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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA Numbers (SDN)
`
`Link to EDR
`
`205834 (835) S-29
`212477 (1)
`
`\\CDSESUB1\evsprod\NDA205834\205834.enx
`\\CDSESUB1\evsprod\NDA212477\212477.enx
`
`Submission Date
`
`02/28/2019
`
`Submission Types
`
`Brand Name
`
`Generic Name
`
`Dosage Regimen
`
`Prior Approval Efficacy Supplement (NDA 205834)
`Original NDA (NDA 212477)
`
`HARVONI®
`
`Ledipasvir/Sofosbuvir (LDV/SOF)
`
`
`
`
`
`Adults and pediatric patients 12 years and older: One tablet (90
`mg of LDV and 400 mg of SOF) taken orally QD with or without
`food.
` 33.75/150
`Pediatric patients 3 years
`mg to 90/400 mg LDV/SOF tablet or oral granules per day with or
`without food.
`
`Route of Administration
`
`Oral
`
`Proposed Indication
`
`Treatment of Hepatitis C Virus (HCV) infection
`
`Applicant
`
`Gilead Sciences, Inc.
`
`OCP Review Team
`
`Hazem E. Hassan, PhD, MS, RPh, RCDS
`Ruojing Li, PhD
`Chao Liu, PhD
`Su-Young Choi, Pharm D, PhD
`
`Reference ID: 4480168
`
`1
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`(b) (4)
`
`

`

`Table of Contents
`1. Executive summary...................................................................................................................................3
`2. Recommendations....................................................................................................................................4
`3. Labeling Recommendations .....................................................................................................................4
`4. Summary of Important Clinical Pharmacology Findings...........................................................................4
`5. Individual Study Review............................................................................................................................5
`6. Data Integrity-Related Consults (OSIS Inspections)................................................................................15
`7. Pharmacometrics Review .......................................................................................................................16
`
`Reference ID: 4480168
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`2
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`

`

`1. Executive summary
`Harvoni® tablet is a fixed-dose combination (FDC) of LDV, an HCV NS5A inhibitor, and SOF, an HCV nucleotide
`analog NS5B polymerase inhibitor. HARVONI® is indicated for the treatment of HCV in adults and pediatrics (12
`years of age and older or weighing at least 35 kg). The recommended dosage in adults and pediatric patients 12
`years and older is one tablet (90 mg of LDV and 400 mg of SOF) taken orally once daily with or without food.
`
`at least 35
`
`90 mg/400 mg per day
`
`The Applicant submitted a Prior Approval Efficacy Supplement (NDA 205834) and an original NDA (212477) in
`support of expanding the indication of HARVONI® to pediatric patients 3 to < 12 years. The proposed pediatric
`dosages for patients 3 years or older are as follows:
`Proposed Dosing for Pediatric Patients 3 Years and Older Using HARVONI Tablets or Oral Granules
`Body Weight (kg) Dosing of HARVONI Tablets or Oral Granules
`HARVONI Daily Dose
`one 90 mg/400 mg tablet once daily
`or
`two 45 mg/200 mg tablets once daily
`or
`two 45 mg/200 mg packets of granules once daily
`one 45 mg/200 mg tablet once daily
`or
`one 45 mg/200 mg packet of granules once daily
`one 33.75 mg/150 mg packet of granules once daily
`
`17 to less than 35
`
`less than17
`
`45 mg/200 mg per day
`
`33.75 mg/150 mg per day
`
`The basis of approval of the current application is extrapolation of the efficacy from adult subjects by
`demonstrating comparable systemic exposures of SOF, GS-331107 (SOF major inactive metabolite) and LDV
`between adults and pediatric patients with HCV infection. The proposed dosage regimens were supported by PK,
`safety and efficacy data from study GS-US-337-1116 in HCV infected pediatric patients. The LDV/SOF FDC doses
`employed in this study targeted systemic exposures similar to those observed in adults at the approved dose
`(LDV/SOF 90/400 mg). Results from this study indicated that there were no clinically relevant differences between
`SOF, GS-331107 and LDV exposures (AUCtau or Cmax) in pediatric subjects and exposures observed in the adult
`Phase 2/3 studies. Population PK analyses and simulations were conducted to evaluate SOF, GS-331007 and LDV
`exposures based on proposed weight band-based dosing regimens. The simulation analyses indicated that
`exposures in pediatrics 3 to < 12 years are comparable to those in adults.
`
`Reference ID: 4480168
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`

