`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205395Orig1s000
`
`MICROBIOLOGY / VIROLOGY REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`
`NDA: 205395 SDN: 000
`
`DATE REVIEWED: 12/19/14
`
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`NDA #: 205395
`
`Supporting Document Numbers: 000
`
`Applicant Name and Address:
`Janssen Research & Development, LLC.
`1125 Trenton-Harbourton Road
`
`Titusville, NJ 08560
`
`Reviewer's Name: Takashi E. Komatsu, Ph.D., RAC
`
`Initial Submission Dates:
`
`Correspondence Date: March 31, 2014
`CDER Receipt Date: March 31, 2014
`Reviewer Receipt Date: April 1, 2014
`
`Review Complete Date: December 19, 2014
`PDUFA Date: January 31, 2015
`
`Amendments:
`
`Response to Information Request (SDN 013): August 11, 2014
`
`Response to Information Request (SDN 017): October 15, 2014
`Response to Labeling Comments (SDN 019): November 24, 2014
`
`Response to Labeling Comments (SDN 020): November 25, 2014
`Response to Labeling Comments (SDN 023): December 18, 2014
`
`RelatedISupporting Documents:
`IND 62,477, IND 113198, NDA 21976, NDA 202895, NDA 203094, DMF W", DMF W", DMF W",
`DMF W", DMF W”, DMF
`"N", DMF 18825, DMF 25188
`
`Product Name(s):
`
`Proprietary: Prezcobix
`Non-ProprietarleSAN: darunavir/cobicistat
`
`Code Name/Number: DRV 800mg/COBI 150mg
`
`Individual
`
`Component
`
`Name
`
`Structure
`
`Chemical
`
`Reference ID: 3676603
`
`{3-[(4-amino-benzenesulfonyl)-
`isobutyl—amino]—1-benzy|—2—
`hydroxypropy|}-carbamicacid
`
`1 ,3-thiazol-5-ylmethyl[(2R,5R)-5-
`{[(ZS)-2-[(methyl{[2—(propan-2-yl )-1 ,3-
`thiazol—4-yl]methyl}carbamoyl)aminol-
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`hexahydro-furo-[2,3-b]furan-3-
`ylester.ethanolate
`C27H37N3O7S.C2H5OH
`
`4-(morpholin-4-yl)butanoyl]amino}-
`1,6-diphenylhexan-2-yl]carbamate
`C40H53N7O5S2
`
`Protease Inhibitor
`
`NDA 21976
`
`776.02
`Pharmacoenhancer
`(No anti-HIV-1 activity)
`NDA 203094
`
`Molecular
`Formula
`Molecular
`Mass
`Drug Class
`Supporting
`Document
`
`Indication(s): In combination with other antiretroviral agents
`immunodeficiency virus (HIV-1) infection in:
` treatment
` naïve adult patients
`(cid:120)
`-experienced patients with no darunavir resistance-associated substitutions
`(cid:120)
`Dosage Form(s): 800 mg of darunavir and 150 mg of cobicistat
`Route(s) of Administration: Oral
`Recommended Dosage: One tablet taken once daily with food
`Dispensed: Rx _ X
`OTC ___ (Discipline relevant)
`
`for
`
`the
`
`treatment of human
`
`Abbreviations: AAG, alpha-1-acid glycoprotein; ABC, abacavir; ADV, adefovir; APV, amprenavir;
`ARV, antiretroviral; ATR, Atripla; ATV, atazanavir; ATV/r, ritonavir-boosted atazanavir; AZT,
`zidovudine; bp, base pair; CC50, 50% cytotoxic concentration; COBI, cobicistat; ddI, didanosine; DHHS,
`Department of Health and Human Services; DRV, darunavir; d4T, stavudine; EC50, effective
`concentration inhibiting viral replication by 50%; EC90, effective concentration inhibiting viral replication
`by 90%; EC95, effective concentration inhibiting viral replication by 95%; EFV, efavirenz; ETR,
`etravirine; ETV, entecavir; FBS, fetal bovine serum; FTC, emtricitabine; HAART, highly active
`antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency
`virus (including HIV-1 and -2); HIV-1, human immunodeficiency virus type 1; HIV-2, human
`immunodeficiency virus type 2; HS, human serum; HSA, human serum albumin; IC50, 50% inhibitory
`concentration; IDV, indinavir; IL-2, interleukin 2; IN, HIV-1 integrase; INSTI, HIV-1 integrase strand
`transfer inhibitor; LAM, lamivudine; LPV, lopinavir; L-dT, telbivudine; L-FMAU, clevudine; MDR,
`multidrug-resistant; MOI, multiplicity of infection; MVC, maraviroc; NDA, new drug application; NFV,
`nelfinavir; NNRTI, HIV-1 non-nucleoside reverse transcriptase inhibitor; NR, virologic non-response;
`N(t)RTI, HIV-1 nucleos(t)ide reverse transcriptase inhibitor; NVP, nevirapine; PBMC, peripheral blood
`mononuclear cell; PCR, polymerase chain reaction; PI, HIV-1 protease inhibitor; PI/r, ritonavir-boosted
`HIV-1 protease inhibitor; PK, pharmacokinetics; PR, HIV-1 protease; QD, once daily; RAL, raltegravir;
