CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205834Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`
` 205834
`NDA:
`Brand Name
`Generic Name
`Clinical Pharmacology
`Reviewers
`Secondary Reviewer
`PM Reviewer
`Secondary PM Reviewer
`OCP Division
`OND division
`Applicant
`Relevant IND(s) and NDA(s)
`Submission Type
`Formulation; Strength(s)
`Indication
`
`
`
`Submission Date(s): February 10, 2014
`To be Determined
`Ledipasvir/Sofosbuvir
`Jenny H. Zheng, Ph.D. (primary), Leslie Chinn, Ph.D.
`
`Shirley K. Seo, Ph.D.
`Jeffry Florian, Ph.D.
`Yaning Wang, Ph.D.
`Division 4
`DAVP
`Gilead Sciences
`INDs 106739, 112681,
`Priority
`Fixed dose combination tablets; 90 mg/400 mg
`Treatment of chronic hepatitis C (CHC) genotype 1 infection in
`adults
`
` 115268 and NDA 204671
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS ............................................................................................................................... 1
`LIST OF ABBREVIATIONS and NOMENCLATURES ................................................................................ 2
`1. EXECUTIVE SUMMARY ......................................................................................................................... 5
`1.1 Recommendation .......................................................................................................................... 5
`1.2
`Phase IV Commitments ................................................................................................................ 5
`1.3
`Summary of Important Clinical Pharmacology Findings ......................................................... 5
`2. QUESTION BASED REVIEW .................................................................................................................. 8
`2.1 General Attributes ............................................................................................................................. 8
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product as they relate to clinical pharmacology review? ... 8
`2.1.3. What are the proposed dosage(s) and route(s) of administration? ........................................... 11
`2.2 General Clinical Pharmacology ..................................................................................................... 11
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support
`dosing or claims? ................................................................................................................................. 11
`2.2.2 What is the basis for selecting the response endpoints (i.e., clinical or surrogate endpoints) or
`biomarkers (collectively called pharmacodynamics (PD)) and how are they measured in clinical
`pharmacology and clinical studies? ..................................................................................................... 12
`2.2.3 Are the active moieties in the plasma (or other biological fluid) appropriately identified and
`measured to assess pharmacokinetic parameters and exposure-response relationships? ................ 12
`2.2.4 Exposure-response ..................................................................................................................... 13
`2.2.5 What are the PK characteristics of the drug and its major metabolite? ...................................... 16
`
`
`Reference ID: 3540737
`
`1
`
`(b) (4)
`
`