`

`The applicant developed and evaluated two pediatric formulations, a low strength HARVONI tablet (45/200 mg)
`and oral granules (SOF/LDV 45/200 mg and 33.75/150 mg). The applicant requested a biowaiver for the low
`strength HARVONI® 45/200-mg tablet and conducted study GS-US-337-2091 to evaluate the bioavailability (BA)
`of the granules relative to the approved tablet formulation, and the food effect on the granules. Overall, there
`were no clinically significant differences in the exposures of SOF, GS-331107 and LDV following a) administration
`of granules and tablets under fasted condition and b) administration of granules under fed and fasted conditions.
`
`2. Recommendations
`The Office of Clinical Pharmacology has reviewed the application and determined that the proposed weight-
`based dosage regimens in pediatrics are acceptable. This original NDA and pediatric efficacy supplement are
`approvable from a clinical pharmacology perspective.
`
`3. Labeling Recommendations
`The following clinical pharmacology related information will be added in HARVONI® USPI:
`Section 2 Dosage and Administration
`Sub-Section 2.4 Recommended Dosage in Pediatric Patients 3 years of Age and Older
`
`Add recommended weight-based doses of HARVONI®.
`
`Add recommended weight-based doses of Ribavirin (RBV) to be given in combination with HARVONI®.
`Section 8 Specific Population
`Sub-Section 8.4 (Pediatric Use)
` Add the summary of findings in study GS-US-337-1116.
`Section 12 Clinical Pharmacology
`Sub-Section 12.3 Pharmacokinetics
` Update the PK table to include exposure parameters of HARVONI® in pediatrics 3 years of age and older
`based on the findings in study GS-US-337-1116.
`
`4. Summary of Important Clinical Pharmacology Findings
`Study GS-US-337-1116:
`
`Comparison of SOF, GS-331007, and LDV exposures between pediatric subjects 3 to < 12 years old and
`adults indicated that there were no clinically significant differences in exposures between pediatrics and
`adults. The proposed weight band based dosing is acceptable.
`
`Reference ID: 4480168
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`

`

`
`
`
`
`Subjects weighing ≥ 35 to < 45 kg experienced lower SOF, GS-331007, and LDV exposures relative to
`subjects in other weight band groups (< 17 kg or ≥ 17 to < 35 kg). This is not a concern because these
`subjects received, per-protocol, only half of the currently approved dose (i.e., they received LDV/SOF;
`45/200 mg).
`Subjects who received tablets tend to have lower exposures of SOF (AUCtau) and GS-331007 (AUCtau and
`Cmax) than those who received packets (granules). This is likely due to the fact that subjects with higher
`body weight within a weight band tended to receive tablets rather than granules.
`
`Study GS-US-337-2091:
`
`Assessment of a) relative bioavailability between LDV/SOF oral granules and LDV/SOF FDC tablet and b)
`food effect on LDV/SOF oral granules indicated that there were no clinically significant differences in
`exposures of LDV/SOF after administration of oral granules relative to LDV/SOF tablet, and that LDV/SOF
`oral granules can be administered without regard to food.
`
`5. Individual Study Review
`Study # 1: GS-US-337-1116 (EDR Link)*
`*This review focuses only on the clinical pharmacology aspects of this trial (Please refer to clinical review regarding efficacy
`and safety).
`Title:
`Investigate the Safety and Efficacy of
`A Phase 2, Open-Label, Multicenter, Multi-cohort Study to
`Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and Children with Chronic HCV-
`Infection.
`Study Period: 05 November 2014 - 15 June 2018
`Objectives:
`Primary objectives:
`
`PK lead-in phase: To evaluate the steady-state PK and confirm the dose of LDV/SOF 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.
`
`
`
`Reference ID: 4480168
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`

