`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
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`
`
`
` APPLICATION NUMBER:
`
`
` 212477Orig1s000
`
`
`
`
` CLINICAL MICROBIOLOGY/VIROLOGY
`
`
`REVIEW(S)
`
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`Reviewer: LALJI MISHRA, Ph.D.
`Date Submitted: 02/28/19
`Date Received: 02/28/19
`
`Date Assigned: 03/5/19
`
`Sponsor: Gilead Sciences, Inc.
`333 Lakeside Drive
`Foster City, CA 94404
`Product Names:
`a. Proprietary: GS-5885, Sovaldi®
`b. Non-proprietary: ledipasvir; sofosbuvir
`
`c. Chemical:
`
`Ledipasvir: Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-[(1R,3S,4S)-2-{(2S)-2­
`[(methoxycarbonyl) amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]­
`1Hbenzimidazol-6-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl}-3­
`methyl-1-oxobutan-2-yl]carbamate
`
`Sofosbuvir: (S)- Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin­
`1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)
`phosphorylamino)propanoate
`
`Structure
`
`LEDIPASVIR
`
`
`SOFOSBUVIR
`
`1
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`Molecular Formula (ledipasvir; sofosbuvir): C49H54F2N8O6 ; C22H29FN3O9P
`Molecular Weight (ledipasvir; sofosbuvir): 889.0; 529.46
`Drug Category: Antiviral
`Indication:
`
`Adult Patients:
` HARVONI is indicated for the treatment of adult patients with chronic hepatitis C virus
`(HCV) genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
` genotype 1 infection with decompensated cirrhosis, for use in combination with ribavirin.
` genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with
`compensated cirrhosis, for use in combination with ribavirin.
`
`Pediatric Patients:
`
`HARVONI is indicated for the treatment of pediatric patients 12 years of age and older or
`weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with
`compensated cirrhosis.
`
`Dosage Form/Route of Administration: Oral/Tablet ( 90 mg ledipasvir/400 mg sofosbuvir
`
`Additional submissions reviewed:
`
`Supplement #
`
`Date of Correspondence Date of Receipt
`
`Date Assigned
`
`N205834 SDN 840
`N205834 SDN 869
`N212477 SDN 001
`N212477 SDN 002
`N212477 SDN 009
`
`03/18/19
`07/10/19
`02/28/19
`03/18/19
`07/10/19
`
`Abbreviations:
`
`03/18/19
`07/10/19
`02/28/19
`03/18/19
`07/10/19
`
`03/18/19
`07/10/19
`02/28/19
`03/18/10
`07/10/19
`
`BLAST, basic local alignment search tool; EC50, effective concentration at 50%; FDC, fixed-
`dose combination; FU, follow-up visit; GT, genotype; HBV, hepatitis B virus; HBcAb, hepatitis
`B virus core antibody; HBsAb, antibody against hepatitis B virus surface protein; HBsAg,
`hepatitis B virus surface protein antigen; HCV, hepatitis C virus; HIV-1, human
`immunodeficiency virus type 1; IFN, recombinant human interferon; LDV, ledipasvir; LiPA,
`line probe assay; RBV; ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; SVR4, 12
`and 24, sustained virologic response at 4 , 12 and 24 weeks after end of treatment
`
`BACKGROUND
`
`2
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
` Gilead Sciences Inc. (GSI) has submitted an efficacy supplement to NDA 205834 in support of
`
`the approval of Harvoni 45/200 mg tablets for use in pediatric patients. In addition, GSI has
`submitted an original NDA 212477 in support of the marketing approval of Harvoni oral
`granules for use in the treatment of hepatitis C virus (HCV) infection in pediatric patients. These
`submissions contain results of Study GS-US-337-1116 entitled “A Phase 2, Open-Label,
`Multicenter, Multi cohort Study to Investigate the Safety and Efficacy of Ledipasvir/Sofosbuvir
`Fixed Dose Combination +/- Ribavirin in Adolescents and Children with Chronic HCV
`Infection”
`
`Study GS-US-337-1116 is also submitted in fulfillment of PMRs 2780-1, 2983-1, and 2985-1
`which state the following:
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained
`virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 to 17 years of age with
`chronic hepatitis C.