`RBV, ribavirin; RPV, rilpivirine; RT, HIV-1 reverse transcriptase; RTE, resistance testing eligible; RTI,
`HIV-1 reverse transcriptase inhibitor; RTV, ritonavir; SD, standard deviation; SI, selective index; SQV,
`saquinavir; SR, suboptimal virologic response; TAM, thymidine analogue mutation; TDF, tenofovir
`disoproxil fumarate; TFV, tenofovir (active moiety of the diester prodrug TDF); TPV, tipranavir; TVD,
`Truvada; T-20, enfuvirtide; VF, virologic failure; VR, virologic rebound;
`
`Reference ID: 3676603
`
`2
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`Table of Contents
`EXECUTIVE SUMMARY ....................................................................................................................... 4
`1. Recommendations.......................................................................................................................... 4
`1.1.
`Recommendation and Conclusion on Approvability:............................................................. 4
`1.2. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, If Approvable .................................................................................................. 4
`2. Summary of OND Virology Assessments ....................................................................................... 4
`3. Administrative................................................................................................................................. 5
`3.1.
`Reviewer’s Signatures......................................................................................................... 5
`OND VIROLOGY REVIEW.................................................................................................................... 7
`1. Introduction and Background.......................................................................................................... 7
`1.1. Important milestones in product development .......................................................................... 7
`1.2. Overview of HIV-1 .................................................................................................................... 7
`2. Nonclinical Virology ........................................................................................................................ 9
`3. Clinical Virology .............................................................................................................................. 9
`3.1. Antiviral Effectiveness (Potency and Durability) of DRV/COBI in Study GS-US-216-0130...... 11
`3.1.1. Virologic Response to DRV/COBI Treatment by Baseline HIV-1 RNA levels ................... 11
`3.1.2. Virologic Response to DRV/COBI Treatment by HIV-1 Subtype ...................................... 12
`3.2. Clinical Resistance in Study GS-US-216-0130 ....................................................................... 12
`3.2.1. Development of PR Resistance........................................................................................ 13
`3.2.2. Development of RT Resistance........................................................................................ 16
`4. Conclusion.................................................................................................................................... 16
`Microbiology Package Insert................................................................................................................ 16
`APPENDICES...................................................................................................................................... 22
`Appendix 1: Virologic Failures with Resistance Data for Study GS-US-216-0130............................. 22
`Appendix 2 ....................................................................................................................................... 25
`
`List of Tables
`Table 1: Virologic Failures in Censored, As-Treated Analyses1 of Study GS-US-216-0130................. 10
`Table 2: Correlation between Baseline HIV-1 RNA Level and Virologic Failure in Study GS-US-216-
`0130 ...................................................................................................................................... 11