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`Trial Design:
`This was an open-label, multicohort, 2-part study [a PK lead-in phase (Part 1) and a treatment phase (Part 2)] that
`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. Both treatment naive or treatment experienced were enrolled. Note: Data
`from subjects aged 12 to < 18 years were previously submitted and reviewed.
`
`PK sampling scheme
`Intensive PK Phase: Blood samples were collected for cohort 2 (6 to <12 years old) pre-dose and 0.5, 1, 2, 3, 4, 5,
`8, and 12 hours post-dose and for cohort 3 (3 to <6 years old) predose and 0.5, 2, 4, 8, and 12 hours post-dose.
`Treatment Phase: a single PK blood sample was collected at Weeks 1, 2, 4, 8, 12, 16, 20 and 24.
`
`Main Inclusion Criteria:
`Males or nonpregnant/nonlactating females 3 to < 18 years of age, with chronic HCV genotype 1, 3, 4, 5, or 6
`infection, HCV RNA ≥ 1000 IU/mL, and were HCV treatment naive or experienced. Weight limits were defined for
`subjects enrolled in the PK lead-in phase only: subjects in Cohort 2 (6 to < 12 years old) were required to weigh ≥
`17 kg and < 45 kg, and Cohort 3 was to include at least 4 subjects weighing ≥ 17 kg and at least 4 subjects weighing
`< 17 kg. Weight limits did not apply to additional subjects of each age group enrolled in the treatment phase.
`
`
`
`
`
`
`
`
`
`Test Product, Dose and Mode of Administration:
`Test product:
`
`LDV/SOF FDC (90/400-mg tablet) (adult-strength tablet)
`LDV/SOF FDC (22.5/100-mg tablet) (low-dose tablet)
`LDV/SOF FDC (11.25/50-mg packets containing granules)
`Placebo-to-match LDV/SOF FDC (90/400-mg tablet)
`Placebo-to-match LDV/SOF FDC (22.5/100-mg tablet)
`
`RBV 40-mg/mL oral solution
`Dosages and formulations by age group:
`
`6 to < 12 years weighing ≥ 45 Kg: once oral daily dose of LDV/SOF 90/400 mg (adult dose).
`6 to < 12 years weighing ≥ 35 to < 45 Kg: once oral daily dose of LDV/SOF 45/200 mg (of note, LDV/SOF 45/200
`is the per protocol dose. However, the currently approved dose of subjects weighing ≥ 35 Kg is LDV/SOF
`90/400).
`
`
`
`Reference ID: 4480168
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`