`
`The original NDA for Harvoni (LDV/SOF) tablets was approved by the FDA for the treatment of
`chronic hepatitis C virus genotype 1 infection on 10 October 2014. Harvoni is currently indicated
`for the treatment of genotypes 1, 4, 5, or 6 hepatitis C virus (HCV) infection in adults and
`pediatric patients 12 years of age and older or weighing at least 35 kg. The clinical data for
`adolescents was submitted as an efficacy supplement and approved on 07 April 2017 for the
`treatment of chronic HCV with genotypes 1, 4, 5, or 6 in patients 12 years of age and older (see
`Virology Review of NDA 205834 SDN 460 dated 03/02/17 by Lisa Naeger Ph.D.
`
`
`Clinical data for subjects 6 to <12 years of age and 3 to <6 years of age are provided in this
`submission which support proposed dosing recommendations for expansion of the current
`indication to include treatment of chronic HCV with genotypes 1, 4, 5, or 6 in pediatric patients
`who are 3 to <12 years of age.
`
`I. Epidemiology and Prevalence of HCV genotypes in HCV infected subjects
`
`Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver disease worldwide.
`HCV infection is known to be associated with cirrhosis and hepatocellular carcinoma and is the
`most common cause for liver transplantation in the United States.
`
`It is estimated that worldwide 177.5 million adults are infected with hepatitis C virus. In the
`United States alone, an estimated 3 million to 4 million persons are chronically infected with
`HCV (Squires and Balistreri 2017) and it is estimated that worldwide approximately 2.1 million
`individuals 15 years of age or younger are chronically infected with HCV (Nwaohiri et al.,
`2018},
`
`HCV is classified into at least six different genotypes and multiple subtypes based on phylogeny.
`GT-3 is endemic in south-east Asia and is variably distributed in different countries. For example
`3
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`GT-3 is the predominant genotype in India, Pakistan and Brazil and accounts for >30% cases in
`Greece, Poland, Netherlands and China (Hernandez et al., 2013). In the United States genotype 1
`
`accounts for 77% of infections, genotype 2 for 11.3%, and genotype 3 for 9.6% (Nainan et al.,
`2006). Genotype 4 has been identified in North Africa and the Middle East; genotype 5 in South
`Africa; and genotype 6 in Asia ( Squires and Balistreri 2017).
`
`II. Biology of HCV
`
`HCV is an enveloped virus which belongs to the Flaviviridae family. Its genome is a 9.6 kb,
`positive-sense, single-stranded RNA that encodes a polyprotein precursor of ~3000 amino acids.
`This polyprotein precursor is proteolytically processed by both cellular and viral proteases to 10
`individual proteins: the structural proteins C, E1, E2, and p7, and the nonstructural proteins NS2,
`NS3, NS4A, NS4B, NS5A and NS5B (Simmonds et al., 2005). The nonstructural protein, NS3,
`
`comprises an N-terminal protease domain of 181 amino acids and a C-terminal helicase domain.
`The serine protease activity of NS3 in complex with the NS4A cofactor is responsible for the
`proteolytic cleavage at four junctions of the HCV polyprotein precursor: NS3-NS4A (self­
`cleavage), NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B.
`
`Nonstructural protein 3 (NS3), NS4A, NS4B, NS5A, and NS5B are sufficient for replication of
`HCV RNA as a replicon in cell culture. NS3-4A is the primary viral protease, and NS5B is an
`RNA-dependent RNA polymerase. NS4B, a hydrophobic protein with multiple trans-membrane
`domains, induces an endoplasmic reticulum-derived membranous web that harbors the HCV
`replication complex.
`
`III. Mechanism of action and antiviral activity of ledipasvir and sofosbuvir
`
`The mechanism of action and antiviral activity of ledipasvir and sofosbuvir are well documented.