`Table 3: Virologic Failures by HIV-1 Subtype in Study GS-US-216-0130............................................. 12
`Table 4: Number of Subjects with Evaluable Resistance Data in Study GS-US-216-0130................... 13
`Table 5: Total Number of Amino Acid Substitutions that Developed in the HIV-1 Protease On-
`Treatment .............................................................................................................................. 14
`Table 6: Amino Acid Substitutions that Developed On-Treatment in the HIV-1 Protease..................... 14
`Table 7: Number of Subjects with Resistance-associated Amino Acid Substitutions at Baseline in HIV-1
`Protease ................................................................................................................................ 14
`
`Appendix 1
`Table A1- 1: Genotypic Data (Study GS-US-216-0130)....................................................................... 22
`Table A1- 2: Genotypic Data (Study GS-US-216-0130)....................................................................... 23
`
`List of Figures
`Figure 1: Structures of COBI and RTV. ................................................................................................. 9
`
`Reference ID: 3676603
`
`3
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`EXECUTIVE SUMMARY
`This application was submitted in support of a new drug application (NDA) for Prezcobix fixed dose
`combination (FDC) tablets containing the approved HIV-1 protease inhibitor (PI) darunavir (DRV; NDA
`21976, approved 6/23/06) and the pharmacokinetic enhancer cobicistat (COBI) (darunavir/cobicistat
`800mg/150mg). The proposed
`indication
`for
`the Prezcobix tablet
`is
`treatment of human
`immunodeficiency virus (HIV-1) infection in combination with other antiretroviral agents in:
`
` treatment-naïve adult patients and
`-experienced patients with no darunavir
`resistance-associated substitutions. This NDA package includes clinical data from two Phase 1 studies
`(TMC114IFD1001 – a phase 1 oral bioavailability study investigating two FDC formulation concepts of
`DRV/COBI
` and TMC114IFD1003 – a phase 1 bioequivalence study of the selected
`FDC formulation compared to DRV and COBI coadministered as single agents) and one Phase 3 study
`(GS-US-216-0130 – a phase 3b open label, single arm study in ART-naïve or – experienced HIV-1
`infected adults with plasma H(cid:44)(cid:57) (cid:20) (cid:53)(cid:49)(cid:36) (cid:79)(cid:72)(cid:89)(cid:72)(cid:79)(cid:86) (cid:149)(cid:24)(cid:19)(cid:19) (cid:70)(cid:82)(cid:83)(cid:76)(cid:72)(cid:86)(cid:18)(cid:80)(cid:47)(cid:12)(cid:17)
`
`Soon after the introduction of protease inhibitors, it was recognized that coadministration of the
`approved HIV-1 protease inhibitor ritonavir (RTV) with other PIs improves the pharmacokinetics of the
`approved PI, increasing the serum half life and thereby permitting a more constant exposure to the PI
`(i.e. reducing Cmax and increasing Cmin). RTV was found to be an inhibitor of the CYP3A enzymes
`involved in the metabolism of PIs. Currently, RTV-boosted HIV-1 PI regimens are a standard of care.
`However, RTV boosting is limited to PIs in protease inhibitor naïve individuals as absence of a PI could
`lead to selection of PI resistance-associated substitutions. RTV boosting of PIs has generated a
`renewed interest in PK principles and their clinical implications.
`
`Cobicistat is structurally similar to ritonavir and was designed to be a specific inhibitor of CYP3A
`without HIV-1 protease inhibitory activity. Enzyme inactivation studies have demonstrated that COBI is
`an efficient inactivator of human hepatic microsomal CYP3A activity, with enzyme kinetic parameters
`(Ki and kinact) comparable to those of ritonavir.
`
`Darunavir, in combination with low-dose RTV as a pharmacokinetic enhancer and other approved
`ARVs, is approved for the treatment of HIV-1 infection (NDA 21976 approved on 6/23/06). DRV/r is
`currently indicated for
`-naïve and
`-experienced adults, as well as
`-experienced pediatric
`patients
`years of age and older.
`
`1. Recommendations
`
`Recommendation and Conclusion on Approvability:
`1.1.