`

`2.3 Intrinsic Factors ............................................................................................................................... 21
`2.3.1 What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism,
`pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and what is the
`impact of any differences in exposure on efficacy or safety responses? What dosage regimen
`adjustments are recommended for each of these groups? ................................................................. 21
`2.4 Extrinsic Factors ............................................................................................................................. 25
`2.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence
`exposure -response and what is the impact of any differences in exposure on response? ................ 25
`2.4.2. Drug-Drug Interactions .............................................................................................................. 25
`2.5 General Biopharmaceutics ............................................................................................................. 33
`2.5.1 Based on the biopharmaceutics classification system (BCS) principles, in what class is this drug
`and formulation? What solubility, permeability, and dissolution data support this classification? ....... 33
`2.5.2 What is the relative bioavailability (BA) of the proposed to-be-marketed formulation to the
`pivotal clinical trial? Is clinical and analytical inspection required? ..................................................... 33
`2.5.3 What is the effect of food on the bioavailability (BA) of the drug from the dosage form? What
`dosing recommendation should be made, if any, regarding administration of the product in relation to
`meals or meal types? ........................................................................................................................... 34
`2.5.4 If different-strength formulations are not bioequivalent based on standard criteria, what clinical
`safety and efficacy data support the approval of the various strengths of the to-be-marketed product?
` ............................................................................................................................................................. 34
`2.6 Analytical Section............................................................................................................................ 34
`2.6.1 How are the active moieties identified and measured in the plasma in the clinical pharmacology
`and biopharmaceutics studies? What bioanalytical methods are used to assess concentrations? .... 34
`2.6.2 For all moieties measured, is free, bound, or total measured? What is the basis for that
`decision, if any, and is it appropriate? ................................................................................................. 35
`3. DETAILED LABELING RECOMMENDATIONS .................................................................................... 35
`4. APPENDICES ......................................................................................................................................... 36
`4.1 Individual Study Review ................................................................................................................. 36
`4.2.1 Biopharmaceutics ..................................................................................................................... 36
`4.2.2 General Pharmacokinetics/Pharmacodynamics ................................................................... 43
`4.2.3 Intrinsic Factors ........................................................................................................................ 64
`4.2.4 Extrinsic Factors ....................................................................................................................... 69
`4.2.5 In vitro Studies (Leslie) .......................................................................................................... 130
`4.2.6 Pharmacometric Review (Jeff) .............................................................................................. 148
`
`
`LIST OF ABBREVIATIONS and NOMENCLATURES
`[14C]
`radiolabeled carbon 14
`3TC
`lamivudine
`ABC
`abacavir
`ADME
`absorption, distribution, metabolism, and excretion
`AE
`adverse event
`ARV antiretroviral
`ATR
`Atripla® (efavirenz/emtricitabine/tenofovir disoproxil fumarate, coformulated)
`ATV atazanavir
` AUCinf area under the plasma/serum/PBMC concentration versus time curve from
`time zero to infinity
`area under the plasma/serum/PBMC concentration versus time curve
`over the dosing interval
`bioavailability
`BA
`BCRP breast cancer resistance protein
`BCS Biopharmaceutics Classification System
`BID twice daily
`BMI
`body mass index
`BOC boceprevir
`BSEP bile salt export pump
`
`
`
` AUCtau
`
`
`Reference ID: 3540737
`
`2
`
`

`

`cathepsin A
`CatA
`carboxyl esterase 1
`CES1
`CI
` confidence interval
`CL/F
`apparent oral clearance
`CLcr
`creatinine clearance
`Cmax maximum observed plasma/serum/PBMC concentration of drug
`COBI cobicistat
`CPA
`Complera® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate,
`coformulated)
`CPT Child-Pugh-Turcotte classification
`CsA cyclosporine (cyclosporin A)
`Ctau observed drug concentration at the end of the dosing interval
`CV
`coefficient of variation
`CYP
`cytochrome P450 enzyme(s)
`d4T
`stavudine
`DAA direct-acting antiviral
`DCV daclatasvir
`DDI drug-drug interaction
`DRV
`darunavir
`EC50/90 half-maximal/90% effective concentration
`ECG eletrocardiogram
`EE
`ethinyl estradiol
`EFV efavirenz
`eGFR estimated glomerular filtration rate
`Emax maximum effect
`ESRD end-stage renal disease
`EU European Union
`EVG elvitegravir
`FDC fixed-dose combination
`FMO flavin monooxygenase
`FTC emtricitabine
`GLSM
`geometric least-squares mean
`GMR
`geometric mean ratio
`GT genotype
`H2RA H2-receptor antagonist
`HCV hepatitis C virus
`HINT1 histidine triad nucleotide binding protein 1
`HIV, HIV-1
`human immunodeficiency virus, type 1
`IC50
`half-maximal inhibitory concentration
`IFN interferon
`IL28 interleukin 28
`IL28B interleukin 28B gene
`LC/MS/MS liquid chromatography/tandem mass spectrometry
`LDV ledipasvir
`LLOQ lower limit of quantitation
`LOD limit of detection
`MATE1 multidrug and toxin extrusion protein 1
`mRNA messenger ribonucleic acid
`MRP2 multidrug resistance-associate protein 2
`N or n
`number of subjects in a population (N) or subset (n)
`NA
`not applicable
`ND
`not determined
` NG
`norgestrel
`NGMN
`norelgestromin
`NI nucleoside inhibitor
`
`
`Reference ID: 3540737
`
`3
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`

