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

`

`OFFICE OF CLINICAL PHARMACOLOGY (OCP) REVIEW
`
`NDAs(Supplement Number)
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`Dosage Form and Strength
`Proposed Indication
`Applicant
`Associated INDs
`OCP Review Team
`
`214187(original), 208341(S-17)
`NDA214187 - (0001), NDA208341 - (0156)
`12/15/2020
`Priority
`Epclusa
`Sofosbuvir/Velpatasvir
`Oral Pellets; 200/50 mg & 150/37.5 mg
`Treatment of chronic hepatitis C in pediatrics.
`Gilead Sciences, Inc.
`IND118605, IND115670, IND106739
`Abhay Joshi, Elyes Dahmane, Jihye Ahn, Jenny Zheng
`
`
`
`Contents
`
`1.
`
`2.
`
`EXECUTIVE SUMMARY .......................................................................................................................... 2
`1.1.
`Recommendations ........................................................................................................................ 3
`1.1.
`Post-Marketing Requirements and Commitments ....................................................................... 3
`SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ..................................................................... 3
`2.1.
`Interchangeability Between Tablets and Pellets ........................................................................... 3
`2.2.
`SOF/VEL Dosing Regimen for Pediatric Patients ≥ 3 Years ........................................................... 4
`2.3.
`Proposed Labeling Changes .......................................................................................................... 4
`3. APPENDICES .......................................................................................................................................... 5
`3.1.
`Summary of Bioanalytical Method Validation and Performance ................................................. 5
`3.2. GS-US-342-1142 ............................................................................................................................ 6
`3.3. GS-US-342-1143 ............................................................................................................................ 9
`3.4.
`Pharmacometrics Review ........................................................................................................... 19
`3.4.1.
`Applicant’s SOF Population PK Analysis in Pediatric Subjects ............................................ 19
`3.4.2.
`Applicant’s VEL Population PK Analysis in Pediatric Subjects ............................................. 28
`3.4.3.
`Assessment of SOF/VEL Exposures with the Proposed Weight Band-Based Dosing in
`Pediatrics 31
`
`
`
`Reference ID: 4799744
`
`

`

`1. EXECUTIVE SUMMARY
`
`This submission is an original NDA for a new oral EPCLUSA® pellets (also referred as granules) proposed
`to be used for the treatment of hepatitis C virus (HCV) infection in pediatric patients (HCV patients).
`EPCLUSA® is a fixed combination drug product for sofosbuvir (SOF) and velpatasvir (VEL). SOF is a HCV
`nonstructural protein 5B (NS5B) polymerase inhibitor and VEL is an HCV NS5A inhibitor. Two SOF/VEL
`fixed dose combination tablet formulations (400 mg/100 mg and 200 mg/50 mg tablets) are currently
`approved by the FDA for the treatment of adults and pediatrics 6 years of age and older or weighing at
`least 17 kg with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis, with compensated
`cirrhosis, or with decompensated cirrhosis. For patients with decompensated cirrhosis, EPCLUSA’s use is
`recommended in combination with ribavirin.
`
`This submission is also in accordance to a Post Marketing Requirement (PMR 3092-2) under the
`Pediatric Research Equity Act (PREA) for NDA 208341 (EPCLUSA, SOF/VEL tablets). The PMR was to
`conduct a study to evaluate the pharmacokinetics, safety, and treatment response (using sustained
`virologic response) of SOF/VEL in pediatrics 3 years to 12 years with chronic HCV infection.
`
`With this submission, the Applicant proposes to extend the indication for EPCLUSA for pediatric HCV
`patients down to 3 years of age and proposes revisions to the currently recommended pediatric dosing
`regimen as summarized in Table 1. The Applicant also proposes revisions to pharmacokinetic
`information included in the clinical pharmacology sections of EPCLUSA labeling. The Applicant’s
`proposals are being supported based on the findings from:
`• A Phase 2 study (Study GS-US-342-1143) that evaluated the safety and efficacy of the currently
`approved SOF/VEL tablet formulations and the to-be-marketed pellet formulation in adolescents
`and children with chronic HCV
`• A Phase 1 relative bioavailability study (Study GS-US-342-1142) that compared the
` SOF/VEL pellet formulation (at the 400/100 mg dose; under fasted and fed conditions)
`to the approved 400 mg/100 mg tablet formulation in healthy adults
`• An updated population PK (POP-PK) analysis (Report CTRA-2020-1044) that characterized and
`estimated individual exposures of SOF, SOF metabolites (GS-331007, GS-566500), and VEL in the
`pediatrics.
`
`Table 1: The Approved Dosage and the Applicant’s Proposed Changes (in red) for Pediatrics
`
`Reference ID: 4799744
`
`(b) (4)
`
`(b) (4)
`
`