`Approval is recommended with respect to Clinical Virology of this original NDA for Prezcobix tablet
`(DRV 800mg/COBI 150mg), once daily, as a treatment of human immunodeficiency virus (HIV-1)
`infection in combination with other
` agents in: (1)
` treatment (
` naïve adult
`patients and (2)
`-experienced patients with no darunavir resistance-associated substitutions.
`
`1.2. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, If Approvable:
`
`2. Summary of OND Virology Assessments
`
`2.1.
`
`Nonclinical Virology
`
`Reference ID: 3676603
`
`4
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`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`The sponsor did not conduct any new nonclinical virology studies for this submission. All of the
`nonclinical virology data have been submitted with the Prezista® and Stribild® original NDA submissions
`(NDA 21976, SDN 000 and NDA 203100, SDN 000). Please see the reviews of Dr. Lisa Naeger, Ph.D.
`(NDA 21976) and Dr. Sung Rhee, Ph.D. and Dr. Takashi Komatsu, Ph.D. (NDA 203100) for more
`details.
`
`Clinical Virology
`2.2.
`This NDA package includes clinical data from two Phase 1 studies (TMC114IFD1001 – a phase 1 oral
`bioavailability study investigating two FDC formulation concepts of DRV/COBI (G003 and G004) and
`TMC114IFD1003 – a phase 1 bioequivalence study of the selected FDC formulation compared to DRV
`and COBI coadministered as single agents) and one Phase 3 study (GS-US-216-0130 – a phase 3b
`open label, single arm study in ART-naïve or –experienced HIV-1 infected adults with plasma HIV 1
`(cid:53)(cid:49)(cid:36) (cid:79)(cid:72)(cid:89)(cid:72)(cid:79)(cid:86) (cid:149)(cid:24)(cid:19)(cid:19) (cid:70)(cid:82)(cid:83)(cid:76)(cid:72)(cid:86)(cid:18)(cid:80)(cid:47)(cid:12)(cid:17) Study GS-US-216-0130 is an open-label, single arm, multicenter, study
`that evaluates the safety and efficacy of a regimen of DRV+COBI plus 2 fully active NRTIs in HIV-1
`infected, ARV treatment-naive and treatment-experienced adult subjects with no DRV resistance-
`associated substitutions. This submission summarizes data through Week 24 for the primary endpoint.
`A total of 36 virologic failures, 30 of 277 (10.8%) and 6 of 17 (35.3%) in the treatment-naïve and
`treatment-experienced subjects, respectively, were identified. At screening, none of the subjects’
`isolates had primary resistance substitutions for DRV. In Study GS-US-216-0130, a total of five amino
`acid substitutions developed in the PR in the virologic failure isolates from the 5 subjects in the
`treatment-naïve subjects compared to a total of 5 amino acid substitutions in the virologic failure
`isolates from the 5 subjects in the treatment-experienced subjects. The presence of DRV in this study
`confounds any possible interpretation of these results with respect to the question of cobicistat
`selecting PI-resistance substitutions. Since COBI is structurally similar to RTV, the question was
`whether the in vivo data support that COBI does not have any antiviral activity. In the Phase 3 (GS-
`US-236-0102) study to support approval of Stribild®, a disproportionate number of substitutions in the
`protease sequence developed on-treatment in the Stribild® treatment arm (16 substitutions/22 subjects)
`compared to the ATR arm (4 substitutions/15 subjects) (see Clinical Virology review for NDA 203100,
`SDN 001). One subject (GS-US-216-0130-0031-4217)
`in
`the
`treatment-experienced subjects
`developed the DRV resistance-associated substitution in protease, I84I/V. The susceptibility to DRV
`was not reduced in the isolate from this subject, which could be due to having a mixture of both
`wildtype (I) and mutant (V) viruses.
`
`3. Administrative
`
`3.1.
`
`Reviewer’s Signatures
`
`________________________________
`Takashi E. Komatsu, Ph.D., RAC
`Clinical Virology Reviewer
`
`3.2.