`

`NNI nonnucleoside inhibitor
`NOAEL no observed adverse effect level
`NOEL no observed effect level
`OAT
`organic anion transporter
`OATP organic anion transporting polypeptide
`OC Ortho Tri-Cyclen Lo®
`OCT organic cation transporter
`PD pharmacodynamic(s)
`Peg-IFN pegylated interferon
`P-gp p-glycoprotein
`PI protease inhibitor
`PK pharmacokinetic(s)
`PPI proton pump inhibitor
`Q1, Q2, Q3, Q4, Q12
`first quartile, second quartile, third quartile, fourth quartile, first 2 quartiles
`QD once daily
`QT
`electrocardiographic interval between the beginning of the Q wave and
`termination of the T wave, representing the time for both ventricular
`depolarization and repolarization to occur
`time-matched, baseline-adjusted, placebo-corrected QTc
`ΔΔQTc
`QTc QT interval corrected for heart rate
`QTcB QT interval corrected for heart rate using the Bazett formula
`QTcF QT interval corrected for heart rate using the Fridericia formula
`QTcI QT interval corrected for heart rate using subject-specific correction factor
`QTcN QT interval corrected for heart rate using population-specific correction
`factor
`RAL raltegravir
`/r boosted with ritonavir
`RAV resistance-associated variant
`RBV ribavirin
`RGT response-guided therapy
`RIF
`rifampin
`RNA ribonucleic acid
`RPV rilpivirine
`RTV ritonavir
`SAE serious adverse event
`SD standard deviation
`
`SMV simeprevir
`SOF sofosbuvir
`SVR sustained virologic response
`SVRXX sustained virologic response “XX” weeks following completion of all
`treatment
`tacrolimus
`TAC
`TDF tenofovir disoproxil fumarate
`TE treatment experienced
`TFV tenofovir
`TGV tegobuvir
`TN treatment naive
`TVD
`Truvada® (emtricitabine/tenofovir disoproxil fumarate, coformulated)
`TVR telaprevir
`UGT uridine disphosphate glucuronosyltransferase
`ULN upper limit of the normal range
`UMP-CMP uridine monophosphate-cytidine monophosphate
`VDV vedroprevir
`vRVR very rapid virologic response
` ZDV
`zidovudine
`
`
`
`
`Reference ID: 3540737
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`1. EXECUTIVE SUMMARY
`
`Gilead Sciences is seeking approval of ledipasvir (LDV, GS-5885) and sofosbuvir (SOF, GS-
`7977) together as an oral fixed-dose combination (FDC) tablet (LDV/SOF 90 mg/400 mg) for
`the treatment of chronic genotype 1 hepatitis C virus (HCV) infection (for both genotypes 1a and
`1b as efficacy was similar between the subgenotypes). LDV/SOF was granted Breakthrough
`Therapy Designation on July 22, 2013.
`
`LDV is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV activity against
`genotype 1a and 1b HCV infection. SOF is a novel nucleotide NS5B polymerase inhibitor that
`inhibits HCV RNA replication and has been approved for use in combination with other agents
`for the treatment of chronic HCV infection in adults (tradename Sovaldi®; NDA 204671).
`
`The proposed LDV/SOF dosage regimen is one 90 mg/400 mg tablet, taken orally, once daily
`with or without food. The following treatment durations are proposed by the applicant, based on
`prior treatment experience and cirrhosis status:
`
`The consideration for approval of this NDA is based on efficacy data from 3 pivotal LDV/SOF
`Phase 3 trials in a total of 1518 subjects with genotype 1 chronic hepatitis C (CHC): 0108 (ION-
`3, HCV treatment-naïve adults without cirrhosis), 0102 (ION-1, treatment-naïve adults with or
`without cirrhosis), and 0109 (ION-2, adults who failed prior therapy with or without cirrhosis ); as
`well as pooled safety data from these three Phase 3 clinical trials and other trials which
`evaluated use of LDV/SOF or LDV/SOF + ribavirin (RBV) for 8, 12, and 24 weeks. The final
`treatment duration recommendation for each patient population remains under review at this
`time.
`
`1.1
`
`The Office of Clinical Pharmacology has determined that there is sufficient clinical
`pharmacology information provided in the NDA to support a recommendation of approval of
`LDV/SOF.
`
`1.2
`
`None.
`
`1.3
`
`Recommendation
`
`Phase IV Commitments
`
`Summary of Important Clinical Pharmacology Findings
`
` A
`
` comprehensive program of Phase 1 clinical studies characterized the PK of SOF and LDV
`when administered either as single agents or as the FDC. Additionally, both intensive and
`sparse plasma concentration data from 391 healthy subjects and 2147 HCV-infected subjects
`who received LDV/SOF FDC, SOF and LDV administered together as single agents, or LDV as
`a single agent from 14 clinical studies (9 Phase 1, 2 Phase 2, and 3 Phase 3 studies) were used
`for population PK evaluation of SOF, its predominant circulating metabolite GS-331007, and
`LDV.
`
`
`Reference ID: 3540737
`
`5
`
`(b) (4)
`
`

