CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207795Orig1s000 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 NDA REVIEW AND EVALUATION Application number: 207795 Supporting document/s: SD 30 (Resubmission) Applicant’s letter date: February 24, 2017 CDER stamp date: February 24, 2017 Product: Latanoprostene bunod (Vyzulta) Proposed indication: Reduction of intraocular pressure for patients with open-angle glaucoma of ocular hypertension Applicant: Bausch & Lomb Inc. Bridgewater, New Jersey 08807 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/Team Leader: Lori E. Kotch, PhD, DABT, DTOP Division Director: Renata Albrecht, MD, DTOP Project Manager: Lois Almoza Reference ID: 4133010 NDA # 207795 Reviewer: A. McDougal 1 Executive Summary On July 21, 2015, pursuant to Section 505(b)(1) of the Federal Food, Drug and Cosmetic Act and 21 CFR §314.50, the applicant and sponsor, Bausch & Lomb Incorporated (B & L; a wholly-owned subsidiary of Valeant Pharmaceuticals International)” submitted an original new drug application (NDA #207795) for VYZULTA® (latanoprostene bunod ophthalmic solution) 0.024%, for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. From a nonclinical perspective, no safety issues would have precluded approval (McDougal, 5/20/2016; Jacobs 5/23/2016; NDA 207795). A Complete Response letter was conveyed to the Applicant on July 21, 2016. A type A meeting was held between the Division and the Applicant on September 1, 2016. A labeling discussion teleconference was held on September 7, 2016. The Applicant’s Class 2 Resubmission was received on February 24, 2017. The Applicant has proposed revisions to the nonclinical sections of labeling, which are reviewed below. Latanoprost bunod (LBN) is a new molecular entity (NME). IND 73435 is the only predecessor IND for this NDA submission. The internal electronic document room (EDR) location is \\CDSESUB1\evsprod\NDA207795\207795.enx 2 Drug Information 2.1 Drug Chemical Abstracts Service 860005-21-6 (CAS) Registry Number Established name Latanoprostene bunod Trade names VYZULTA (accepted by CDER) Vesneo (proposed by the Applicant but rejected by CDER) Code names (b) (4) BOL-303259-X (Bausch & Lomb) PF-03187207 (Pfizer) NCX-116 (Nicox) (b) (4) (b) (4) Chemical name 4-(Nitrooxy)butyl (5Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy- 2 Reference ID: 4133010 NDA # 207795 Reviewer: A. McDougal 2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5- enoate Molecular formula C27H41NO8 Molecular weight 507.62 g/mol Pharmacologic class1 prostaglandin F2α analogue Figure 1: Structure of latanoprostene bunod (LBN) Note: structure of LBN has 5 chiral centers. 2.2 Notable Cross-Reference As noted previously (McDougal, 5/20/2016, NDA 207795), NDA 207795 is submitted under the 505(b)(1) pathway. The NDA includes a letter of authorization from Pharmacia & Upjohn Co. for NDA 025097 (Xatalan®, latanoprost ophthalmic solution 0.005%). NDA 207795 included the embryofetal development (EFD) studies for latanoprost, as supporting information. 1 Note: the pharmacologic class for Xalatan® (NDA 20597) is “prostaglandin F2α analogue”. For latanoprost bunod, the Applicant proposed (b) (4) (b) (4) 3 Reference ID: 4133010 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- ANDREW J MCDOUGAL 08/01/2017 LORI E KOTCH 08/01/2017 Reference ID: 4133010 Comments on NDA 207795 lantanoprostene bunod From: A. Jacobs, AD Date: 5/23/16 1. I concur that there are no pharm-tox approval issues. 2. I have conveyed other comments to the reviewer and they will be addressed as appropriate. Reference ID: 3935040 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- ABIGAIL C JACOBS 05/23/2016 Reference ID: 3935040 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION Application number: 207795 Supporting document/s: • SD 1 (new NDA) • SD 10 (Response to Nonclinical Information Request, received 1/27/2016) • SD 16 (Response to Nonclinical Information Request, received 3/30/2016) • SD18 (Response to Nonclinical Information Request, received 4/27/2016) Applicant’s letter date: July 21, 2015 CDER stamp date: July 21, 2015 Product: Latanoprostene bunod (Vyzulta) Proposed indication: Reduction of intraocular pressure for patients with open-angle glaucoma of ocular hypertension Applicant: Bausch & Lomb Inc. Bridgewater, New Jersey 08807 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/Team Leader: Lori E. Kotch, PhD, DABT, DTOP Division Director: Renata Albrecht, MD, DTOP Project Manager: Lois Almoza Reference ID: 3934629 NDA # 207795 Reviewer: Andrew J. McDougal TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 8 1.1 INTRODUCTION .................................................................................................... 8 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8 1.3 RECOMMENDATIONS .......................................................................................... 13 2 DRUG INFORMATION .......................................................................................... 22 2.1 DRUG ............................................................................................................... 22 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ......................................................... 23 2.3 DRUG FORMULATION ......................................................................................... 23 2.4 COMMENTS ON NOVEL EXCIPIENTS ..................................................................... 24 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 24 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 26 2.7 REGULATORY BACKGROUND .............................................................................. 27 3 STUDIES SUBMITTED .......................................................................................... 27 3.1 STUDIES REVIEWED ........................................................................................... 27 3.2 STUDIES NOT REVIEWED ................................................................................... 29 3.3 PREVIOUS REVIEWS REFERENCED...................................................................... 34 4 PHARMACOLOGY ................................................................................................ 35 4.1 PRIMARY PHARMACOLOGY ................................................................................. 35 4.2 SECONDARY PHARMACOLOGY ............................................................................ 61 4.3 SAFETY PHARMACOLOGY ................................................................................... 63 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 63 5.1 PK/ADME ........................................................................................................ 63 6 GENERAL TOXICOLOGY ..................................................................................... 70 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 70 6.2 REPEAT-DOSE TOXICITY .................................................................................... 74 7 GENETIC TOXICOLOGY ...................................................................................... 99 7.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) ....................... 99 7.2.1 IN VITRO ASSAYS IN MAMMALIAN CELLS ........................................................ 101 7.2.2 IN VITRO ASSAYS IN MAMMALIAN CELLS ........................................................ 104 7.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) ................ 104 7.4 SUPPORTING GENETIC TOXICITY STUDY DATA ................................................... 108 8 CARCINOGENICITY ........................................................................................... 108 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 109 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT ............................................. 109 9.2 EMBRYONIC FETAL DEVELOPMENT ................................................................... 109 9.3 PRENATAL