`

`Source: Adapted from the annotated draft label submitted by the Applicant
`
`The key clinical pharmacology review issues are listed below:
`(1) Interchangeability between tablets and pellets
`(2) SOF/VEL dosing regimen for pediatric HCV patients ≥ 3 years
`(3) Labeling revisions to the clinical pharmacology sections
`
`1.1. Recommendations
`The Office of Clinical Pharmacology has reviewed the information provided by the Applicant in
`NDA214187 as well as NDA208341 and recommends approval for the new EPCLUSA oral pellet
`formulation.
`
`1.1. Post-Marketing Requirements and Commitments
`None.
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`2.1. Interchangeability Between Tablets and Pellets
`The Applicant proposes interchangeable use of tablets and pellets and this proposal is primarily
`supported by the findings from a Phase 1 relative bioavailability study (Study GS-US-342-1142). The
`Phase 1 study compared the to-be-marketed SOF/VEL pellet formulation to the currently approved
`SOF/VEL tablet formulation (400/100 mg) in healthy adults. The findings from Study GS-US-342-1142
`show that the exposures to SOF, GS-566500, GS-331007, and VEL from the to-be-marketed SOF/VEL
`pellet formulation was comparable to the SOF/VEL tablet formulation under fasted conditions. The
`comparison of exposures was based on the determination if geometric least-squares mean (GLSM) and
`associated 90% confidence intervals (CI) for drug exposure parameter estimates (AUC and Cmax)
`contained within the traditionally used boundaries of 80% to 125% for bioequivalence studies. The AUC
`estimates for SOF were also comparable between the SOF/VEL pellet and tablet formulations, however,
`the mean of SOF Cmax estimate from the SOF/VEL pellet formulation was approximately 20% lower
`compared to the tablet formulation (GLSM ratio: 0.8, 90% CI: 0.72-0.9). The reduced SOF Cmax from the
`new pellet formulation is not expected to be clinically relevant for the pediatric patients ≥ 3-6 years of
`age. The Applicant proposes that the SOF/VEL pellet formulation can be administered without regard to
`
`Reference ID: 4799744
`
`(b) (4)
`
`

