF165 (SPR analysis) (report # E1108S031.01).................................................................................22 Table 10: SPR results for anti-VEGFs at 25oC (report # RD-2018-00365).....................25 Table 11: SPR results for anti-VEGFs at 37oC (report # RD-2018-00365).....................25 Table 12: Inhibition of VEGF-induced human endothelial cell proliferation (report # RD- 2018-00365) ...................................................................................................................26 Table 13: VEGF competition for VEGFR2 binding (report # RD-2018-00365)...............26 Table 14: VEGF isoform selectivity of brolucizumab (report # E1008S032.01) .............27 Table 15: Species screen for brolucizumab binding to VEGF (by SPR) (report # E1008S030.01)...............................................................................................................29 Table 16: Comparison of brolucizumab and ranibizumab for in vitro inhibition of HREC migration and BREC proliferation (report # TDOC-0013037).........................................30 Table 17: Brolucizumab (intravitreal and intraperitoneal injections) reduced choroidal neovascularization following laser in mouse eyes (report # TDOC-0013037)................33 Table 18: Serum TK parameters following a single intravenous dose (2 mg/kg) to cynomolgus monkeys (report # TDOC-0012016)...........................................................37 Table 19: Ocular TK for the single-dose ivt rabbit study (report # E1008S029.01) ........39 Table 20: Ocular distribution for the single-dose ivt monkey study (report # TDOC- 0012998).........................................................................................................................40 Table 21: Selected ocular distribution parameters for the single-dose OU ivt monkey study (report # TDOC-0016874).....................................................................................42 Table 22: Ocular distribution data (AUC and Cmax) for Group 1 (12% brolucizumab) for the single-dose OU ivt monkey study (report # TDOC-0016874)...................................42 Table 23: OD ERG amplitude results for the first repeat-dose ivt monkey toxicology study (report # TDOC-001462).......................................................................................52 Table 24: Selected OD histopathology for the first repeat-dose ivt monkey toxicology study (report # TDOC-001462).......................................................................................53 Table 25: Serum TK for the first repeat-dose ivt monkey toxicology study (report # TDOC-001462) ...............................................................................................................53 Table 26: male spleen weights for the first GLP monkey ivt (Q3Wx3) toxicology study (report # TDOC-0012707)...............................................................................................60 Table 27: female spleen weights for the first GLP monkey ivt (Q3Wx3) toxicology study (report # TDOC-0012707)...............................................................................................60 Table 28: Selected male histopathology for the first GLP monkey ivt (Q3Wx3) toxicology study (report # TDOC-0012707).....................................................................................62 3 Reference ID: 4477547 BLA # 761125 Reviewer: Dr. Andrew J. McDougal Table 29: Selected female histopathology for the first GLP monkey ivt (Q3Wx3) toxicology study (report # TDOC-0012707)....................................................................63 Table 30: Serum TK for the first GLP monkey ivt (Q3Wx3) toxicology study (report # TDOC-0012707) .............................................................................................................65 Table 31: Vitreous humor concentrations