`

`
`
`
`
`
`
`
`
`a.
`b.
`
`6 to < 12 years weighing ≥ 17 to < 35 Kg: once oral daily dose of LDV/SOF 2 × 22.5/100-mg tablets or LDV/SOF
`4 × 11.25/50-mg packets containing granules.
`3 to < 6 years weighing ≥ 17 kg: once oral daily dose of LDV/SOF 4 × 11.25/50-mg packets containing granules.
`3 to < 6 years weighing < 17 kg: once oral daily dose of LDV/SOF 3 × 11.25/50-mg packets containing granules.
`RBV: the following RBV doses were used as indicated based on the genotype.
`Body Weight (kg)
`Oral Ribavirin Daily Dosagea, b
`15 mg per kg per day
`(divided dose AM and PM)
`600 mg per day
`(1 x 200 mg AM, 2 x 200 mg PM)
`800 mg per day
`(2 x 200 mg AM, 2 x 200 mg PM)
`1000 mg per day
`(2 x 200 mg AM, 3 x 200 mg PM)
`1200 mg per day
`(3 x 200 mg AM, 3 x 200 mg PM)
`The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
`Ribavirin dosage regimens used in this study were slightly different than those listed in REBETOL® USPI.
`
`less than 47
`
`47–49
`
`50–65
`
`66–80
`
`greater than 80
`
`
`
`Bioanalytical method:
`All PK samples were analyzed using validated liquid chromatography-tandem mass spectroscopy (LC/MS/MS)
`methods. The precision and accuracy were acceptable for calibration curve and QC runs. All samples were
`analyzed within the long-term storage stability duration.
`
`Results:
`Main Subject Demographics and Baseline Disease Characteristics
`6 to < 12 Years Old
`Ninety two subjects were enrolled, of which, 89 subjects were enrolled to receive LDV/SOF for 12 weeks, 1 subject
`was enrolled to receive LDV/SOF for 24 weeks, and 2 subjects with genotype 3 HCV infection were enrolled to
`receive LDV/SOF+RBV for 24 weeks. Most subjects had genotype 1 HCV infection (95.7%, 88 subjects). Two
`subjects (2.2%) had genotype 3 HCV infection, and 2 subjects (2.2%) had genotype 4 HCV infection. Two subjects
`(2.2%) had cirrhosis. The mean (SD) baseline eGFR using the Schwartz formula was 156.4 (24.38) mL/min/1.73 m2.
`
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`Most subjects were males (58.7%), white (79.3%), and non-Hispanic/Latino (84.8%), with a mean age of 9 years.
`The mean (SD) body weight for subjects was 32.8 (10.84) kg. Most subjects were treatment naive (78.3%).
`3 to < 6 Years Old
`Thirty four subjects were enrolled and received LDV/SOF for 12 weeks. All subjects completed study treatment
`except for one subject who prematurely discontinued study treatment due to an AE of product taste. Most
`subjects were female (70.6%), white (79.4%), and non-Hispanic/Latino (82.4%), with a mean age of 4 years. The
`mean (SD) body weight for subjects was 19.2 (5.03) kg. Most subjects had genotype 1 HCV infection (97.1%, 33
`subjects). One subject (2.9%) had genotype 4 HCV infection. No subjects had cirrhosis. The mean (SD) baseline
`eGFR using the Schwartz formula was 169.1 (28.04) mL/min/1.73 m2. All subjects were treatment naive (100.0%).
`Pharmacokinetics
`Exposures of LDV, SOF, and GS-331007 in the PK Lead-In phase were compared with population PK (POPPK)-
`derived exposure data from adult Phase 2/3 studies (Table 1). In addition, a POPPK modeling approach was used
`to estimate LDV, SOF, and GS-331007 PK parameters in pediatrics. Table 2. represents a comparison of
`exposures of LDV, SOF and GS-331007 based on POPPK analyses and POPPK-derived exposure data from adult
`Phase 2/3 studies (Please refer to section 7, Pharmacometrics review for more details about the POPPK
`analyses). Overall, there were no clinically significant differences between pediatrics and adults with respect to
`exposures of LDV, SOF, and GS-331007. The popPk analyses demonstrated similar results (Refer to Section 7,
`Pharmacometrics review for further details).
`Table 1. Statistical Analysis of Intensive LDV, SOF and GS-331007 Exposures in Pediatric Subjects from the PK
`Lead-In phase Compared with Population PK-Based Exposures in the Adult Phase 2/3 Population
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`Source: Clinical Study Report, P. 147
`Table 2. Statistical Comparison of SOF, GS-331007 and LDV Exposures (based on population PK analyses)
`Between Pediatric Subjects 3 to < 12 Years Old and the Adult Phase 2/3 Population
`
`Source: Summary of Clinical Pharmacology, P. 20
`
`Reviewer’s analyses
`The applicant submitted the summary results by age groups. However, as the dosing recommendation will be
`based on body weight, exposures (determined by intensive PK) of proposed body weight bands were compared.
`In addition, exposures were compared between the tablet and granule formulations to confirm that there is no
`formulation-dependent differences in exposures in pediatric patients.
`
`1. Exposures of SOF, GS331007, and LDV by weight bands
`There were lower exposures of SOF, GS-331007 and LDV in subjects weighing ≥ 35 to < 45 kg (Figure 1). This is
`mainly attributed to the subjects receiving the lower dose (LDV/SOF; 45/200 mg QD) per protocol than the
`approved dose (LDV/SOF; 90/400 mg QD).
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`Figure 1. Exposures of SOF, GS-331007 and LDV by body weight bands. Based on intensive PK data. No subjects
`weighed > 45 Kg. Solid horizontal lines represent mean pediatric exposure values across all body weight bands.
`
`2. Exposures of SOF, GS331007, and LDV by formulation
`There were trends towards lower exposures of SOF (AUCtau) and GS-331007 (AUCtau and Cmax) in subjects who
`were administered tablets versus those who were administered packets (granules) (Figure 2). This is likely due
`to the fact that subjects with higher body weight within a weight band tended to receive tablets rather than
`granules.
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`Reference ID: 4480168
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`