`

`food. The Applicant’s proposal is based on the findings from Study GS-US-342-1142 that assessed the
`effect of food on the systemic exposure to SOF, GS-331007, GS-566500, and VEL following the
`administration of a single SOF/VEL dose of 400/100 mg after a high fat meal in healthy adult subjects.
`Given that the currently approved tablet formulations are recommended to be taken with or without
`food, the findings reported on food-effect for pellet formulation from Study GS-US-342-1142 were
`compared against the reported findings on food-effect for tablet formulation in the Clinical
`Pharmacology Biopharmaceutics Review (Link). The comparison shows that the food-effect on the PK of
`SOF/VEL is comparable between the new pellet formulation and the approved tablet formulation (Table
`6). Therefore, the Applicant’s proposal that the to-be-marketed SOF/VEL pellet formulation can be
`administered without regard to food is acceptable. It is noteworthy that in Study GS-US-342-1143, which
`evaluated the safety and efficacy of the new pellet formulation, SOF/VEL doses were administered in
`pediatric patients without regard to food. Please refer to Section 3.2 for additional details on Study GS-
`US-342-1142 findings.
`
`An inspection for the bioanalytical sites was also requested for Study GS-US-342-1142 and Study GS-US-
`342-1143. The Office of Study Integrity and Surveillance (OSIS) concluded that an inspection of the
`analytical site is not warranted at this time (OSIS review, NDA214187 dated 02/18/2021). The
`bioanalytical site
`) for Studies GS-US-342-1142 and GS-US-342-1143 was inspected in
` (OSIS review,
`, dated 02/15/2019) and the final classification was NAI. The OSIS
`reviewer concluded “…the data from the audited studies are reliable to support a regulatory decision.”
`Therefore, we determined that the favorable inspection results at the bioanalytical site under
` can be applied to this submission and we accept PK results from the abovementioned
`
`
`
`studies.
`
`2.2. SOF/VEL Dosing Regimen for Pediatric Patients ≥ 3 Years
`The results from the Applicant’s population PK analysis and simulations suggest that the proposed
`weight band-based dosing regimen of 150 mg/37.5 mg once daily for SOF/VEL in pediatric patients with
`body weight < 17 kg is appropriate. The proposed regimen provides exposure comparable to the
`exposure expected from the already approved dosing in pediatric patients with body weight ≥17 kg and
`within the range of the observed exposures in adults. Please see Section 3.4 for additional details.
`
`2.3. Proposed Labeling Changes
`The Applicant proposed labeling changes related to clinical pharmacology aspects are summarized in
`Table 2 below along with the clinical pharmacology assessments.
`
`Table 2: Prescription Drug Labeling Changes (Selected)
`
`Section
`
`Summary of Significant Labeling Changes
`Applicant Proposed Changes
`
`INDICATIONS AND
`USAGE
`
`- Lower the minimum age for treatment eligibility
`from 6 years to 3 years and remove lower weight
`cutoff of at least 17 kg
`
`DOSAGE AND
`
`- Corresponding changes to align with INDICATIONS
`
`Clinical Pharmacology
`Assessment
`The proposed changes
`are acceptable. See
`Section 2.2 for
`additional details.
`The proposed changes
`
`Reference ID: 4799744
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`AND USAGE
`- Proposed a new dosing regimen (to-be-
`administered with the pellet formulation) for
`patients weighing less than 17 kg
`- Proposed interchangeable use of pellets with
`tablets for patients weighing 17 kg or greater
`- Inserted new pharmacokinetic information for the
`EPCLUSA components in pediatric patients
`weighing less than 17 kg
`- Proposed revisions to pharmacokinetic information
`for the EPCLUSA components in pediatric patients
`weighing 17 kg or greater
`
`are acceptable. See
`Sections 2.1 and 2.2
`for additional details.
`
`The proposed changes
`are acceptable. See
`Section 2.2 for
`additional details.
`
`ADMINISTRATION
`
`CLINICAL
`PHARMACOLOGY
`
`
`
`3. APPENDICES1
`
`Note: The following is the summary of individual study reports that support the OCP review. The
`conclusions drawn by the Applicant are listed at the end of individual study summary. The Applicant’s
`conclusions are found to be reasonable by the Reviewer unless noted otherwise in a Reviewer’s
`Assessment section.
`
`3.1. Summary of Bioanalytical Method Validation and Performance
`
`
`
`Table 3: Summary of Bioanalytical Method Validation and Performance
`
`Method/Report
`Study: GS-US-342-1142
`Analyte/assessment
`Method
`Matrix
`Validation reports
`
`Findings
`
`SOF, GS-566500, GS-331007, and VEL
`LC-MS/MS
`Human plasma (K2EDTA)
`Validation report provided
`Report
` 60-1323 Amendment 5 for SOF, GS-566500, GS-
`331007
` 60-1393 Amendment 3 for VEL
`Report
`Validation report acceptable
`Note: Report
` 60-1323 Amendment 5 and prior amendments of
`the Report
` 60-1393 were reviewed during NDA209195 review
`for Vosevi (SOF/VEL/Voxilaprevir) and the pertinent clinical
`pharmacology review (Date: 05/08/2017) deemed these reports
` 60-1393 Amendment 3 was reviewed from
`acceptable. Report
`a clinical pharmacology perspective.
`
`☒ Yes ☐ No
`
`☒ Yes ☐ No
`
`
`1The new SOF/VEL oral pellets formulation is noted as the granule formulation interchangeably throughout the
`NDA submission. Therefore, for the purpose of this review, pellets and granules terms are used interchangeably.
`
`Reference ID: 4799744
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Performance reports provided
` 60-1708A for SOF (GS-7977), GS-566500, GS-331007
` 60-1708B for VEL
`
`
`Samples analyzed within the established stability period
