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761065Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761065Orig1s000 CLINICAL MICROBIOLOGY/VIROLOGY REVIEW(S) DIVISION OF ANTIVIRAL PRODUCTS CLINICAL VIROLOGY REVIEW BLA: 761065 SDN: 000 Addendum (Original BLA, SDN 012 in DARRTS) REVIEW COMPLETED: 01/19/2018 Clinical Virology Reviewer: Eric F. Donaldson, Ph.D. BLA#: 761065 SDN 000 (Original BLA) Reviewer Name(s): Eric F. Donaldson, Ph.D. Sponsor: TaiMed Biologics, Inc. 5251 California Ave., Suite 230 Irvine, CA 92617 Helen P. Shu, Ph.D. Vice President of Regulatory Affairs and Quality 858-481-6863 858-724-1844 (FAX) [email protected] Initial Complete Submission Dates: Correspondence Date: 5/3/2017 CDER Receipt Date: 5/3/2017 Assigned Date: 5/3/2017 Review Complete Date: 10/03/2017 PDUFA Date: 1/3/2018 extended to: 4/3/2018 Proprietary Name (Proposed): TROGARZO Drug Names: ibalizumab, TNX-355, Hu5A8, Mu5A8, TMB-355 Drug Class: CD4 post-attachment HIV-1 inhibitor Parent IND #: IND009776 Ibalizumab heavy chain primary structure (IgG4) QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYM ELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Ibalizumab light chain primary structure (κ) DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTI SSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Amendments: none Related/Supporting Documents: This BLA was submitted as a rolling submission starting with SDN 000. Additional/updated clinical virology information was submitted to the BLA in the following SDNs: 0003 (proprietary name review), 0011 (TMB-301 Clinical Virology Study Report), 0012 (Original BLA), 0015 (TMB-301 electronic database), 0018 (TMB-202 and TMB-301 neutralizing antibody ligand binding testing of clinical samples), 0020 (response to IR regarding resistance algorithm), 0023 (response to Clinical Virology IR requesting define files), 0026 (response to Clinical Virology IRs sent on 6/5/17 and 6/20/17), and 0033 (response to Clinical Virology IR sent on 7/20/1966). For this addendum review, the following submissions have been reviewed: 0055 (response to labeling comments), 0057 (Clinical Virology study reports for TMB 301 and TMB 202), 0059 (slides for Late Cycle Meeting), 0063 (update on pending review issues for Product Quality), 0064 (FASTQ files for Clinical Virology data submitted in 0057), 0065 (revised label), 0066 (product quality), 0068 (label revision), 0070 (label revision), 0071(response to Virology and Pharm/Tox PMRs), 0073 (revised label). Dosage Form and Route of Administration: A loading dose of 2000 mg followed by a maintenance dose of 800 mg every 2 weeks; intravenous injection 1 Reference ID: 4210367 DIVISION OF ANTIVIRAL PRODUCTS CLINICAL VIROLOGY REVIEW BLA: 761065 SDN: 000 Addendum (Original BLA, SDN 012 in DARRTS) REVIEW COMPLETED: 01/19/2018 Clinical Virology Reviewer: Eric F. Donaldson, Ph.D. Dispensed: Rx Proposed Indication(s): Treatment of adults infected with HIV-1 resistant to at least one agent in three different classes Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral; CD4, cluster of differentiation 4 molecule; D2, domain 2 of CD4; DM, dual mix or dual tropic; Env, envelope protein; gp, glycoprotein; GSS, genotypic susceptibility score; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitor; IV, intravenous; mAb, monoclonal antibody; MDR, multiple drug resistance; MHC-II, major histocompatibility complex class II; MPI, maximal percent inhibition; NGS, next generation sequencing; NNRTI, non-nucleos(t)ide reverse transcriptase inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NRS, non-recycled score; OBR, optimized background regimen; OSS, overall susceptibility score; PBMC, Peripheral blood mononuclear cell; PI, protease inhibitor; PNGS, potential N-linked glycosylation site; PSS, phenotypic susceptibility score; Q2W, administered once every two weeks; Q4W, administered once every 4 weeks; R5, CCR5 coreceptor; X4, CXCR4 coreceptor; Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................3 1. RECOMMENDATIONS.............................................................................................................................4 2. SUMMARY OF OND VIROLOGY ASSESSMENTS .................................................................................4 2.1 Nonclinical Virology.............................................................................................................................4 3. ADMINISTRATIVE ....................................................................................................................................6 OND CLINICAL VIROLOGY REVIEW .................................................................................................................6 4. IBALIZUMAB RESISTANCE IN CLINICAL TRIALS .................................................................................6 4.1 Overview of Ibalizumab Resistance Mechanism ................................................................................6 5. PRIOR TMB-202 AND TMB-301 RESISTANCE ANALYSES..................................................................7 6. ADDITIONAL SUBMISSIONS TO BLA761065.......................................................................................10 6.1 Resistance Analyses.........................................................................................................................10 6.1.1 Submission 0057 (Clinical Virology study reports for TMB 301 and TMB 202)..................10 6.1.2 Submission 0064 (FASTQ files for Clinical Virology data submitted in 0057)....................16 6.2 Labeling Communications, Revisions, and Agreements...................................................................16 6.2.1 Submission 0055 (response to labeling comments)...........................................................16 6.2.2 Submission 0065 (revised label) ........................................................................................17 6.2.3 Submission 0068 (label revision) .......................................................................................18 6.2.4 Submission 0070 (label revision) .......................................................................................18 6.2.5 Submission 0071 (PMR response).....................................................................................18 6.3 Product Quality (major amendment to BLA) .....................................................................................19 6.3.1 Submission 0066 (product quality) .....................................................................................19 7. CONCLUSIONS.....................................................................................................................................19 8. PRESCRIBING INFORMATION (LABEL)...............................................................................................20 8.1 Proposed Prescribing Information (with initial Reviewer-recommended changes) ...........................20 8.2 Agreed Upon Prescribing Information (clean) ...................................................................................20 8.3 Final Approved Package Insert .........................................................................................................21 9. RECOMMENDATIONS..........................................................................................................................22 2 Reference ID: 4210367 DIVISION OF ANTIVIRAL PRODUCTS CLINICAL VIROLOGY REVIEW BLA: 761065 SDN: 000 Addendum (Original BLA, SDN 012 in DARRTS) REVIEW COMPLETED: 01/19/2018 Clinical Virology Reviewer: Eric F. Donaldson, Ph.D. EXECUTIVE SUMMARY The original Biologics License Application (BLA) for ibalizumab (previously known as Mu5A8 [original mouse monoclonal antibody], Hu5A8, TNX-355, and TMB-355) which targets the CD4 HIV-1 receptor, was reviewed and archived on 10/3/2017 with a PDUFA goal date of 1/3/18. The goal date was extended to 4/3/18 due to a major Product Quality amendment. The submissions covered in this addendum Clinical Virology review were received after the original review was archived (see BLA761065 SDN 000). Of note, submissions 0057 (Clinical Virology study reports for TMB 301 and TMB 202), 0064 (FASTQ files for Clinical Virology data) provided additional information regarding the HIV-1 from subjects who failed treatment while on ibalizumab plus an optimized background regimen (OBR). Additional submissions pertained to the label or CMC issues, and were reviewed briefly and updated below. In the BLA, the sponsor provided resistance data for TMB-301 (NCT02475629) and TMB-202 (NCT00784147); however, the dataset for TMB-202 was incomplete in that it was limited to 17 of the 30 subjects identified by the sponsor as treatment failures. The approval of ibalizumab was predominantly based upon the pivotal clinical trial TMB-301, with support from TMB-202, therefore, to better characterize the resistance pathways for ibalizumab we have consistently
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