`

`Figure 2. Exposures of SOF, GS-331007 and LDV by formulation. Based on intensive PK data. Packet (granules)
`and Tablets were of LDV/SOF 11.25/50 and 22.5/100 mg strength, respectively. Solid horizontal lines represent
`mean pediatric exposure values across formulations.
`
`3. Exposures of SOF, GS331007, and LVD in one subject who experienced relapse.
`Subject
` experienced a treatment relapse. Subject
` is an 8 years old, white,
`female, HCV genotype 1 infected subject weighing 26.5 kg who received LDV/SOF 45/200 mg as granules.
`LDV exposure in this subject was noticeably lower than the typical population LDV exposure (Table 3).
`However, it is unclear if the relapse was mainly due to the lower exposures of LDV or SOF as these exposures
`are still expected to be efficacious based on the exposure-response relationship observed in pediatrics and
`adults.
`
`Table 3: PK Exposure parameters of SOF, GS-331007 and LDV in Subject
`AUCtau (hr∙ng/mL)
`Cmax (ng/mL)
`SOF
`967 (1454)
`525.2 (683.2)
`GS-331007
`8252 (10590)
`914.9 (935.1)
`LDV
`3986 (8949)
`206.5 (440.5)
`Mean values for subjects (3 to <12 yr) are in parenthesis.
`Source: POPPK Study Report. P.121
`
`Ctau (ng/mL)
`--
`--
`121.7 (294.8)
`
`Conclusions
`
`Following the administration of proposed doses of HARVONI, there are no clinically significant differences
`between pediatrics (3 to <12 years old) and adults with respect to exposures of SOF, GS-331007 and LDV.
`
`Reference ID: 4480168
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`11
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`(b) (6)
`
`(b) (6)
`
`(b) (6)
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`

`

`Study # 2/ GS-US-337-2091 (EDR Link)
`Title:
`A Phase 1 Relative Bioavailability and Food Effect Study of a Pediatric Oral Granule Formulation of
`Ledipasvir/Sofosbuvir in Healthy Adult Subjects.
`Study Period: 24 May 2016 – 27 July 2016
`Objectives:
`Primary objectives:
`
`
`To evaluate the relative bioavailability of a pediatric oral granule formulation of LDV/SOF relative to tablet
`formulation
`
`
`
`To evaluate the effect of concomitant food intake on the PK of a pediatric oral granule formulation of
`LDV/SOF
`
`Trial Design:
`This was a Phase 1, randomized, open-label, single-center, single-dose, 3-period, crossover study that evaluated
`the BA of a pediatric oral granule formulation of LDV/SOF relative to the adult tablet formulation in healthy adult
`subjects. The safety and tolerability of the pediatric oral granule formulation of LDV/SOF and the effect of food
`on its PK were also evaluated. A total of 42 eligible subjects were randomized to 1 of 6 treatment sequences, with
`a 9-day washout interval between each treatment, as follows:
`
`
`Treatment A: Single dose of LDV/SOF tablet (90/400 mg; 1 × 90/400 mg tablet) administered orally under
`fasted condition.
`
`
`
`
`
`Treatment B: Single dose of LDV/SOF oral granules (90/400 mg; 8 × 11.25/50 mg units) administered orally
`under fasted condition.
`
`Treatment C: Single dose of LDV/SOF oral granules (90/400 mg; 8 × 11.25/50 mg units) administered orally
`under fed condition.
`
`Product, Dose and Mode of Administration:
`Test product:
`
`Treatment B: LDV/SOF oral granules (90/400 mg; 8 × 11.25/50 mg units) were administered orally as a single
`dose under fasted condition.
`Treatment C: LDV/SOF oral granules (90/400 mg; 8 × 11.25/50 mg units) were administered orally as a single
`dose under fed condition (high fat meal).
`Reference product:
`
`
`
`12
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`Reference ID: 4480168
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`