`Please refer to Virology Review of NDA 205834 SDN 000 dated 07/10/14 by Lisa Naeger, Ph.D.
`The antiviral activities of ledipasvir and sofosbuvir are reproduced here from the Virology
`Review of NDA 205834 by Lisa Naeger, Ph.D.
`
`Ledipasvir (LDV) inhibits HCV replication by interfering with the viral NS5A protein which is
`essential for both RNA replication and the assembly of HCV virions. Although the precise
`
`mechanism of inhibition has not been elucidated, several lines of evidence support NS5A as the
`target of LDV. Cell culture resistance selection studies, as well as LDV monotherapy clinical
`studies, identified LDV resistance substitutions in the NS5A gene. Additionally, HCV replicons
`
`encoding resistance substitutions to daclatasvir, another NS5A inhibitor, were shown to be cross-
`
`resistant to LDV. In biochemical studies, LDV does not inhibit NS3 protease, NS3 helicase,
`NS5B polymerase, the HCV IRES, or a broad panel of kinases.
`
`The EC50 values of ledipasvir against HCV genotypes 1a and 1b were 0.031 nM and 0.004 nM,
`respectively. In addition, LDV had EC50 values ranging from 0.15 to 530 nM against genotypes 2
`to 6 replicons. LDV had an EC50 value of 21 nM against the GT2a JFH-1 replicon with L31 in
`4
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
` NS5A, but had a reduced activity with an EC50 value of 249 nM against the GT2a J6 HCV strain
`
`with M31, a common resistance polymorphism. It has less antiviral activity compared to GT1
`against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM and 1.1 nM,
`respectively. LDV had substantially lower activity against genotypes 3a and 6e with EC50 values
`of 168 nM and 264 nM, respectively.
`
`No cytotoxicity was observed in the GT1b Rluc-2 and GT1a HRlucP replicon cells at the highest
`concentrations of LDV tested (CC50 value >44,400 nM) giving a selectivity index for LDV in
`these assays of >837,000 after 3 and 7 days of drug exposure.
`
`Ledipasvir did not have inhibitory activity against bovine viral diarrhea virus, respiratory
`
`syncytial virus, hepatitis B virus and human immunodeficiency virus (Virology Review of NDA
`
`205834 SDN 000 dated 07/10/14). No antiviral activity was detected for LDV against a panel of
`
`flaviviruses (Yellow Fever virus, Dengue 2 virus, West Nile virus, and Benzi virus) human
`rhinovirus (HRV) (infectious mixture of HRV1A, HRV16 and HRV14), and influenza A and B
`viruses at the highest concentration tested without cytotoxicity (50 µM for HRV; 100 µM for
`other viruses) (except SOF had EC50 values of 88 µM and 73 µM for influenza B virus and
`Yellow Fever virus, respectively).
`
`Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is
`essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular
`metabolism to form the pharmacologically active uridine analog triphosphate form (GS-461203)
`which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain
`terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the
`recombinant NS5B from HCV genotype 1b, 2a, 3a, and 4a with IC50 values ranging from 0.7 to
`2.6 µM.
`
`Sofosbuvir had EC50 values ranging from 14-110 nM in stable full-length replicon cells of
`genotype 1a, 1b, 2a, 3a and 4a; and chimeric GT1b Con-1 replicons carrying NS5B coding
`
`
`sequences from genotypes 2b, 5a, or 6a. The median EC50 values of sofosbuvir against chimeric
`
`replicons encoding NS5B sequences from clinical isolates were 62 nM for genotype 1a (range
`29-128 nM; N=67), 102 nM for genotype 1b (range 45-170 nM; N=29), 29 nM for genotype 2
`(range 14-81 nM; N=15) and 81 nM for genotype 3a (range 24-181 nM; N=106). In infectious
`virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 30 and 20 nM,
`respectively.