`

`
`Key PK characteristics for LDV as a single agent are summarized below:
`• A high-fat meal reduced LDV AUC and Cmax by approximately 45%.
`• LDV is >99.8% bound to human plasma proteins.
`• The half-life of LDV is approximately 47 hours
`• Following a single 90 mg oral dose of [14C]-LDV, mean total recovery of the [14C]-
`radioactivity in feces and urine was approximately 87%, with most of the radioactive dose
`recovered from feces (approximately 86%). Unchanged LDV excreted in feces accounted
`for a mean of 70% of the administered dose and the oxidative metabolite M19 accounted for
`2.2% of the dose. The data indicate that biliary excretion of unchanged LDV is a major route
`of elimination with renal excretion being a minor pathway.
`• LDV exhibits dose linearity for AUCinf and Cmax over the 3- to 100-mg range.
`• LDV PK is not affected by race (as determined by both popPK analysis of phase 3 data as
`well as one dedicated phase 1 study in Japanese subjects) or age (18-80 years)
`• Relative to healthy subjects, LDV AUC0-24 and Cmax were 24% lower and 32% lower,
`respectively, in HCV patients.
`• AUC and Cmax of LDV were 77% and 58% higher, respectively, in females than males. After
`correcting for body weight differences between genders, females still have approximately
`40% higher exposure as compared to males. This observation has no clinical relevance
`because neither response rate nor rate or severity of adverse events was significantly
`different between genders.
`• Renal impairment has no clinically significant effect on LDV PK and no dose adjustment of
`LDV is needed. The effect of hemodialysis on LDV PK was not evaluated; however, due to
`the high protein binding of LDV, hemodialysis is unlikely to have a significant impact.
`• Hepatic impairment (including cirrhosis) has no clinically significant effect on LDV PK, and
`no dose adjustment of LDV is needed for any degree of hepatic impairment.
`• LDV solubility decreases as pH increases. Drugs that increase gastric pH are expected to
`decrease systemic concentrations of LDV.
`o A substantial decrease in LDV plasma exposure (~ 42% to 48% lower AUC and Cmax)
`was observed upon administration of the proton pump inhibitor (PPI) omeprazole (20
`mg) 2 hours prior to LDV administration.
`o LDV absorption was unaffected upon simultaneous or staggered (12 hours)
`administration of the H2-receptor antagonist (H2RA) famotidine (20 mg).
`• LDV is a substrate of the drug transporters P-gp and BCRP.
`• LDV is an inhibitor of P-gp and BCRP.
`• LDV is not expected to inhibit OATP1B1, OATP1B3 and BSEP at concentrations achieved
`in vivo at the recommended dose
`• LDV 30 mg once daily increased SMV Cmax and AUC by 161% and 169%, respectively,
`due to P-gp inhibition, which is a similar magnitude of the effect of DRV/RTV on simeprevir
`(SMV) and DRV/RTV is not recommended to be coadministered with simeprevir. Thus, SMV
`is not recommended to be coadministered with LDV/SOF.
`• At the supratherapeutic dose of 120 mg twice daily, LDV does not prolong QTc to a clinically
`relevant extent.
`
`
`SOF is a nucleotide prodrug that undergoes intracellular metabolism to form the
`pharmacologically active uridine analog triphosphate (GS-461203). GS-461203 is not
`measureable in plasma. The PK characteristics for SOF and its major metabolite GS-331007
`following oral administration of SOF as a single agent are summarized below:
`• When SOF was administered as a single agent, a high-fat meal slowed the rate of
`absorption of SOF but did not substantially affect the extent of absorption as compared to
`
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`Reference ID: 3540737
`
`6
`
`