`Quality control (QC) samples range acceptable
`Chromatograms provided
`Accuracy and precision of the calibration curve acceptable
`Accuracy and precision of the quality control samples acceptable
`Incurred sample reanalysis (ISR) acceptable
`Overall performance reasonable
`Will an inspection for bioanalytical site be requested?
`
`☒ Yes ☐ No
`
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`
`Performance reports
`
`Inspection
`Study: GS-US-342-1143
`Analyte/assessment
`Method
`Matrix
`Validation reports
`Performance reports
`
`SOF, GS-566500, GS-331007, and VEL
`LC-MS/MS
`Human plasma (K2EDTA)
`Same as Study: GS-US-342-1142
`Performance reports provided
` 60-1672A for SOF (GS-7977), GS-566500, GS-331007
` 60-1672B for VEL
`Samples analyzed within the established stability period
`Quality control (QC) samples range acceptable
`Chromatograms provided
`Accuracy and precision of the calibration curve acceptable
`Accuracy and precision of the quality control samples acceptable
`Incurred sample reanalysis (ISR) acceptable
`Overall performance reasonable
`Will an inspection for bioanalytical site be requested?
`Inspection
`Source: Compiled by the Reviewer
`#Note: A request for biopharmaceutical inspections was sent to the Office of Study Integrity and
`Surveillance (OSIS). OSIS determined that inspections are not warranted because the sites pertaining to
`these studies were inspected by OSIS in
`, which falls within the surveillance interval. The
`final classification for the inspections in
` was No Action Indicated (NAI).
`
`☒ Yes ☐ No
`
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`☒ Yes ☐ No
`
`
`
`3.2. GS-US-342-1142
`Overview:
`This was a Phase 1 pharmacokinetic study that assessed the relative bioavailability (BA) of sofosbuvir
`(SOF), SOF metabolites (GS-331007 and GS-566500), and velpatasvir (VEL) from the to-be-marketed
`granule formulation and compared to the tablet formulation following administration of a single
`SOF/VEL dose of 400/100 mg in healthy adult subjects under fasted conditions. The study also assessed
`the effect of food on the systemic exposure to SOF, GS-331007, GS-566500, and VEL following
`administration of a single SOF/VEL dose of 400/100 mg granule formulation after a high fat meal in
`healthy adult subjects.
`
`The study evaluated the following treatments in a cross-over manner separated by 9-10 days:
`
`Reference ID: 4799744
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`TreatmentA:Single dose of SOF/VEL tablet 400/100 mg (1 X 400/100 mgtablet) administered under
`fasted conditions
`TreatmentC: Single dose of SOF/VEL granules 400/100 mg (8 X 50/12.5 mg packets) administered under
`fasted conditions
`TreatmentG: Single dose of SOF/VEL granules 400/100 mg (8 X 50/12.5 mgpackets) administered under
`fed conditions (high-fat meal)
`
`Prior to administering each treatment, subjects fasted overnight for a minimum of 10 hours except for
`Treatment G. For TreatmentG, subjects started the standardized meal approximately 30 minutesprior
`to drug administration and complete it within
`5 minutes of dosing. The composition of meal contained total 1000 calories (~50% from fat).
`
`In total, 56 subjects were randomized and 38 (68%) were male, 35 (63%) were white, and 42 (75%) were
`Hispanic or Latino. All subjects completed the study and wereincluded in the safety as well as PK
`analysis. The age and weight of enrolled patients ranged between 19 to 45 years and between 49 to 97
`kg.
`
`The patients remained at the study center up to Day 24 post-dose. For PK assessments, 17 blood
`samples were collected between pre-dose to 120 hours post-dose. SOF, GS-566500, GS-331007, and VEL
`concentrations in plasma were measuredusing validated LC-MS/MS methods.
`
`Pharmacokinetic Results:
`Plasma concentrationsofall four analytes were analyzed using noncompartmentalanalysis to derive PK
`parameterestimates reported in Table 4. Exposure parameter estimates (Cmax and AUC)for all analytes
`from Treatment C (granules 400/100 mg fasted) were compared against the estimates from Treatment
`A (tablet 400/100 mgfasted) (Table 5). In addition, exposure parameter estimates (Cmax and AUC)forall
`analytes from Treatment G (granules 400/100 mg fed) were compared against the estimates from
`TreatmentC (granules 400/100 mgfasted) (Table 5). Comparison between administration of tablet and
`granule formulation under fasting conditions showed that Cmax and AUC estimates following a single
`400/100 mg dose were comparableforall analytes except for SOF, which had approximately 20% lower
`Cmaxwith the lower bound of 90% confidence interval (Cl) at 72% (Table 5). When granules formulation
`was administered with high-fat meal, Tmax was delayed by approximately one hour(Table 4) forall
`analytes. The mean estimates for Cmax for SOF, GS-566500, GS-331007, and VEL underfed condition
`were 105%, 119%, 64%, and 101%, respectively, compared to estimates under fasted condition (Table 5).
`The meanestimates for AUCja: for SOF, GS-566500, GS-331007, and VEL underfed condition were 168%,
`154%, 104%, and 122%, respectively, compared to estimates under fasted condition (Table 5).
`
`Table 4: Mean (CV%) for Exposure and Pharmacokinetic Parameter Estimates for SOF, GS-566500, GS-331007, and
`VEL (N=56)
`
`ek cay|tae| at
`
`Meal condition)
`(ng-h/mL)
`(ng/mL)
`
`A (Table-Fasting) 1474.6 (49.9)|0.75 (0.5-4)|0.49 (32,n=49)1730.4 (54.5)
`
`
`
`
`C (Granules-Fasting) 1171.8 (44.8)|1(0.5-3)|0.53 (60,n=47)1598.3 (45.6)
`G (Granules-Fed) 2(0.5-4)|0.65 (29, n=42)2494.5 (36.1) 1194.1 (43.0)
`
`
`
`GS-566500
`
`2.09 (11)
`
`A (Table-Fasting)
`
`1912.3 (37.2)
`
`491.8 (39.1)
`
`2 (1-4)
`
`Reference ID: 4799744
`
`