`
`The cytotoxicity of sofosbuvir was measured using the MTS assay in Huh7 (human hepatoma),
`HepG2 (human hepatocellular carcinoma), BxPC3 (human, pancreatic adenocarcinoma), and
`CEM (human acute T lymphoblast leukemia) cells for 8 days. The CC50 value for sofosbuvir in
`all cell lines tested was greater than 90 μM with a therapeutic index of >800 (Virology Review
`of IND 106739 SDN 000 dated 11/23/09).
`
`5
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`No antiviral activity was detected for SOF against a panel of flaviviruses (Yellow Fever virus,
`Dengue 2 virus, West Nile virus, and Benzi virus) human rhinovirus (HRV) (infectious mixture
`of HRV1A, HRV16 and HRV14), and influenza A and B viruses at the highest concentration
`tested without cytotoxicity (50 µM for HRV; 100 µM for other viruses) (except SOF had EC50
`values of 88 µM and 73 µM for influenza B virus and Yellow Fever virus, respectively).
`
`In cell culture, the combination of LDV and SOF exhibited additive antiviral activity. No
`antiviral antagonism was observed, and no significant change in cell viability was observed in
`combination studies of LDV and SOF. In combination studies with LDV and SOF, no antiviral
`antagonism was observed with NS3 protease inhibitors, the NS5A inhibitor daclatasvir,
`
`Interferon-α (IFN-α), ribavirin (RBV), nucleotide polymerase inhibitor R7128, non-nucleotide
`polymerase inhibitor GS-9190 or HIV-1 inhibitors.
`
`
`Genotypic analyses of resistant replicon RNA substitutions emerging in the NS5A gene
`
`identified Q30E and Y93H as the primary LDV resistance substitutions selected in GT1a
`replicons. These substitutions resulted in approximately 1,000- and 3,000-fold increases,
`respectively, in the EC50 values of LDV relative to wild-type 1a replicon. The mutant NS5A
`replicons exhibited cross-resistance to another NS5A inhibitor (daclatasvir, BMS-790052), but
`remained sensitive to SOF and ribavirin. Genotypic analyses of resistant GT1b replicon RNA
`
`and subsequent phenotypic analyses of substitutions emerging in the NS5A gene identified
`Y93H as the primary resistance substitution to LDV. Y93H confers 3,310-fold resistance (EC50
`
`value = 4.3 nM) to LDV in transient replicon assays. Y93H was cross-resistant to the NS5A
`
`
`inhibitor GS-432567, but was fully susceptible to the adenine nucleotide NS5B inhibitor 2’-C­
`Me-A.
`
`HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for
`multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a, and 6a. Reduced susceptibility to sofosbuvir
`
`was associated with the NS5B substitution S282T in all replicon genotypes examined. An
`M289L substitution developed along with the S282T substitution in genotype 5 and 6 replicons.
`Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to
`18-fold reduced susceptibility to sofosbuvir.
`
`Cell culture studies demonstrated no cross-resistance between LDV and SOF when tested
`individually against HCV substitutions resistant to other classes of HCV inhibitors. The NS5B
`S282T mutant replicon, which confers reduced susceptibility to SOF, was susceptible to LDV.
`Similarly, SOF was fully active against a panel of NS5A mutants that showed reduced
`susceptibility to LDV. Furthermore, double-class mutants (NS5B S282T + NS5A resistance-
`associated variants) displayed a significant reduced replication capacity compared to wild type or
`single NS5A resistant variants in the replicon. In addition, LDV retained antiviral activity in cell
`culture against HCV mutants resistant to other classes of HCV inhibitors including NS3/4A
`protease inhibitors and nucleoside and non-nucleoside NS5B polymerase inhibitors. GT1
`replicons encoding substitutions conferring resistance to NS5A inhibitors, NS3/4A inhibitors, or
`
`non-nucleoside NS5B inhibitors also remained fully susceptible to SOF indicating that there is
`6
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`no cross resistance between SOF and HCV NS3/4A inhibitors, non-nucleotide NS5B inhibitors,
`or NS5A inhibitors.