`
`Concurrence
`
`_________________________
`HFD-530/Clin.Virol.TL/J. O’Rear, Ph.D.
`
`Reference ID: 3676603
`
`5
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`CC:
`HFD-530/NDA # 205395
`HFD-530/Division File
`HFD-530/PM/Mani
`
`Reference ID: 3676603
`
`6
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`OND VIROLOGY REVIEW
`
`1. Introduction and Background
`1.1. Important milestones in product development
`Cobicistat (COBI, TYBOST) is a pharmacokinetic enhancer of the HIV-1 protease inhibitors (PIs)
`atazanavir and darunavir. Cobicistat is structurally similar to ritonavir and was designed to be a specific
`inhibitor of CYP3A without HIV-1 protease inhibitory activity. Ritonavir boosting is limited to PIs in
`treatment-naïve individuals as absence of a PI could lead to selection of PI resistance-associated
`substitutions. Darunavir (DRV, Prezista®), in combination with low-dose ritonavir (RTV) as a
`pharmacokinetic enhancer and other approved antiretrovirals (ARVs), is approved for the treatment of
`HIV-1 infection. A fixed dose combination (FDC)
`tablet darunavir/cobicistat (800mg/150mg)
`is
`proposed in this NDA. This NDA package includes clinical data from two Phase 1 studies
`(TMC114IFD1001 – a phase 1 oral bioavailability study investigating two FDC formulation concepts of
`DRV/COBI
` and TMC114IFD1003 – a phase 1 bioequivalence study of the selected
`FDC formulation compared to DRV and COBI coadministered as single agents) and one Phase 3 study
`(GS-US-216-0130 – a phase 3b open label, single arm study in ART-naïve or –experienced HIV-1
`infected adults with plasma H(cid:44)(cid:57) (cid:20) (cid:53)(cid:49)(cid:36) (cid:79)(cid:72)(cid:89)(cid:72)(cid:79)(cid:86) (cid:149)(cid:24)(cid:19)(cid:19) (cid:70)(cid:82)(cid:83)(cid:76)(cid:72)(cid:86)(cid:18)(cid:80)L). The Division has determined that study
`TMC114IFD1001 is the pivotal study to support this NDA. A pre-NDA meeting with the sponsor was
`held on 12/19/12.
`
`1.2. Overview of HIV-1
`Approximately 33.3 million people worldwide are estimated to be living with human immunodeficiency
`virus type 1 (HIV-1) infection worldwide (UNAIDS Global Report, 2010). The infection, if left untreated
`or suboptimally treated, leads to the development of Acquired Immune Deficiency Syndrome (AIDS),
`characterized by deterioration in immune function, the subsequent occurrence of opportunistic
`infections, and malignancies, ultimately resulting in death. Standard-of-care for the treatment of HIV-1
`infection involves the use of a combination of antiretroviral drugs to suppress viral replication to below
`quantifiable limits (<50 copies/mL), increase CD4+ T cell counts, and delay disease progression.
`Current treatment guidelines (DHHS, updated in March, 2012) for treatment-naïve HIV-1 infected
`patients suggest that initial therapy generally consists of two nucleoside or nucleos(t)ide analog
`reverse transcriptase inhibitors (N(t)RTIs) in combination with a non-nucleoside reverse transcriptase
`inhibitor (NNRTI), a protease inhibitor (PI, preferably “boosted” with ritonavir [RTV]), an integrase stand
`transfer inhibitor (INSTI), or a CCR5 co-receptor antagonist (namely maraviroc [MVC]). For treatment-
`experienced HIV-1 infected patients, a new regimen contains at least two, preferably three, fully active
`ARVs to combine with an optimized background antiretroviral regimen, based on the patient’s
`treatment history, and past and current resistance test results.
