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`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`APPLICATION NUMBER:
`214187Orig1s000
`
`CLINICAL MICROBIOLOGY/VIROLOGY
`REVIEW(S)
`
`

`

`DIVISION OF ANTIVIRALS, CDER/OND/OID
`CLINICAL VIROLOGY REVIEW
`NDA: 214187 SDN: 001 (Original) eCTD: 0001; sNDA: 208341 S-17 SDN: 800 eCTD: 0156
`DATE REVIEWED: 1/28/2021
`Reviewer: Patrick R. Harrington, Ph.D.
`Date Submitted: 12/15/2020
`Date Received: 12/15/2020
`
`Date Assigned: 12/16/2020
`
`Sponsor: Gilead Sciences, Inc.
`333 Lakeside Drive
`Foster City, CA 94404
`
`Product Names
`(Class)
`
`Sofosbuvir (GS-7977)
`(Uridine Nucleotide Analogue HCV
`NS5B Polymerase Inhibitor)
`
`Velpatasvir (GS-5816)
`(HCV NS5A Inhibitor)
`
`Structures
`
`Chemical Names
`
`(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
`
`Molecular
`formula
`Molecular
`weight
`
`C22H29FN3O9P
`
`529.46
`
`Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-
`{(2R)-2-[(methoxycarbonyl) amino]-2-
`henylacetyl}-4-(methoxymethyl)pyrrolidin-2-
`yl]-1H-imidazol-5-yl}-1,11-
`dihydroisochromeno[4',3':6,7]naphtho[1,2-
`d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-
`methyl-1-oxobutan-2-yl}carbamate
`C49H54N8O8
`
`883.00
`
`Drug Category: Antiviral
`Indication: Treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection
`Dosage Form/Route of administration: SOF/VEL fixed-dose combination tablet or pellets/oral
`Supporting documents: Clinical Virology review of NDA 208341 S-14 by Dr. Takashi Komatsu; NDA 214187
`SDN 10 (updated labeling), NDA 208341 SDN 847 (updated labeling)
`Abbreviations: GT, genotype; HCV, hepatitis C virus; LiPA, Line Probe Assay; LLOQ, lower limit of
`quantification; NGS, next generation sequencing; PMR, post-marketing requirement; RAP(/V), resistance-
`associated polymorphism(/variant); SOF, sofosbuvir; SVR, sustained virologic response; VEL, velpatasvir;
`
`1. CONCLUSIONS AND LABELING RECOMMENDATIONS
`
`This set of submissions consists of a new sNDA (208341 S-17) to expand the sofosbuvir (SOF)/velpatasvir
`(VEL) (Epclusa®) indication to include the treatment of pediatric patients 3 years of age and older, and a new
`NDA (214187) for a new pediatric formulation of SOF/VEL pellets.
`
`sNDA 208341 S-17 and NDA 214187 are approvable from a Clinical Virology perspective. Minor changes
`were proposed for Section 12.4 Microbiology, which are acceptable to this reviewer. We have no
`
`Reference ID: 4781401
`
`1
`
`