`
`Study GS-US -337-1116
`
`Study Title: A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety
`and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and
`
`Children with Chronic HCV-Infection
`
`OBJECTIVES
`
`Primary
`
` Pharmacokinetic (PK) lead-in phase: To evaluate the steady-state PK and confirm the dose
`of LDV/SOF fixed-dose combination (FDC) in chronic HCV-infected pediatric subjects.
` Treatment phase: To evaluate the safety and tolerability of LDV/SOF FDC ± RBV for 12
`or 24 weeks in chronic HCV-infected pediatric subjects
`
`Secondary
`
` PK lead-in phase: To evaluate the safety, tolerability, and antiviral activity of 10 days of
`dosing of LDV/SOF FDC in chronic HCV-infected pediatric subjects.
`
`Treatment phase:
`
` To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC ± RBV treatment
`
`in chronic HCV-infected subjects (including the impact of HCV genotype, IL28B
`genotype, and prior treatment experience), as assessed by the proportion of subjects with
`sustained viral response (SVR) 12 weeks after completion of treatment (SVR12).
`
` To determine the antiviral efficacy of 12 or 24 weeks of LDV/SOF FDC ± RBV
`treatment in chronic HCV-infected subjects, as assessed by the proportion of subjects
`with SVR 4 and 24 weeks after completion of treatment (SVR4 and SVR24).
` To evaluate the kinetics of circulating HCV RNA during treatment and after completion
`of treatment.
` To evaluate the emergence of viral resistance to LDV and SOF during treatment and after
`completion of treatment.
` To evaluate acceptability assessed by swallowability of tablets and palatability of
`granules.
` To evaluate the effect on growth and development of pediatric subjects during and after
`treatment.
`
`The exploratory objective of this study was as follows:
`
`7
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
` To identify or validate genetic markers that may be predictive of the natural history of
`disease, response to therapy, and/or tolerability of medical therapies through genetic
`discovery research (e.g., pharmacogenomics), in subjects who provide their separate and
`specific consent.
`
`Study Design
`
`Comment
`
`Please note the efficacy results and resistance analyses presented in this NDA submission for
`subjects 12 to 18 years are the same as previously reviewed by Dr. Lisa K. Naeger. Please refer
`to Virology Review of NDA 205834 SDN 460 dated 03/03/17 for efficacy and resistance
`analysis for subjects 12 to 18 years enrolled in study GS-US 377-1116.
`
`This review includes efficacy and resistance analysis for subjects 6 to <12 years and 3 to <6
`years enrolled in study GS-US 337-1116.
`
`This Phase 2, open-label, multicohort, 2-part study evaluated the PK, safety, and efficacy of
`LDV/SOF±RBV in pediatric subjects aged 3 to <18 years with chronic genotype 1, 3, 4, 5, or 6
`HCV infection. Per the study protocol, subjects with genotype 2 HCV infection were eligible for
`enrollment once data in adult patients were available; however, no subjects with genotype 2
`HCV infection were enrolled because LDV/SOF was not approved for treatment of adults with
`
`genotype 2 HCV infection in any country in which this study was conducted, at the time of
`enrollment.
`
`Approximately 220 pediatric subjects were planned to be enrolled: approximately 100
`adolescents subjects 12 to <18 years old and approximately 120 pediatric subjects 3 to <12 years
`old. Subjects could be either treatment naive or treatment experienced, with up to 40 subjects
`
`allowed to be treatment experienced.
`
`Subjects of 3 age groups were enrolled in a sequential fashion: 12 to <18 years old followed by 6
`to <12 years old and 3 to 6 years old.
`
`Subjects received 1 of the following treatments based on country of enrollment, HCV genotype,
`prior treatment experience, and cirrhosis status, as presented in Table 1.
`
`8
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`Table 1: GS-US-337-1116: Treatment Regimens Based on Country of Enrollment,
`Genotype, Treatment Experience, and Cirrhosis Status (Source NDA 205834, SDN 835,
`Page 34, Table 2)
`
`NA = not applicable
`
`This study consisted of a PK lead-in phase and a treatment phase.