`

`na
`(ng/mL)
`(ng-h/mL)
`Mealcondition)
`C(Granules-Fasting)|__1868.2 (35.4)
`G (Granules-Fed)|___2719.5 (19.0)
`GS-331007
`A(Table-Fasting)|11077.1(25.6)|_910.3(29.2)|3(1-6)| 28.49(18)|
`
`C(Granules-Fasting)|__11315.9(23.9)|988.2(24.4)|2.5(1-4)|27.78(28)
`G(Granules-Fed)|__11678.3 (22.0)
`VEL
`
`au
`
`A(Table-Fasting)|__4068.8 (62.4)
`C(Granules-Fasting)|__3740.3 (56.5)
`G (Granules-Fed)|_3906.8 (44.0)
`a: Median [Range], b: From Reviewer’s analysis, h: Hours
`Source: Adaptedfrom Study GS-US-342-1142 report
`
`
`
`Table 5: Summary ofthe Bioavailability Assessment
`
`
`
`vermeters|____APRIRtEstimates(90%ConfidenceInterval)
`
`
`
`
`
`
`
`
`
`
`% Point Estimates (90% ConfidenceInterval)
`
`C (Granules-Fasting)/A (Tablet-Fasting)
`
`G (Granules-Fed)/C (Granules-Fasting)
`
`AUCs
`
`Cmax
`
`AUCs
`
`Cmax
`
`AUCs
`
`Cae
`
`AUCs
`
`SOF
`
`GS-566500
`
`GS-331007
`
`VEL
`
`Cae
`Source: Adaptedfrom Study GS-US-342-1142 report
`
`e
`
`Applicant’s Conclusions:
`e
`Systemic exposure to VEL and GS-331007 were similar/comparable after administration of the
`SOF/VELgranule andtablet formulations.
`SOF and GS-566500 exposures were also comparable between the granule formulation and the
`tablet formulation.
`e The effect of food on the PK of the SOF/VEL granule formulationis similar to that observed with
`the approved tablet formulation (EPCLUSA®), hence, SOF/VEL granules can be administered
`withoutregardto food.
`
`Reviewer's Assessments:
`
`Reference ID: 4799744
`
`

`

`The Applicant concludes that SOF exposures were comparable betweenthe granule formulation
`andthe tabletformulation. On average, SOF had approximately 20% lower Cmax with the lower
`bound of 90% confidence interval (CI) at 72% and the observed 20% lower Cmax is not expected
`to be clinically relevant.
`
`The study report notes that the meal containedtotal 1000 calories with ~50% calories from fat,
`however, the report did not include information on the meal’s proteins or carbohydrates
`contents.
`
`The Applicant concludes that the food-effect on the PK of the SOF/VEL granule formulationis
`similar to that observed with the approved tabletformulation (EPCLUSA® 2017). This conclusion
`is reasonable based on the comparison of (A) the observedfood-effectfor the new granule
`formulation in this study and (B) the reportedfood-effectfor EPCLUSA tablet formulation in the
`Clinical Pharmacology Biopharmaceutics Review of NDA208341 (Pages 39-40, Link) (Table 6).
`
`The Applicant proposes to administer the new granule formulation without regard to food. The
`Applicant’s proposalis reasonable based on the abovementioned comparison as well as the
`efficacy and safetyfindings from Study GS-US-342-1143 that administered granule formulation
`withoutregardto foodin pediatrics 3 to < 6 years old.
`
`Table 6: Comparison of Food Effect Between EPCLUSA Tablet Formulation and the Proposed Granule Formulation
`
`ecemeters
`
`% Point Estimates (90% Confidence Interval)
`Tablet-Fed/Tablet-Fasted
`Granules-Fed/ Granules-Fasted
`
`AUCs
`
`Crna
`
`AUCs
`
`Cras
`
`AUCies
`
`Coax
`
`SOF
`
`GS-566500
`
`GS-331007
`
`VEL
`
`122 (101-148)
`122 (99-149)
`AUCiast
`101 (85-120)
`105 (87-127)
`Cmax
`Source: Adaptedfrom Study GS-US-342-1142 report and EPCLUSA originalClinical Pharmacology
`Biopharmaceutics Review
`
`
`
`3.3. GS-US-342-1143
`
`Overview:
`This was an open-label Phase 2 study that evaluated safety and efficacy of SOF/VEL tablets and the to-
`be-marketed pellets in adolescents and children with chronic HCV infection.
`
`The study design included three cohorts across two age-based groupsandthe enrolled patients received
`SOF/VELdosing (once a day with or without food) for 12 weeks as described below:
`
`Group1:
`
`Reference ID: 4799744
`
`