`

`fasting conditions. The exposure of GS-331007 was not altered in the presence of a high-fat
`meal. Protein binding is about 65% for SOF, minimal for GS-331007.
`• The half-life is approximately 0.4 hr for SOF, and 27 hrs for GS-331007.
`• Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was
`greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine,
`feces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine
`was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. These data indicate that
`Renal clearance is the major elimination pathway for GS-331007.
`• Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg
`to 1200 mg.
`• SOF and GS-331007 PK are not affected by gender, race, disease state, or age.
`• For renal impairment, the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild,
`moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and
`451% higher, respectively. No dose adjustment is required for patients with mild or
`moderate renal impairment. Use of SOF is currently not recommended for use in patients
`with severe renal impairment or ESRD.
`• For hepatic impairment (including cirrhosis): no clinically significant effect was observed.
`Therefore, no dose adjustment of SOF is recommended for any degree of hepatic
`impairment.
`• SOF is a substrate of drug transporters P-gp and BCRP while GS-331007 is not.
`• Drugs that are intestinal P-gp inducers (e.g., rifampin (RIF), St. John’s Wort) may alter the
`concentrations of SOF and thus should not be used with SOF.
`• The interaction between SOF and the following drugs was evaluated in clinical trials and no
`dose adjustment is needed for either drug: cyclosporine (CsA), darunavir/ritonavir
`(DRV/RTV), efavirenz (EFV), emtricitabine (FTC), methadone, raltegravir (RAL), rilpivirine
`(RPV), tacrolimus (TAC), tenofovir disoproxil fumarate (TDF), or oral contraceptive agents
`containing ethinyl estradiol (EE) and norgestimate.
`• At a dose three times the maximum recommended dose, sofosbuvir does not prolong QTc
`to a clinically relevant extent
`• LDV causes a 2.3- and 2.2-fold increase in SOF AUCinf and Cmax respectively, due to P-gp
`and BCRP inhibition by LDV. Therefore, the results of SOF PK as a single agent should be
`carefully interpreted in the context of the increased SOF concentrations in LDV/SOF FDC as
`compared to SOF as a single dose.
`
`
`Key PK characteristics for SOF, GS-331007 and LDV following oral administration of LDV/SOF
`FDC are summarized below:
`• When administered as the LDV/SOF FDC, a high-fat meal caused a similar magnitude of
`effect on SOF and GS-331007 as compared to the single agent and also did not affect LDV
`AUC and Cmax to a clinically relevant extent. Thus, LDV/SOF FDC can be administered
`without regard to food (as instructed in phase 3 studies).
`• LDV/SOF FDC tablets have been studied with: abacavir/lamivudine (ABC/3TC), Atripla®
`(ATR), Complera® (CPA), atazanavir/ritonavir (ATV/RTV), DRV/RTV, elvitegravir+cobicistat
`(EVG+COBI), and acid-reducing agents. The following are the results from these studies:
`o No clinically significant effects on SOF and GS-331007 exposures were observed
`with any of the above agents, which is similar to what was observed for SOF as a
`single agent
`o The effects of these drugs on LDV AUC or Cmax is in the range of 34%↓ by ATR to
`~100%↑ by ATV/RTV
`o Famotidine (40 mg single dose) was administered either with simultaneous
`administration or 12 hours apart with LDV/SOF, while omeprazole (20 mg) was
`
`
`Reference ID: 3540737
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`7
`
`