`
`The use of antiretroviral combination therapy, introduced in the early 1990s, greatly reduced the
`morbidity and mortality associated with AIDS. However, combination therapy increased adherence
`challenges for patients due to the regimen-associated factors such as frequent dosing, differential
`dosing frequency for regimen components,
`increased pill burden, dietary restrictions, and safety
`concerns. Poor adherence increases the risk of incomplete viral suppression, development of drug-
`resistance virus, and disease progression (Chesney, 2000; Chesney et al., 2000). Clinical studies have
`demonstrated high levels of adherence and treatment success with simple, once-daily, highly active
`antiretroviral therapy (HAART) regimens, resulting in persistent suppression of HIV-1 viral load (Arribas
`et al., 2004; Felizarta et al., 2004; Maggiolo et al., 2001). Recently, a meta-analysis of 11 randomized,
`controlled trials involving 3,029 subjects also demonstrated that the adherence rate was better with
`once-daily regimens (+2.9%; 95% confidence interval, 1.0-4.8%) than with twice-daily regimens (Jean-
`
`Reference ID: 3676603
`
`7
`
`(b) (4)
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`Jacques et al., 2009). Additionally, with some combinations patients may take an incomplete regimen,
`leading to increased risk of resistance development. This risk can be reduced if a complete treatment
`regimen (i.e., 2 N(t)RTIs plus one ARV from another class) is available in a once-daily, single pill, fixed-
`dose combination tablet (FDC), reducing pill burden. To date, three complete regimens in a single-pill
`have been approved. Two are NNRTI-based with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
`as a preferred N(t)RTI backbone, for once-daily administration in the treatment of HIV-1 infection:
`Atripla® (ATR; 600 mg EFV/200 mg FTC/300 mg TDF; approved on July 12, 2006; NDA 21937,
`reviewed by Virology Reviewer Narayana Battula, Ph.D.) and Complera® (27.5 mg rilpivirine [RPV]/200
`mg FTC/300 mg TDF; approved on August 10, 2011; NDA 202123, reviewed by Virology Reviewer
`Lisa Naeger, Ph.D.). The third is an INSTI-based FDC with FTC/TDF as a preferred N(t)RTI backbone:
`Stribild® (150 mg EVG/150 mg COBI/200 mg FTC/300 mg TDF; approved on August 27, 2012; NDA
`203100, reviewed by Virology Reviewer Sung Rhee, Ph.D. and Virology Reviewer Takashi Komatsu,
`Ph.D.).
`
`Soon after the introduction of protease inhibitors, it was recognized that coadministration of the
`approved HIV-1 protease inhibitor ritonavir (RTV) with other PIs improves the pharmacokinetics of the
`approved PI (Kempf et al., 1997; NDA 20659), increasing the serum half-life and thereby permitting a
`more constant exposure to the PI (i.e. reducing Cmax and increasing Cmin). RTV was found to also be an
`inhibitor of the CYP3A enzymes involved in the metabolism of PIs. Currently, RTV-boosted HIV-1 PI
`regimens are a standard of care. However, RTV boosting is limited to PIs in protease inhibitor naïve
`individuals as absence of a PI could lead to selection of PI resistance-associated substitutions. RTV
`boosting of PIs has generated a renewed interest in PK principles and their clinical implications. The
`PK rationales for the combination of PIs and ritonavir (RTV) have been reviewed in various articles and
`include reduction in dose and dosing frequency, achieving additive or synergistic antiretroviral effects,
`overcoming established low-level reduced sensitivity through increased drug exposure, and creating a
`higher genetic barrier to resistance (Heeswijk et al., 2001; Rathbun and Rossi, 2002).