`

`- Cohort 1 (12 to < 18 years old): SOF/VEL 400/100 mg (total daily dose)
`
`
`Group 2:
`- Cohort 2 (6 to < 12 years old): SOF/VEL 200/50 mg (total daily dose)
`- Cohort 3 (3 to < 6 years old):
`o Patients with ≥ 17 kg weight: SOF/VEL 200/50 mg (total daily dose)
`o Patients with < 17 kg weight: SOF/VEL 150/37.5 mg (total daily dose)
`
`The PK data from Cohorts 1 and 2 have been reviewed in the Clinical Pharmacology Review dated
`02/25/2020 (Link). The distribution of patients from Cohort 3 is summarized in the table below.
`
`Table 7: Patients’ Distribution
`
`
`Source: Adapted from Study GS-US-342-1143 report
`
`The study collected intensive PK samples predose and up to 12 hours postdose on Day 7 in a lead-in
`phase and sparse samples during treatment phase to assess systemic exposure to sofosbuvir (SOF), SOF
`metabolites (GS-331007 and GS-566500), and velpatasvir (VEL) for the to-be-marketed pellet
`formulation. A population-PK (POP-PK) approach was used to analyze the PK data collected from the
`lead-in phase and the treatment phase as well as other pediatric studies. Please refer to the
`Pharmacometrics Review section for discussion of findings from POP-PK analysis.
`
`Please refer to the clinical review for the safety and efficacy findings. Pharmacokinetic results from the
`lead-in phase is summarized below.
`
`Pharmacokinetic Results from the Lead-In Phase:
`In total, 18 patients from Cohort 3 completed the lead-in PK phase and underwent an intensive PK
`evaluation. Selected demographic information of patients in the lead-in PK phase is summarized in Table
`8 below.
`
`Table 8: Demographic Information Summary for Patients in Lead-in PK Phase
`
`Planned Treatment
`Groups
`3 to <6 years
`
`N Weight Range
` (kg)
`12.9-24.9
`
`18
`
`Race
`
`Age Range
` (Years)
`3-5
`
`White-13
`Black/African American-1
`Other-4
`Source: Compiled by the Reviewer from Study GS-US-342-1143 report
`
`
`
`Reference ID: 4799744
`
`

`

`The reported mean plasma concentration-time profiles for SOF, GS-566500, GS-331007, and VEL from
`Cohort 3 (3 to < 6 years old) are presented in Figure 1, Figure 2, Figure 3, and Figure 4, respectively,
`along with the concentration-time profiles from other two cohorts, i.e., Cohort 1 (12 to < 18 years old)
`and Cohort 2 (6 to < 12 years old). Plasma concentrations (from Cohort 3) of all four analytes were
`subjected to noncompartmental analysis to derive PK parameter estimates reported in Table 9. These
`estimates from pediatric patients were also compared to the estimates for adults patients, which were
`derived by the Applicant using a POP-PK analysis approach (Table 10).
`
`Figure 1: Mean (SE) Concentrations of SOF in Plasma (A: linear scale, B: semi-logarithmic scale)
`
`Source: Reviewer’s Analysis
`
`
`
`
`
`
`Reference ID: 4799744
`
`

`

`Figure 2: Mean (SE) Concentrations of GS-566500 in Plasma (A: linear scale, B: semi-logarithmic scale)
`
`
`Source: Reviewer’s Analysis
`
`
`
`
`
`
`
`Reference ID: 4799744
`
`

`

`Figure 3: Mean (SE) Concentrations of GS- 331007 in Plasma (A: linear scale, B: semi-logarithmic scale)
`
`Source: Reviewer’s Analysis
`
`
`
`
`
`
`
`
`Reference ID: 4799744
`
`