`

`studied only with simultaneous administration with LDV/SOF. Since the onset of the
`antisecretory effect of H2RAs occurs within 1 hour, while the onset of antiscretory
`effect of PPls may be delayed and prolonged, staggered administration of LDV/SOF
`with H2RAs or PPls may result in lower LDV concentrations. As shown in Study GS-
`US-256-0110, a substantial decrease in LDV plasma exposure (~42% to 48% lower
`AUC and Cmax) was observed upon administration of omeprazole 2 hours earlier
`than LDV as a single agent. Therefore, H2RAs should only be administered
`simultaneously or 12 hours apart with LDV/SOF, and PPls should only be
`administered simultaneously with LDV/SOF at doses comparable to omeprazole 20
`mg once daily (or lower).
`
`2. QUESTION BASED REVIEW
`
`2.1 General Attributes
`
`2.1.1 What are the highlights of the chemistg and physical—chemical properties of the drug
`substance and the formulation of the drug product as they relate to clinical pharmacology
`
`review?
`
`SOF is a nucleotide prodrug of 2’-deoxy—2’-fluoro—2’-C—methyluridine monophosphate that is
`converted to the active uridine triphosphate form (GS-461203) within the hepatocyte and is a
`HCV NS5B-directed inhibitor that has displayed potent inhibition of HCV replicon RNA
`replication in vitro. Please refer to Clinical Pharmacology Review for NDA 204671 for additional
`details on the physical-chemical properties of the SOF drug substance.
`
`Ledipasvir
`
`“M" is defined as the drug substance.
`
`M"
`
`properties of the drug substance
`
`"M"
`
`The following shows physical-chemical
`
`Chemical Name:
`
`(mo
`
`Empirical Formula:
`Molecular Weight:
`Chemical Structure:
`
`“M"
`“M" (889 for LDV)
`
`(5) (4)
`
`pKa:
`
`0)“)
`
`Partition Coefficient: log P =
`
`(m4)
`
`Reference ID: 3540737
`
`

`

`Solubility:
`
`LDV/SOF fixed-dose combination tablets contain 400 mg of sofosbuvir and 90 mg of LDV. The
`tablet formulation utilizes LDV
` The quantitative
`composition of LDV/SOF tablets is listed in Table 1.
`
`
`
`
`Reference ID: 3540737
`
`9
`
`(b) (4)
`
`(b) (4)
`
`

`

`Table 1:
`
`Component
`
`Intragranular
`
`Quantitative Composition of Ledipasvir/Sofosbuvir Tablets
`Composfihn UnnFonnum eumny
`(% wlw)
`mg/tablet)
`tandard
`
`Function
`
`‘ctive Ingredient Ledmasvk""
`
`ln-house
`
`‘cfivelngredmnt
`
`.
`
`.
`
`W”—
`
`Wm
`
`M"
`
`(b) (4:
`
`Lactose Monohydrate
`
`m
`
`\1F,Ph—Eur
`
`W W
`
`W W
`
`W W
`
`W W
`
`(b) (4
`
`dF,Ph.Eun
`
`dF,Ph.Eun
`
`dF,Ph.Eun
`
`
`
`n-house
`
`JSP, Ph. Eur.
`
`(WM)
`
`10
`
`Reference ID: 3540737
`
`