`
`PK Lead-In Phase
`
`The PK lead-in phase evaluated and/or confirmed the age-appropriate LDV/SOF dose by
`analyzing PK and safety data of LDV/SOF through 10 days of dosing. Two cohorts, each with at
`
`least 10 treatment-naive subjects without history of cirrhosis, were sequentially enrolled:
` Cohort 1: 12 to <18 years old weighing ≥ 45 kg
` Cohort 2: 6 to <12 years old weighing >17 kg and <45 kg
` Cohort 3: 3 to <6 years old (at least 4 subjects weighing ≥17 kg and at least 4 subjects
`weighing <17 kg)
`
`Intensive PK and safety results through Day 10 of treatment for each cohort were reviewed to
`
`confirm the appropriateness of the evaluated LDV/SOF dose prior to initiating the treatment
`phase of that age group and determining the age-appropriate dose to be evaluated in the PK lead-
`in phase of the next age group.
`
`Treatment Phase
`
`Subjects who participated in the PK lead-in phase were immediately rolled over into the
`treatment phase with no interruption of study drug administration.
`9
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`Additional treatment-naive or treatment-experienced subjects were enrolled in the treatment
`phase upon confirmation of the age-appropriate LDV/SOF dose from the PK lead-in phase. The
`treatment phase was initiated sequentially by age group as defined in Cohorts 1, 2, and 3 of the
`PK lead-in phase. No weight limits applied to the additional subjects enrolled in the treatment
`phase.
`
`All subjects were to complete the following visits: screening, Day 1, Weeks 1, 2, 4, 8, and 12
`(and Weeks 16, 20, and 24 for the 24-week treatment group) during the treatment phase followed
`by post-treatment visits 4, 12, and 24 weeks after discontinuation of therapy. For subjects who
`participated in the PK lead-in phase, the first visit in the treatment phase was the Week 2 visit.
`
`Subjects 3 to <6 years old providing written consent were eligible for participation in an optional
`intensive PK substudy. Intensive serial PK blood samples were collected at Week 4 or 8 at the
`following time points: 0 (predose), 0.5, 1, 2, 3, 4, 5, 8, and 12 hours postdose (with predose also
`serving as t = 24).
`
`Subjects providing separate and specific consent were eligible for participation in the
`pharmacogenomics substudy. A blood sample was drawn for this substudy at the Day 1 visit or
`at any time during the study.
`
`Subjects who attained SVR24, or those who did not attain SVR24 and did not initiate
`experimental or approved anti-HCV therapy, could enroll in a long-term registry study (GS-US­
`334-1113) for assessment of growth, quality of life, and long-term viral suppression (if
`applicable).
`
`Microbiology Specific Inclusion Criteria
`
`1. Aged 3 years to <18 years as determined at Day 1 (consent of parent or legal guardian).
`2. PK lead-in phase only: all subjects must be treatment naive (no prior exposure to any IFN,
`RBV, or other approved or experimental HCV-specific direct-acting antiviral [DAA] agent)
`3. Treatment-experienced subjects: prior treatment failure on a regimen including IFN either
`with or without RBV that was completed at least 8 weeks prior to Day 1
`a) IFN intolerant: subject who discontinued therapy (≤12 weeks total) due to ≥1 AE
`b) IFN nonresponder: subject who did not achieve undetectable HCV RNA levels while on
`treatment
`c) Relapse/breakthrough: subject who achieved undetectable HCV RNA during treatment or
`within 4 weeks of the end of treatment but did not achieve SVR
`4. Chronic HCV infection documented by either:
`a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping
`test at least 6 months prior to the Day 1 visit, or
`b) A liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV infection
`5. Infection with HCV as determined at screening:
`10
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`a) UK only: As of protocol amendment 4.0, the study enrolled pediatric subjects with
`genotypes 1, 3, 4, 5, and 6 HCV infection and subsequently enrolled subjects with
`genotype 2 HCV infection once adult data were available, if appropriate.