`

`
`
`
`
`
`Figure 4: Mean (SE) Concentrations of VEL in Plasma(A:linear scale, B: semi-logarithmic scale)
`
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`Time (Hours) Time (Hours)
`
`—=Cohort 1 (12 to <18 years):SOF/VEL 12 Weeks
`-* Cohort 2 (6 to <12 years):SOF/VEL 12 Weeks
`—- Cohort 3 (3 to <6 years):SOF/VEL 12 Weeks
`
`Treatment
`
`Source: Reviewer’s Analysis
`
`Table 9: Mean (CV%) for Exposure and Pharmacokinetic Parameter Estimates for SOF, GS-566500, GS-331007, and
`VEL
`
`Teer Loew|terieay [tm|wim||M
`(ng-h/mL)
`(ng-h/mL)
`(ng/mL)
`(ng/mL)
`SOF
`3to<6yr(18)|2348.6(93)|3306.2(105.8)|1207.8(65.5)|—-S|2(0.5-12)|1(48,n=7)|
`
`Adults(>982)_[|—-Ss1261.6(37.2)|566.3(314)|-|-| -ist
`GS-566500°
`3to<6yr(18)__| _2023.6(52)|2083.9(56)|466.6(55)_|~—-|2.5(1-12)|2(13,n=12)|
`
`Adults(>982)_[|-|- --
`GS-331007
`
`3to<6yr(18)__|_7524.7(16)_|11604.0(23.5)|1105.5(23.0)|—-|3.5(1-4)_|5.1(27,n=8)_|
`Adults (>982)_[|__—-___—i|_:13966.7(28.0)|_868.2(27.6)| -|-|-
`VEL
`
`3 to <6 yr (18)
`
`Adults(>982)_ |_|2967.3(50.2)|259.0(53.9)|42.5(65.02)|-|
`a: From Reviewer's analysis, b: AUCo-24 calculated using pre-dose sample as 24 hr sample, c: Median [Range], h: Hours, yr:
`years, Parameterestimates for adults derived based on a POP-PK analysis approach.
`Source: Adaptedfrom Study GS-US-342-1143 report
`
`Reference ID: 4799744
`
`

`

`Table 10: Comparison of SOF, GS-566500, GS-331007, and VEL Exposures BetweenAdults and Pediatrics 3 to less
`than 6 years of age
`
`% Point Estimates (90% Confidence Interval) for
`3 to <6 years /Adults
`GS-331007
`
`VEL
`
`123 (101, 149)
`199 (160, 246)
`
`re eeee ee)
`
`SOF
`
`Analyte
`Parameters
`
`AUCo24
`Cmax
`
`Applicant’s Conclusions:
`e
`Intensive PK analyses in the PK lead-in phase indicated that the PK of SOF, GS-331007, and VEL
`in adolescent and pediatric subjects were as expected and similar to those observed in the adult
`population.
`e These findings confirm the appropriateness of the dose evaluated in the treatment phase.
`
`Reviewer's Assessments:
`
`e
`
`e
`
`This Phase 2 study enrolled pediatric patients across three different cohorts based on a patient’s
`age and consequently, the study report included PK parameter summaryfrom the lead-in PK
`phase based on the age-based groups(reported above). The recommended SOF/VEL dosing
`regimenis based on a patient’s weight and therefore, additional non-compartmentalanalysis
`(NCA) was done by the Reviewer to summarize the lead-in PK phase data using the weight-based
`groups. The weight-based groups usedin this additional NCA were kept sameas the Applicant
`proposed dosing regimen(Table 11-Table 13).
`
`The currently approved EPCLUSA label include PK parameterestimates for two weight-based
`groups: 230 kg and 17 to <30 kg. These estimates were derived using a POP-PK analysis
`approach. With this submission, the Applicant is proposing to update the currently listed PK
`estimates as well as proposing to add POP-PK derived estimates for patients <17 kg weight.
`Therefore, the Applicant’s parameter estimates from POP-PK analysis were also compared
`against the NCA parameterestimates derivedfrom the lead-in PK phase (Table 11-Table 13). The
`comparison of estimatesfrom these two different analyses methods showthatin general, AUC
`estimates were comparable (<+30% difference). The cutoff of +30% difference is an arbitrary
`cutoffselected by the Reviewerfor the purposesof this review only. SOF and VEL Cmax estimates
`derivedfrom POP-PK analysis tended to be lower than NCA estimates. The observeddifference in
`Cmax estimates could be due to (A) differences in methodology and (B) sampling schedule
`differences between POP-PK analysis conducted using lead-in phase as well as treatment phase
`data and NCA analysis conducted using lead-in phase PK data.It is noteworthy that Cmax
`estimatesfor GS-331007 (major inactive circulatory metabolite) and Ctau estimates for VEL were
`comparable.
`
`Reference ID: 4799744
`
`