`

`DIVISION OF ANTIVIRALS, CDER/OND/OID
`CLINICAL VIROLOGY REVIEW
`NDA: 214187 SDN: 001 (Original) eCTD: 0001; sNDA: 208341 S-17 SDN: 800 eCTD: 0156
`DATE REVIEWED: 1/28/2021
`recommended additions or edits to the prescribing information to forward to the sponsor.
`
`From a Clinical Virology perspective, this set of submissions also satisfies PMR 3092-2, “Conduct a study to
`evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of
`sofosbuvir and velpatasvir in pediatric subjects 3 through less than 12 years of age with chronic hepatitis C
`virus infection.”
`
`2. BACKGROUND
`
`The fixed-dose combination of sofosbuvir (SOF, uridine nucleotide analogue NS5B polymerase inhibitor) and
`velpatasvir (VEL, NS5A inhibitor) (SOF/VEL), marketed as Epclusa®, was approved in 2016 for the treatment
`of chronic HCV genotype (GT) 1-6 infection. The current indication includes treatment of adult and pediatric
`patients 6 years and older or weighing at least 17 kg.
`
`In support of the expanded indication to include pediatric subjects aged 3 to < 6 years, the sponsor provided
`the final clinical study report and datasets from clinical trial GS-US-342-1143, “A Phase 2, Open-
`Label, Multicenter, Multi-cohort, Study to Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in
`Adolescents and Children with Chronic HCV Infection.” Data from this trial for adolescent subjects 12 to <18
`years old and pediatric subjects 6 to <12 years old were previously submitted and reviewed; see the Clinical
`Virology review of NDA 208341 S-14 by Dr. Takashi Komatsu for details.
`
`This review covers the submitted clinical virology and drug resistance data from pediatric patients aged 3 to <6
`years of age enrolled in clinical trial GS-US-342-1143.
`
`3. CLINICAL TRIAL GS-US-342-1143
`
`Study Design
`Clinical trial GS-US-342-1143 was a 2-part study evaluating the PK, safety, and antiviral activity of SOF/VEL in
`pediatric subjects aged 3 to <18 years with chronic HCV infection. The study consisted of a PK lead-in phase
`and a treatment phase within each age group. Approximately 200 subjects were planned to be enrolled:
`approximately 100 adolescent subjects 12 to <18 years old and approximately 100 pediatric subjects 3 to <12
`years old. The PK lead-in phase evaluated and confirmed age-appropriate SOF/VEL doses by analyzing the
`PK, safety, and antiviral activity of SOF/VEL through 7 days of dosing. Subjects who completed the PK lead-in
`phase were immediately enrolled into the treatment phase with no interruption of study drug administration until
`the appropriateness of the dose had been confirmed by PK and safety results from the PK lead-in phase.
`
`All HCV GTs were eligible. Subjects could be either treatment-naive or treatment-experienced, except that
`prior receipt of an HCV NS5A inhibitor was exclusionary. Subjects could be noncirrhotic or have compensated
`cirrhosis. Coinfection with HIV, acute hepatitis A virus, or hepatitis B virus (HBV surface antigen positive) was
`exclusionary.
`
`Among subjects aged 3 to <6 years, two different SOF/VEL doses were evaluated. Subjects weighing ≥17 kg
`received SOF/VEL 200/50 mg QD, while subjects weighing <17 kg received SOF/VEL 150/37.5 mg QD. The
`planned treatment duration was 12 weeks.
`
`All subjects were to be followed to Post-Treatment Week 24. After completing all required study visits, all
`subjects were eligible to enroll into a registry study (GS-US-334-1113) to be followed for a total of 5 years for
`assessments of growth, quality of life, and long-term viral suppression (if applicable).
`
`Reference ID: 4781401
`
`2
`
`

`

`DIVISION OF ANTIVIRALS, CDER/OND/OID
`CLINICAL VIROLOGY REVIEW
`NDA: 214187 SDN: 001 (Original) eCTD: 0001; sNDA: 208341 S-17 SDN: 800 eCTD: 0156
`DATE REVIEWED: 1/28/2021
`
`HCV RNA levels in plasma were measured using the Roche COBAS® AmpliPrep/COBAS® TaqMan HCV
`Quantitative Test, v2.0, which has a lower limit of quantification of 15 IU/mL. HCV genotype was determined at
`screening using the VERSANT® HCV Genotype 2.0 Line Probe Assay (LiPA). Genotype and subtype were
`subsequently confirmed or refined by BLAST analysis of HCV NS5A and NS5B sequences. Resistance
`analyses based on next generation nucleotide sequencing (NGS) were conducted by
`
` on baseline samples for all subjects (no subjects in this age group
`experienced virologic failure). Baseline HCV amino acid polymorphisms were reported based on a 15% assay
`sensitivity cutoff.
`
`Subject Population (3 to <6-year age group)
`Baseline subject characteristics for the GS-US-342-1143 3 to <6-year age group are summarized in Table 1
`(compiled by reviewer). A total of 41 subjects were enrolled and received at least 1 dose of study drug.
`
`Table 1. Baseline characteristics of GS-US-342-1143 study population (3 to <6-year age group).
`N (%)
`
`Age (years)
`3
`4
`5
`Tx history
`Treatment-Naive
`Cirrhosis
`Unknown
`Non-Cirrhotic
`HCV Genotype/Subtype*
`29 (71%)
`1a
`2 (5%)
`1b
`1 (2%)
`1c
`1 (2%)
`2-unknown subtype
`1 (2%)
`2a
`4 (10%)
`2b
`2 (5%)
`3a
`1 (2%)
`4a
`19.2 (12.9-35)
`WEIGHT (kg) Median (Range)
`5.9 (undet.-7.3)
`Baseline HCV RNA (Log10 IU/mL) Median (Range)
`*38/41 results confirmed or refined by nucleotide sequencing analysis; all
`others based on LiPA assay.
`
`10 (24%)
`11 (27%)
`20 (49%)
`
`41 (100%)
`
`31 (76%)
`10 (24%)
`
`Efficacy Results (3 to <6-year age group)
`Efficacy results based on SVR12 are summarized in Table 2 (FDA analysis). The overall SVR12 rate was
`82.9% (34/41). Of the 7 subjects who did not achieve SVR12, none were due to reported virologic failure. All
`7 subjects discontinued treatment early after 1 (n=3), 2, (n=1), 5, (n=1), 7 (n=1), or 20 (n=1) days.
`
`Reference ID: 4781401
`
`3
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`(b) (4)
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`