`b) US/Australia/New Zealand only: As of protocol amendment 4.0, the study enrolled
`pediatric subjects with genotypes 1, 4, 5, and 6 HCV infection and subsequently enrolled
`subjects with genotype 2 HCV infection once adult data were available, if appropriate.
`
`6. HCV RNA ≥ 1000 IU/mL at screening.
`
`Microbiology Specific Exclusion Criteria
`
`1. Treatment-naive subjects with genotype 3 HCV infection as determined at screening.
`Treatment naive was defined as no prior exposure to any IFN, RBV, or other approved or
`experimental HCV-specific DAA agent.
`2. Decompensated liver disease defined as international normalized ratio (INR)>1.2 x the upper
`limit of normal (ULN), platelets <50,000/mm3, serum albumin <3.5 g/dL, or prior history of
`clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal
`hemorrhage).
`3. Chronic liver disease of a non-HCV etiology (e.g,, hemochromatosis, Wilson’s disease,
`
`alpha-1 antitrypsin deficiency).
`4. Evidence of hepatocellular carcinoma or other malignancy (with the exception of certain
`resolved skin cancers).
`
`5. Coinfection with HIV-1, acute hepatitis A virus (HAV), or HBV (i.e,, hepatitis B surface
`antigen [HBsAg]-positive at screening).
`6. History of solid organ or bone marrow transplantation.
`7. Investigational agents taken within the past 28 days (except with the express approval of the
`sponsor).
`8. Known hypersensitivity to the study drug, the metabolites, or formulation excipients.
`
`Treatments Administered
`
`Treatment Regimen:
`
`Following screening and confirmation of eligibility by the investigator, 226 subjects (100
`subjects 12 to <18 years old, 92 subjects 6 to <12 years old, and 34 subjects 3 to <6 years old),
`were assigned to treatment with LDV/SOF±RBV for 12 or 24 weeks based on country of
`
`enrollment, HCV genotype, prior treatment experience, and cirrhosis status (see Table 1, Page 8).
`
`LDV/SOF Dosages:
`
` Subjects 12 to <18 years old enrolled in the PK lead-in phase or in the treatment phase:
`LDV/SOF FDC (90/400 mg) orally once daily.
`
`11
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
` Subjects 6 to <12 years old enrolled in the PK lead-in phase or in the treatment phase:
`LDV/SOF FDC (45/200 mg) orally once daily
` Subjects 3 to <6 years old enrolled in the PK lead-in phase or in the treatment phase:
` If weight was ≥17 kg: LDV/SOF FDC (45/200 mg) orally once daily
` If weight was <17 kg: LDV/SOF FDC (33.75/150 mg) orally once daily
`
`
`
`Selection of Doses in the Study
`
`LDV/SOF FDC (90/400 mg) is the marketed dose of LDV/SOF for the treatment of HCV
`infection in adults. LDV/SOF FDC (90/400 mg) ± RBV demonstrated favorable safety and
`efficacy profiles in approximately 6900 subjects in the LDV/SOF clinical program.
`
`The selection of doses of LDV/SOF for adolescents and younger age groups targeted systemic
`exposures similar to those observed in adults at the marketed dose.
`
`
`Assay Methodology
`
`HCV antibody, HIV-1, HIV-2 antibody, HBs antigen, HBs antibody, HBc antibody, and HAV
`
`antibody tests were performed at screening
`
`Determination of HCV genotype and subtype
`
`HCV genotype and subtype were determined at screening by the Siemens VERSANT® HCV
`Genotype INNO-LiPA 2.0 Assay. Additionally, subtype was confirmed by BLAST analyses of
`NS5A and NS5B sequences.
`
`Plasma samples were collected at Day 1 and on Weeks 1, 2, 4, 8, 12, during early termination
`and at post-treatment weeks 4, 12 and 24 and stored for potential HCV sequencing and other
`virology studies.