`

`
`
`Treatment A: LDV/SOF tablet (1 × 90/400 mg tablet) was administered orally under fasted condition.
`
`Bioanalytical method:
`All PK samples were analyzed using validated LC/MS/MS methods. The precision and accuracy were acceptable
`for calibration curve and QC runs. All samples were analyzed within the long-term storage stability duration.
`
`Results:
`Main Subject Demographics and Baseline Characteristics
`Most subjects were male (71.4%, 30 subjects), white (54.8% white, 23 subjects), and of Hispanic or Latino ethnicity
`(66.7% Hispanic or Latino, 28 subjects). Subjects had a mean (SD) age of 29 (6.0) years, mean (SD) BMI of 25.0
`(2.81) kg/m2, and mean (SD) CLcr of 117.17 (21.142) mL/min at baseline.
`
`Pharmacokinetics
`Table 4: Relative bioavailability data between LDV/SOF oral granules and LDV/SOF FDC Tablet
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`(b) (6)
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`(b) (6)
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`Source: Clinical Study report, P. 6
`•
`There were slight decreases in LDV and SOF exposures; however, they are not clinically significant based
`on exposure-response relationship.
`
`Table 5. Food effect on exposures of LDV/SOF after oral granules administration with high fat meal.
`
`Source: Clinical Study report, P. 7
`•
`The 90 % CI of the GLSM ratios of test versus reference formulations are outside of the predefined no-
`effect boundary (80 – 125%) for LDV Cmax (90% CI; 71.26 – 85.71), for GC-331007 Cmax (90% CI; 59.90 –
`67.59) and SOF AUC (90% CI; 145.00 – 190.30). These are not considered clinically significant based on
`exposure-response relationship and food effect results from historical data listed in Harvoni USPI.
`Conclusions
`•
`There are no clinically significant differences in exposures of LDV/SOF after administration of oral
`granules relative to LDV/SOF tablet.
`The LDV/SOF oral granule formulation can be administered without regard to food.
`
`•
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`Reference ID: 4480168
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`14
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`(b) (6)
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`(b) (6)
`
`(b) (6)
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`(b) (6)
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`

`6. Data Integrity-Related Consults (OSIS Inspections)
`Clinical site inspection for Study GS-US-337-2091 and Analytical site inspection for Studies GS-US-337-2091 and
`GS-US-337-1116 were not conducted by the Office of Study Integrity and Surveillance (OSIS) because clinical and
`analytical inspections were conducted in December 2017 and January 2019, respectively, which fall within the
`surveillance interval. The inspections were conducted under the following submissions:
`
`. The final classification for the inspections was No Action Indicated (NAI). (Refer to Dr.
`James J Lumalcuri’s memorandum for details).
`
`Reference ID: 4480168
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`7. Pharmacometrics Review
`Population pharmacokinetics (PPK) models were developed by the Applicant for both Harvoni and
`Sovaldi to describe the PK of sofosbuvir (SOF) and its primary metabolite, GS-331007, in hepatitis C
`virus (HCV)-infected pediatric subjects administered SOF+ ribavirin (RBV) or ledipasvir/sofosbuvir
`(LDV/SOF) fixed-dose combination (FDC) +/- RBV. The impact of statistically significant covariates on
`SOF, GS-331007 and LDV exposures in pediatrics were explored by sensitivity analysis. The exposures
`of SOF, GS-331007 and LDV in pediatric patients were estimated and compared with the exposures in
`adult patients. In this review, the FDA Pharmacometrics Reviewer evaluated the Applicant’s PPK model
`for SOF, GS-331007 and LDV, and the Applicant’s exposure-response analysis for safety.
`Two clinical studies were included in the PPK model development as summarized in
`Table 1.
`
`Table 1 Summary of participants included in the PPK analysis
`Study
`Population
`Phase
`Treatment
`
`Sampling
`(Intensive/Sparse)
`Intensive PK in PK
`lead-in phase;
`Sparse PK in
`treatment phase.
`
`Intensive PK in PK
`lead-in phase;
`Sparse PK in
`treatment phase.
`
`GS-US-334-
`1112
`
`GS-US-337-
`1116
`
`2
`
`2
`
`Pediatrics aged
`3 to < 18 years
`with chronic
`genotype 2, 3
`HCV infection.
`
`Pediatrics aged
`3 to < 18 years
`with chronic
`genotype 1, 3,
`4, 5, or 6 HCV
`infection.
`
`a. 200 mg SOF for subjects 6 to
`<12 years old;
`b. 200 mg SOF for subjects 3 to
`<6 years old
`weighing > 17 kg;
`c. 150 mg for subjects 3 to <6
`years old weighing <17 kg.
`a. 45/200 mg LDV/SOF for
`subjects 6 to <12 years old;
`b. 45/200 mg LDV/SOF for
`subjects 3 to <6 years old
`weighing > 17 kg;
`c. 33.75/150 mg LDV/SOF for
`subjects 3 to <6 years old
`weighing <17 kg.
`Source: adapted from Applicant’s population PK report.
`
`Reference ID: 4480168
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`