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`DIVISION OF ANTIVIRALS, CDER/OND/OID
`CLINICAL VIROLOGY REVIEW
`NDA: 214187 SDN: 001 (Original) eCTD: 0001; sNDA: 208341 S-17 SDN: 800 eCTD: 0156
`DATE REVIEWED: 1/28/2021
`Table 2. SVR12 rates in GS-US-342-1143 (3 to <6-year age group).
`SVR12 Rate
`82.9% (34/41)
`87.5% (28/32)
`25/29
`2/2
`1/1
`50% (3/6)
`0/1
`1/1
`2/4
`100% (2/2)
`2/2
`100% (1/1)
`1/1
`
`All Subjects
`All GT1
`1a
`1b
`1c
`All GT2
`2
`2a
`2b
`All GT3
`3a
`All GT4
`4a
`
`Baseline Resistance Analyses (3 to <6-year age group)
`Analyses of baseline HCV NS5A and NS5B resistance-associated polymorphisms were conducted for 33
`subjects in the 3 to <6-year age group. This analysis excluded the 7 subjects who did not achieve SVR12 for
`reasons not attributed to virologic failure, as well as one subject who had an HCV RNA level of 9,970 IU/mL at
`Screening but undetected HCV RNA at Baseline.
`
`The HCV NS5A resistance-associated polymorphisms were defined by the sponsor as specific amino acid
`changes that conferred >2.5-fold reduced phenotypic susceptibility to NS5A inhibitors. These specific
`polymorphisms are summarized in Table 3 (GS-US-342-1143 Study Report pg. 162).
`
`Table 3. Sponsor-defined NS5A resistance-associated polymorphisms (or “variants”, i.e., “RAVs”).
`
`Nucleotide analogue NS5B polymerase inhibitor resistance-associated polymorphisms were defined as: S96T,
`N142T, L159F, E237G, S282-any, C289I/L, L320F/I/V, and V321A/I.
`
`Based on these listings, excluding the 7 subjects without SVR12 virologic outcome results, NS5A and NS5B
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`Reference ID: 4781401
`
`4
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`

`

`DIVISION OF ANTIVIRALS, CDER/OND/OID
`CLINICAL VIROLOGY REVIEW
`NDA: 214187 SDN: 001 (Original) eCTD: 0001; sNDA: 208341 S-17 SDN: 800 eCTD: 0156
`DATE REVIEWED: 1/28/2021
`resistance-associated polymorphisms were detected in 18% (6/33) and 3% (1/33) of subjects, respectively
`(FDA analysis). Note that full-length NS5B sequence analysis data were available from 30 of these 33
`subjects; the other 3 subjects had a short fragment analyzed that did not cover all pre-specified resistance-
`associated positions. Therefore, the sponsor’s denominator for NS5B analysis was 30 subjects, not 33
`subjects. Nevertheless, all 33 subjects with or without detected NS5A and NS5B resistance-associated
`polymorphisms achieved SVR12.
`
`SVR24 Results (all age groups)
`All 34 subjects in the 3 to <6 year-age group who achieved SVR12 also achieved SVR24 (FDA analysis). It
`does not appear that the sNDA/NDA submission included HCV RNA datasets for the 12 to <18-year and 6 to
`<12-year age groups to confirm durability of SVR12. However, according to the GS-US-342-1143 final study
`report, all subjects in these age groups who achieved SVR12 also achieved SVR24 (97/97 and 68/68,
`respectively).
`
`4. LABELING
`
`The sponsor proposed only a minor edit to Section 12.4 of the Epclusa prescribing information, to update the
`numbers of subjects identified with baseline resistance-associated polymorphisms in clinical trial GS-US-342-
`1143:
`
`Pediatrics
`In Study 1143, the presence of NS5A and NS5B RAPs did not impact treatment outcome; all
`pediatric subjects 3 years of age and older with baseline NS5A RAPs ( 15%;
`29/
`199)
`or NS5B nucleoside inhibitor RAPs (3%; 6/
`195) achieved SVR following 12 weeks
`treatment with EPCLUSA.
`
`Incorporating the results from the 3 to <6-year group with the numbers currently described in the Epclusa label,
`the denominators for subjects analyzed for baseline NS5A and NS5B resistance-associated polymorphisms
`would be 198 and 194, each of which differs by 1 subject from the sponsor’s updated labeling. This
`discrepancy has no substantive impact and is presumably due to an updated result from one of the other age
`groups.
`
`The sponsor’s proposed edits to Section 12.4 Microbiology are acceptable from a Clinical Virology perspective.
`
`5. SIGNATURE AND CONCURRENCES
`
`CONCURRENCE
`
` Patrick R. Harrington, Ph.D.
` Senior Clinical Virology Reviewer
`
` Date:
`DAV/Clin Virol TL/J O’Rear
`
`
`
`cc: DAV/RPM/Lindheimer
`
`Reference ID: 4781401
`
`5
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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`PATRICK R HARRINGTON
`04/19/2021 12:24:34 PM
`
`JULIAN J O REAR
`04/19/2021 12:39:59 PM
`
`Reference ID: 4781401
`
`