`

`Table 11: Comparison of Exposure Parameter Estimates for SOF from NCA and POP-PKAnalysesAcross Different
`Cohorts
`
`Group(n)|( (%Cv, n)
`
`a [aa
`
`[ea
`
`Se ss
`
`
`AUCS,,, (ng-h/ml)
`Cmax (ng/ml)
`3 to <6 yr
`2410 (64%, 11)
`AUC#y, (ng-h/ml)
`150/37.5
`(18)
`(9)
`Cmax (ng/mL)
`AUCTay (ng-h/mt)|1336(39%)|
`Cmax (ng/ml)|1089(17%)|
`AUC?ay (ng-h/mL)
`(17)
`Cmax (ng/ml)
`AUCZ,,, (ng-h/mL)
`12 to <18
`Cmax (ng/ml)
`yr (16)
`
`AUC#ay (ng-h/ml) 3753.5(NA)|-
`(1) Cmax (ng/ml)|iseo(NA)|-
`
`a: From Reviewer’s analysis AUCo-tau calculated using pre-dose sample as 24 hr sample, b: The Applicant
`proposedestimatesderivedfrom a POP-PK analysis
`(0) (4) p,. Hours, yr: years, Numbers markedin
`Bold Red are when percentratio (PR) > +30% calculated as PR=100*(POP-PK estimate-NCA estimate)/ NCA
`estimate.
`
`2010 (82%, 89)
`
`) )
`
`) ) ) )
`
`)
`
`(9)
`
`(11)
`
`400/100
`
`Table 12: Comparison of Exposure Parameter Estimates for GS-331007 from NCA and POP-PK Analyses Across
`Different Cohorts
`
`Source: Reviewer’s analysis andfrom the Applicant’s POP-PK report
`Source: Reviewer’s analysis andfrom the Applicant’s POP-PK report
`
`Sr”|crust|tworney|mT|MARCO|Porreeenn
`
`(SOF/VEL)
`
`(n)
`
`Pat 200/50
`
`3 to <6 yr
`
`(9)
`
`(18) ee150/37.5
`(9)
`|AUCSy(ngrh/mt)|__8447(16%)|
`
`
`6t0<12 [-—Samlng/mt)|792(as%[idvoo/so
`
`(17)
`17-30 kg
`
`12 to <18
`yr (16)
`17-30 kg|AUCHy(ng-h/mt)|19265(NA)_|Cd
`(1)|Cmax(mg/mt)|_—-2220(NA)_|Cd
`a: From Reviewer’s analysis AUCo-tqu calculated using pre-dose sample as 24 hr sample, b: The Applicant
`proposedestimatesderivedfrom POP-PKanalysis
`(b) (4) h: Hours, yr: years, No percent ratio (PR) >
`+30% identified when calculated as PR = 100*(POP-PK estimate-NCA estimate)/ NCA estimate.
`
`400/100
`
`Table 13: Comparison of Exposure Parameter Estimates for VEL from NCA and POP-PK Analyses AcrossDifferent
`Cohorts
`
`(SOF/VEL)
`
`SS=os
`(0)
`200/50
`
`150/37.5
`
`Group(n)
`
`3 to <6 yr
`(18)
`
`17.30k
`
`<17
`
`(98
`
`Reference ID: 4799744
`
`

`

`(SOF/VEL)
`Group(n)
`AUCFay (ngrh/mt)|2948(62%)| -
`
`230 kg (6)
`Cmax(ng/mt)
`_|__-413(56%)|
`6 to <12 yr Crou(ng/mt)|__—-25(78%)|Cd
`
`(17)
`:
`
`17-30 kg
`(11)
`
` [ee=[ome
`
`
`
`12 to <18
`
`yr (16)
`
`.
`
`Crou (ng/ml)
`
`17-30 kg (ng-h/mt)|2384(NA)_|AUCTay
`
`(1) Cmax(ng/mt)|289(NA)_|
`
`|53(NA)|Cd
`a: From Reviewer’s analysis AUCo-tau calculated using pre-dose sample as 24 hr sample, b: The Applicant
`proposedestimates derivedfrom POP-PK analysis
`(©) 4) p,- Hours, yr: years, Numbers markedin Bold
`Red are whenpercentratio (PR) > +30% calculated as PR = 100*(POP-PK estimate-NCA estimate)/ NCA
`estimate.
`
`Source: Reviewer’s analysis andfrom the Applicant’s POP-PK report
`
`Wedo notagree with the Applicant’s first conclusion above,i.e., the observed PK ofSOF and VEL
`in adolescent and pediatric subjects were similar to those observed in the adult population. The
`ratios (as percent point estimates) of Cmax and AUC estimates for both SOF and VEL between
`the 3 to <6 years pediatric patient subgroup andadults were greater than 100% with lower
`bound of 90% CI was 2100% and upper bound of 90% CI ranging from 149% to 246% (Table 10).
`The AUC estimates for GS-331007, the predominantcirculatory inactive SOF metabolite, in the 3
`to <6 years pediatric patient subgroup were 84% (76%-94%) compared to adults (Table 10).
`However, from a clinical pharmacology perspective, the observed differences in SOF and VEL
`exposuresin the 3 to < 6 years pediatric patients group and adults not