`
`COBI is structurally similar to ritonavir and was designed to be a specific inhibitor of CYP3A without
`HIV-1 protease inhibitory activity (Figure 1). Enzyme inactivation studies have demonstrated that COBI
`is an efficient inactivator of human hepatic microsomal CYP3A activity, with enzyme kinetic parameters
`(Ki and kinact) comparable to those of ritonavir. CYP3A-mediated oxidative metabolism is the major
`biotransformation pathway for COBI, as it is for ritonavir; however, unlike ritonavir, COBI is a more
`specific CYP enzyme inhibitor. It is a weak inhibitor of CYP2D6 and does not inhibit CYP1A2, CYP2C9,
`or CYP2C19. In addition, COBI displays low liability for induction through activation of xenobiotic
`receptors, including the aryl hydrocarbon receptor, pregnane X receptor, and the constitutive
`androstane receptor, in human hepatocytes. In contrast, ritonavir, a known potent pregnane X receptor
`activator, produces significant induction of phase I enzymes, including CYP3A, as well as phase II
`uridine 5’-diphospho-glucuronosyltransferase enzymes and drug transporters, including P-gp, that lead
`to clinically significant drug–drug interactions. Other favorable characteristics of COBI are reduced
`perturbation of the normal adipocyte functions of lipid accumulation and/or response to insulin (please
`refer to the Clinical Pharmacology reviews by Dr. Vikram Arya, Ph.D. and Dr. Stanley Au, Ph.D., for
`NDAs 203100 and 203094, respectively).
`
`Reference ID: 3676603
`
`8
`
`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`Figure 1: Structures of COBI and RTV.
`
`Darunavir, in combination with low-dose RTV as a pharmacokinetic enhancer and other approved
`ARVs, is approved for the treatment of HIV-1 infection (please see the original NDA review of Dr. Lisa
`Naeger, Ph.D. for NDA 21976 approved on 6/23/06). DRV/r is currently indicated for ART-naïve and
`ART-experienced adults, as well as ART-experienced pediatric patients years of age and older. The
`oral dose of darunavir 800 mg QD taken with RTV 100 mg q.d. and with food is recommended in
`treatment-naïve adult patients as well as in treatment-experienced adult patients with no DRV
`resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and
`L89V). The oral dose of darunavir 600 mg BID taken with RTV 100 mg b.i.d. and with food is
`recommended in treatment-experienced adult patients with at least one DRV resistance-associated
`substitution (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V).
`
`2. Nonclinical Virology
`
`The sponsor did not conduct any new nonclinical virology studies for this submission. All of the
`nonclinical virology data have been submitted and reviewed with the Prezista® (NDA 21976, SDN 000)
`and Stribild® submissions (NDA 203100, SDN 000). Please see the Clinical Virology reviews of NDA
`21976 SDN 000 (Dr. Lisa Naeger, Ph.D.) and NDA 203100 SDN 000 (Dr. Sung Rhee, Ph.D. and Dr.
`Takashi Komatsu, Ph.D.) for a detailed analysis of the mechanism of action, antiviral activity in cell
`culture, cytotoxicity, combination antiviral activity relationships with approved antiretroviral drugs as well
`as the methods that were used for the analyses for DRV and COBI.
`
`3. Clinical Virology
`The development of the FDC DRV/COBI 800mg/150 mg QD is intended for the same population in
`which the dose regimen DRV/rtv 800mg/100 mg QD is recommended and approved: i.e.
`-naïve
`adult subjects and
`-experienced adult subjects without DRV resistance-associated substitutions.
`The development for this FDC is based on the development of the individual products, DRV (in
`combination with ritonavir) and COBI. The bridging clinical program contains the following:
`1. TMC114IFD1001 – a phase 1 oral bioavailability study investigating two FDC formulation
`concepts of DRV/COBI
`2. TMC114IFD1003 – a phase 1 bioequivalence study of the selected FDC formulation compared
`to DRV and COBI coadministered as single agents.
`3. GS-US-216-0130 – a phase 3b open label, single arm study in ART-naïve or – experienced
`HIV-(cid:20) (cid:76)(cid:81)(cid:73)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71) (cid:68)(cid:71)(cid:88)(cid:79)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:83)(cid:79)(cid:68)(cid:86)(cid:80)(cid:68) (cid:43)(cid:44)(cid:57) (cid:20) (cid:53)(cid:49)(cid:36) (cid:79)(cid:72)(cid:89)(cid:72)(cid:79)(cid:86) (cid:149) (cid:24)(cid:19)(cid:19) (cid:70)(cid:82)(cid:83)(cid:76)(cid:72)(cid:86)(cid:18)(cid:80)(cid:79)(cid:17)
`
`Reference ID: 3676603
`
`9
`
`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`VIROLOGY REVIEW
`NDA: 205395 SDN: 000 DATE REVIEWED: 12/19/14
`Clinical Virology Reviewer: Takashi E. Komatsu, Ph.D., RAC
`
`Studies TMC114IFD1001 and TMC114IFD1003 are bioavailability and bioequivalence studies in
`healthy subjects so will not be covered in this review. Please see the review of the Dr. Stanley Au,
`Ph.D., Clinical Pharmacology Reviewer, for more details.