`

`2.1.2. What are the prowsed mechanisms) of action and therapeutic indication(s)?
`LDV is an HCV inhibitor targeting the HCV NS5A protein, which is essential for both RNA
`replication and the assembly of HCV virions. Biochemical confirmation of NSSA inhibition of
`LDV is not currently possible as NSSA has no enzymatic function. In vitro resistance selection
`and cross-resistance studies indicate LDV targets NSSA as its mode of action.
`
`SOF is a pan-genotypic inhibitor of the HCV NSSB RNA-dependent RNA polymerase, which is
`essential for viral replication. SOF is a nucleotide prodrug that undergoes intracellular
`metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203),
`which can be incorporated by HCV NS5B and acts as a chain terminator. In a biochemical
`assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV
`genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 uM. GS—461203 is not an
`inhibitor of human DNA and RNA polymerases or an inhibitor of mitochondrial RNA polymerase.
`
`2.1.3. What are the progsed dosagegs) and routegs) of administration?
`
`The proposed dose of LDV ISOF is 90 mg/400 mg, taken orally, once daily with or without food.
`The proposed duration of treatment is based on treatment experience and cirrhosis status.
`(m4)
`
`The recommended duration of treatment is still under review. Although the applicant has
`proposed
`
`M"
`
`DAVP is under active negotiations with the applicant for extending the treatment durations.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?
`
`A comprehensive range of clinical studies was conducted to characterize the pharmacokinetics
`(PK) of SOF, its predominant circulating metabolite GS-331007, and LDV. This submission
`includes 18 SOF single-agent studies, 19 LDV single-agent studies, and 10 LDV/SOF FDC
`studies containing biopharmaceutic and clinical pharmacology data that were conducted as part
`of the LDV/SOF clinical development program. In vitro studies for SOF, GS-331007 and LDV
`were also conducted to assess the potential for drug-drug interactions (DDI). Most of the clinical
`pharmacology studies for SOF as a single agent have been reviewed in NBA 204671, with the
`exception of the DDI study with oral contraceptives.
`
`Dose Selection: The dose of LDV 90 mg was selected based on the results from the Phase 1, 3-
`day proof-of-concept dose-ranging monotherapy study (GS-US-256-0102, LDV dose range: 1
`mg to 90 mg) and the data from the Phase 2 study in genotype 1 HOV-infected subjects (GS-
`US-248—0120). Although the maximum effect (Emax) modeling indicated that exposures
`achieved following administration of LDV 230 mg provide >95% of maximal antiviral response in
`genotype 1a HCV—infected subjects, and LDV dosing beyond 90 mg was unlikely to cause
`further meaningful reductions in HCV RNA, study GS-US—248-0120 showed that the incidence
`of virologic breakthrough in the LDV 90 mg-containing group was approximately half of that
`observed in the LDV 30 mg-containing group (10.6% versus 19.6%). Treatment with LDV 90 mg
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`Reference ID: 3540737
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`1 1
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`plus DAAs for 12 or 24 weeks resulted in numerically higher, though not statistically different,
`SVR24 rates as compared with LDV 30 mg plus DAAs for 24 weeks. These findings supported
`further evaluation of the 90-mg dose of LDV in the clinical development program for LDV/SOF.
`
`SOF 400 mg is approved for use in combination with other agents for the treatment of chronic
`HCV infection in adults. No dose adjustment for either agent was required on co-administration
`(Study GS-US-334-0101) because the increase in the systemic exposure of SOF by LDV was
`not considered clinically significant. Therefore, LDV/SOF (90 mg/400 mg) FDC tablets were
`used to support initiation of Phase 3.
`
`Phase 2 and 3 Clinical Efficacy and Safety Development Program:
`
`The efficacy and safety of LDV/SOF FDC were evaluated in 3 pivotal Phase 3 studies: GS-US-
`337-0102 (ION-1), GS-US-337-0109 (ION-2), and GS-US-337-0108 (ION-3); as well as 3 Phase
`2 clinical studies: P7977-0523 (ELECTRON) Part 4 (Groups 12 and 13) and Part 6 (Groups 16
`to 18, 20, and 21), GS-US-337-0118 (LONESTAR), and GS-US-337-0122 (ELECTRON-2
`[Cohort 2, Groups 3 and 4]).
`
`The Phase 3 studies were all conducted in subjects with genotype 1 HCV infection.
`o Study GS-US-337-0102 evaluated 12 or 24 weeks of LDV/SOF±RBV in treatment-naïve
`subjects;
`o Study GS-US-337-0109 evaluated 12 or 24 weeks of LDV/SOF±RBV in treatment-
`experienced subjects; and
`o Study GS-US-337-0108 evaluated LDV/SOF+RBV for 8 weeks and LDV/SOF (without
`RBV) for 8 and 12 weeks in treatment-naive subjects.
`
`Studies GS-US-337-0102 and GS-US-337-0109 each included a subset of subjects (≤ 20%)
`with compensated cirrhosis. Each of the Phase 3 studies have