`7.1. SOF Joint Model
`Applicant developed a semi-mechanistic joint parent-metabolite PPK model to describe the exposures
`of SOF and GS-331007 (primary metabolite) in a pooled population of pediatric (3 to <18 years) HCV-
`infected subjects administered SOF + ribavirin (RBV) or LDV/SOF fixed dose combination (FDC) +/- RBV.
`Overall, the model development dataset had a total of 1579 SOF data points from 245 subjects, 1642
`GS-566500 data points from 330 subjects, and 2392 GS-331007 data points from 330 subjects.
`The structural model, depicting metabolism of SOF to the intermediate metabolite GS-566500, which is
`subsequently metabolized to and cleared from the body as GS-331007, is illustrated in
`Figure 1.
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`Figure 1 PPK model diagram for SOF and SOF metabolites
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`Source: Applicant’s PPK study report page 30 Figure 2
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`Parameter estimates for the final PPK model are provided in Table 2.
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`Table 2 Summary of final model PK parameters
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`Applicant’s PPK study report page 34 Table 3
`The goodness-of-fit plots of the joint PPK model for pediatric subjects are shown in Figure 2.
`Figure 2 Goodness-of-fit plots for the final joint PPK model
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`Source:
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`Source: Applicant’s PPK study report page 37 Figure 3 & 4
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`Shrinkage of the final model parameters is presented in Table 3.
`Table 3 Shrinkage estimates of inter-individual in the final model
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`Source: Applicant’s PPK study report page 45 Table 6
`The Applicant conducted sensitivity analysis to evaluate the impact of statistically significant covariates
`on steady-state SOF and GS-331007 exposures. The effect of total body weight (WT) was the most
`influential covariate with ≤ ~50% change in SOF exposures for subjects with extreme covariate values
`(i.e., 5th and 95th WT percentile) relative to the median exposures. The covariate effect of LDV usage
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`on F1 results in an approximately 50% increase in SOF exposures in pediatric subjects receiving
`LDV/SOF compared to subjects without LDV. The hypothetical combination of WT and LDV accounted
`for the majority of the observed PK variability, with an approximately -50% to +90% change in
`exposures for subjects with extreme covariate values relative to the median exposures. Other
`covariates, including age, sex, race, ethnicity, baseline creatinine clearance derived by the Schwartz
`equation (CLCRSW), HCV genotype (HCVGT), food, BSA, IL28B, or BMI did not show a statistically
`significant impact on the PK of SOF.
`Within pediatric subjects, WT was the most influential covariate with ≤ an approximately 50% change
`in GS-331007 exposures for subjects with extreme covariate values (i.e., 5th and 95th WT percentile)
`relative to the median exposures. The covariate effect of CLCRSW on CL007 resulted in ≤ 40% change in
`GS-331007 exposures for the observed range of CLCRSW. The covariate effect of LDV resulted in an
`approximately 15% increase in GS-331007 exposures in subjects receiving LDV/SOF compared to
`subjects receiving SOF. Other covariates, including age, sex, race, ethnicity, HCVGT, food, BSA, IL28B, or
`BMI did not show a statistically significant impact on the PK of GS-331007.
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`Reviewer’s comment: The Applicant’s final joint PPK model is acceptable. The goodness-of-fit plots
`show a good agreement between the predicted concentrations and the observed concentrations for the
`metabolites GS-566500 and GS-331007. For the parental drug SOF, the model was slightly
`underestimated at lower concentrations. Overall, no apparent bias was observed in the residual plots
`versus time, time after last dose, and population predicted concentrations. Therefore, the final joint PPK
`model was reliable for prediction of CLSOF, V500 and CL007, and comparison to simulated values in adults
`(discussed in section 7.4). WT was identified as a significant covariate that could affect ≤ ~50% change
`in SOF and GS-331007 exposures for subjects with extreme body weights (95th percentile WT: 86.2 kg;
`5th percentile WT: 17.5 kg). Thus, it is reasonable to propose dosing regimens based on weight bands
`for pediatric subjects (discussed in the section 7.4). GS-331007 is renally eliminated. In adult patients,
`renal function was observed as a statistically significant covariate, while it was not in pediatric patients.
`One possible reason is that all pediatric subjects had relatively normal renal function in the pediatric