`
`Study GS-US-216-0130
`This ongoing study is an open-label, single arm, multicenter, study that evaluates the safety and
`efficacy of a regimen of DRV+COBI plus 2 fully active NRTIs in HIV-1 infected, ARV treatment-naive
`and treatment-experienced adult subjects with no DRV resistance-associated substitutions. The study
`consisted of an eligibility screening (within 35 days before baseline/Day 1 visit), a 48-week open-label
`treatment period, and a follow-up visit 30 days after last drug intake. After 48 weeks of treatment,
`subjects were given the option to participate in an open-label rollover study to receive DRV, COBI, and
`investigator-selected NRTIs, and attend study visits every 12 weeks until COBI becomes commercially
`available (or until Gilead Sciences, Inc elects to terminate its development). Subjects who complete
`treatment through the Week 48 visit and decide not to participate in the rollover study were required to
`complete the 30-day follow-up visit.
`
`Treatment consisted of DRV 800 mg (2 x 400-mg tablets; once daily [QD] with food) and COBI 150 mg
`(1 x 150-mg tablet; QD with food) plus 2 investigator-selected NRTIs, determined by resistance testing
`at screening. In subjects with the M184V/I reverse transcriptase substitution present on the screening
`genotype report, emtricitabine (Emtriva®, FTC) or lamivudine (Epivir®, 3TC) could be included as a third
`(not-fully active) NRTI for the purpose of maintaining the M184V substitution. Use of a fixed-dose
`combination tablet (i.e., Combivir®, Truvada®, or Epzicom®/Kivexa®) plus an additional NRTI may have
`been used for these subjects (e.g., Truvada + zidovudine). This submission summarizes data through
`Week 24 for the primary endpoint.
`
`Clinical virology analyses were conducted using the censored, as-treated subject population (n=294)
`including all randomized subjects who received at least one dose of study medication with at least one
`virologic observation after Baseline but excludes subjects who discontinued their assigned treatment
`before the primary efficacy assessment while they had a suppressed viral load (HIV-1 RNA <50
`copies/mL).
`
`For the analyses, virologic failures were identified as follows:
`
`(cid:120) Subjects who failed to achieve HIV-1 RNA <50 copies/mL either at Week 24 (snapshot analysis
`during the 24-week evaluation window) or at the time of early discontinuation.
`
`A total of 36 virologic failures, 30 of 277 (10.8%) and 6 of 17 (35.3%) in the treatment-naïve and
`treatment-experienced subjects, respectively, were identified (Table 1).
`
`Table 1: Virologic Failures in Censored, As-Treated Analyses1 of Study GS-US-216-0130
`Treatment Naïve (n=277)
`Treatment Experienced (n=17)
`Virologic Failure (VF)2
`30 (10.8%)
`6 (35.3%)
`Virologic Poor Response (PR)3
`18 (6.5%)
`3 (17.6%)
`Virologic Rebound (VR)4
`12 (4.3%)
`3 (17.6%)
`1. The censored, as-treated analysis was done using the censored, as-treated population that includes all randomized subjects who received
`at least one dose of study medication with at least one HIV-1 RNA measurement after Baseline but excludes subjects who discontinued
`their assigned treatment while they had a suppressed viral load (HIV-1 RNA <50 copies/mL).
`2. VF, virologic failure (virologic non-responders, suboptimal virologic responders, and virologic rebounders), is defined as subjects who failed
`
`Reference ID: 3676603
`
`10
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`DIVISION OF A