`
`HCV RNA Quantification
`
`Blood samples were collected to determine serum levels of HCV RNA at screening,
`baseline/Day 1, and at each study visit during the on-treatment and posttreatment periods. The
` COBAS® AmpliPrep/COBAS®TaqMan® HCV Quantitative Test, v2.0 was used to quantify HCV
`
`
`
`RNA in this study. The lower limit of quantitation (LLOQ) of the assay was 15 IU/mL.
`
`
`
` HCV RNA was quantified at baseline/Day 1, Day 3, at Weeks 1, 4, 8, 12, during treatment, early
`termination and at post-treatment Week 4, 12 and 24.
`
`HBV DNA Quantification
`
`12
`
`
`Reference ID: 4468256
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`HBV DNA was quantified at baseline, Wks 4, 8, 12, 16, 20, 24 during treatment, at early
`termination and at post-treatment Weeks 4, 12 and 24. Testing for HBV DNA was performed
`only for subjects who were HBcAb positive at screening.
`
`Viral Resistance Monitoring
`
`The HCV nonstructural protein (NS) 5A and NS5B coding regions were amplified by
`
` using standard reverse transcription polymerase
`chain reaction (RT-PCR) technology. Following amplification, the polymerase chain reaction
`(PCR) products were deep sequenced with a 1% cutoff.
`
`Baseline NS5A and NS5B deep sequencing analysis was performed for all subjects. For subjects
`
`with virologic failure, deep sequencing of HCV NS5A and NS5B was performed at the first
`virologic failure time point with HCV RNA >1000 IU/mL. Amino acid substitutions in NS5A
`and NS5B in the samples collected at virologic failure were compared with the respective
`baseline sequence for each subject at a 15% cutoff.
`
`Virology Data
`
`
`Electronic HCV baseline or postbaseline sequencing data were extracted directly from the
`) to Gilead. The Gilead Clinical Virology team processed all sequencing
`server (
`data and stored the results electronically in the Gilead Virology Database.
`
`
`
`HCV RNA Result Reporting Conventions
`
`
`When the calculated HCV RNA value was within the linear range of the assay, then the result
`was reported as the “<<numeric value>>IU/mL.” In this reprt, this result is referred to as the
`numeric result or as “≥LLOQ detected” for a categorical result.
`
`When HCV RNA was not detected, the result was reported as “No HCV RNA detected” or
`“target not detected.” In this report, this result is referred to as “< LLOQ target not detected” or
`“< LLOQ TND.”
`
`When the HCV RNA IU/mL was <LLOQ of the assay, the result was reported as “<15 IU/mL
`HCV RNA detected.” In this report, this result was referred to as “< LLOQ detected.”
`
`The overall category of HCV RNA <LLOQ included “<LLOQ TND” and “<LLOQ detected.”
`
`For numerical HCV RNA data, values <LLOQ were set to the LLOQ minus 1 (i.e., 14 HCV
`RNA IU/mL). HCV RNA values returned as “No HCV RNA detected” were also set to 14
`IU/mL.
`
`Primary Efficacy Endpoint
`
`13
`
`Reference ID: 4468256
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`VIROLOGY REVIEW
`DIVISION OF ANTIVIRAL PRODUCTS (HFD-530)
`NDA 205834 SE 029, SDN 835; NDA 212477 SDN 1
`Review Completed: 05/01/19
`
`The primary efficacy endpoint was SVR12, defined as HCV RNA <LLOQ 12 weeks after
`discontinuation of the study drug, in the Full Analysis Set.
`
`Secondary Efficacy Endpoints
`
`Proportion of Subjects with SVR4 and SVR24
`
`The proportions of subjects with SVR4 and SVR24, defined as HCV RNA <LLOQ at 4 and 24
`weeks, respectively, after discontinuation of study drug, were summarized.
`
`Virologic Failure
`
`
`Virologic outcomes, including the proportion of subjects with SVR12, overall virologic failure
`(with subgroups for on-treatment virologic failure and relapse), and other (those who did not
`achieve SVR12 and did not meet virologic failure criteria