`clinical study.
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`7.2. LDV Model
`The model development dataset had a total of 1445 data points from 225 subjects.
`A 2-compartment model was used to describe the pediatric data, with a zero-order input followed by
`first order absorption and first order elimination from the central compartment (Figure 3).
`Figure 3 PPK model diagram for LDV
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`Source: Applicant’s PPK study report page 59 Figure 16
`Parameter estimates for the final PPK model are provided in Table 4.
`Table 4 Summary of final model PK parameters for LDV
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`Source: Applicant’s PPK study report page 61 Table 27
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`The goodness-of-fit plots of the LDV PPK model in pediatric subjects are shown in Figure 4.
`Figure 4 Goodness-of-fit plots for LDV final PPK model
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`Source: Applicant’s PPK study report page 63 Figure 17 & 18
`Shrinkage of the final model parameters is presented in Table 5.
`Table 5 Shrinkage estimates of inter-individual in the final model of LDV
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`Source: Applicant’s PPK study report page 67 Table 30
`The Applicant conducted sensitivity analysis to evaluate the impact of statistically significant covariates
`on steady-state LDV exposures. The sensitivity analysis showed that within pediatric subjects, the
`effect of WT was the most influential covariate with ≤ ~70% change in LDV exposures for subjects with
`extreme covariate values (i.e., 5th and 95th WT percentile) relative to the median exposures. Other
`covariates, including age, sex, race, ethnicity, CLCRSW, HCVGT, food, BSA, IL28B, BMI, or RBV usage did
`not show a statistically significant impact on the PK of LDV.
`Reviewer’s comment: The Applicant’s final LDV PPK model is generally acceptable. The goodness-of-fit
`plots show a good agreement between the observations and individual predictions. No significant bias
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`was observed in the residual plots versus time, time after last dose, and population predicted
`concentrations. Thus, the final PPK model for LDV was acceptable for describing LDV PK in pediatric
`subjects, and for simulations of the pediatric exposures at steady-state (discussed in section 7.4).
`Weight was identified as a significant covariate with substantial impact on LDV exposures (≤ ~70%
`change in LDV exposures for subjects with extreme covariate values). Thus, it is reasonable to propose
`dosing regimens based on weight bands in pediatric subjects (discussed in section 7.4).
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`7.3. Exposure-response analyses
`The Applicant conducted exposure-response analyses based the estimated individual exposures of SOF,
`GS-331007 and LDV in the pediatric population. Due to the high sustained virologic response (SVR) rate
`in subjects 6 to < 12 years old (98.9%, 91 of 92 subjects) and subjects 3 to <6 years old (97.1%, 33 of 34
`subjects) and low number of virologic failures (one subject in 6 to < 12 years old age group), exposure-
`response (E-R) relationships for efficacy were not evaluated.
`The Applicant performed E-R analyses for the 4 most commonly reported AEs in subjects 6 to < 12
`years old and subjects 3 to < 6 years old in Study GS-US-337-1116. For subjects 6 to < 12 years old, the
`4 most commonly reported AEs were headache (18.5%), pyrexia (17.4%), abdominal pain (15.2%), and
`fatigue (15.2%). For subjects 3 to < 6 years old, the 4 most commonly reported AEs were vomiting
`(23.5%), pyrexia (20.6%), cough (20.6%), and rhinorrhea (17.6%). The E-R analysis dataset included all
`pediatric subjects 3 to < 12 years old with chronic HCV infection who received LDV/SOF and had
`evaluable PPK data and AUCtau estimates for SOF (N = 95), GS-331007 (N = 125) and LDV (N = 125). As
`shown in Figure 5, overall, SOF, GS-331007, and LDV exposures in pediatric subjects were similar
`regardless of the presence or absence of the evaluated AEs (headache, pyrexia, abdominal pain,
`fatigue, vomiting, cough, or rhinorrhea).
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`Figure 5 Exposure-response of SOF, GS-331007 and LDV to safety in all pediatric subjects 3 to < 12
`years old across treatment groups
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`Note: For each box, the bottom and top edges are located at the sample 25th (Q1) and 75th (Q3) percentiles, respectively;
`the center horizontal line is drawn at the 50th percentile (median); and the outliners (beyond 1.5 × interquartile range) are
`displayed as small squares. SOF AUCtau is shown in the upper panel, GS-331007 AUCtau is shown in the middle pan