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

`

`Comments on N205,834 Harvoni: ledipasvir and sofosbuvir fixed-dosed combination
`
`Sofosbuvir was previously approved as part of a different combination
`
`1. I concur that there are no pharm-tox approval issues, and that the pregnancy category of B is
`appropriate.
`
`2. I conveyed a comment to the reviewer that he will address as appropriate.
`
`Reference ID: 3593185
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ABIGAIL C JACOBS
`07/15/2014
`
`Reference ID: 3593185
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`205,834
`001, 022
`February 8, 2014
`February 10, 2014
`Harvoni™ is a fixed-dose combination (FDC)
`tablet of ledipasvir (LDV), an HCV NS5A
`inhibitor, and sofosbuvir (SOF), an HCV
`nucleotide analog NS5B polymerase inhibitor
`Harvoni™ is indicated for the treatment of
`chronic hepatitis C (CHC) genotype 1 infection
`Gilead Sciences
`Division of Antiviral Products
`Christopher Ellis, Ph.D.
`Hanan Ghantous, Ph.D., DABT
`Debra Birnkrant, M.D.
`Linda Onaga, M.P.H.
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA #205,834 are owned by Gilead Sciences or are data for
`which Gilead Sciences has obtained a written right of reference.
`Any information or data necessary for approval of NDA #205,834 that Gilead Sciences
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`#205,834.
`
`Reference ID: 3540127
`
`1
`
`

`

`NDA # 205,834
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 7
`1.1
`INTRODUCTION .................................................................................................... 7
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7
`1.3 RECOMMENDATIONS ............................................................................................ 8
`2 DRUG INFORMATION .......................................................................................... 11
`2.1 DRUG ............................................................................................................... 11
`2.1.1
`LEDIPASVIR ................................................................................................... 11
`2.1.2
`SOFOSBUVIR ................................................................................................. 12
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ......................................................... 12
`2.3 DRUG FORMULATION ......................................................................................... 12
`2.4 COMMENTS ON NOVEL EXCIPIENTS ..................................................................... 14
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 14
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 14
`2.7 REGULATORY BACKGROUND .............................................................................. 14
`3 STUDIES SUBMITTED .......................................................................................... 14
`3.1
`STUDIES REVIEWED ........................................................................................... 14
`3.2
`STUDIES NOT REVIEWED ................................................................................... 18
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 18
`4 PHARMACOLOGY ................................................................................................ 18
`4.1
`PRIMARY PHARMACOLOGY ................................................................................. 18
`4.2
`SECONDARY PHARMACOLOGY ............................................................................ 19
`4.3
`SAFETY PHARMACOLOGY ................................................................................... 19
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 21
`5.1
`PK/ADME ........................................................................................................ 21
`5.2
`TOXICOKINETICS ............................................................................................... 26
`6 GENERAL TOXICOLOGY ..................................................................................... 26
`6.1
`SINGLE-DOSE TOXICITY ..................................................................................... 26
`6.2 REPEAT-DOSE TOXICITY .................................................................................... 26
`7 GENETIC TOXICOLOGY ...................................................................................... 42
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) ....................... 42
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS .............................................................. 43
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY) .................. 44
`7.4 OTHER GENETIC TOXICITY STUDIES .................................................................... 45
`8 CARCINOGENICITY ............................................................................................. 45
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 65
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT ............................................... 65
`
`Reference ID: 3540127
`
`2
`
`

`

`NDA # 205,834
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`9.2
`9.3
`10
`
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 69
`PRENATAL AND POSTNATAL DEVELOPMENT ......................................................... 78
`SPECIAL TOXICOLOGY STUDIES ................................................................... 86
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION ................................. 89
`
`APPENDIX/ATTACHMENTS ............................................................................. 97
`12
`12.1 HISTOPATHOLOGY INVENTORY (FOR SOF CARCINOGENICITY STUDIES) ..................... 97
`
`
`
`Reference ID: 3540127
`
`3
`
`

`

`NDA # 205,834
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`Table of Tables
`Table 1: Composition of LDV/SOF FDC tablets ............................................................ 13
`Table 2: Summary of plasma PK parameters of LDV in rats, dogs and monkeys
`following oral gavage administration ............................................................................. 22
`Table 3: Summary of plasma PK parameters of LDV in rats, dogs and monkeys
`following intravenous administration.............................................................................. 22
`Table 4: Selected tissue to plasma ratios of LDV and related metabolites from male
`Sprague-Dawley rats administered a single 10 mg/kg dose of 14C-LDV. ...................... 23
`Table 5: Percent of total plasma AUC for LDV and metabolites following oral
`administration of 14C-LDV.............................................................................................. 25
`Table 6: Mean plasma TK parameters for GS-5885 in rats following 1 or 14 days of GS-
`5885 administration at 10, 30 or 100 mg/kg dose levels ............................................... 27
`Table 7: Mean plasma TK parameters for GS-5885 in dogs following 1 or 14 days of
`GS-5885 administration at 3, 10 or 30 mg/kg dose levels ............................................. 28
`Table 8: Summary of ALP, ALT and Liver/Gall Bladder Weight Mean % Change
`Relative to Mean Control Values in High Dose (300 mg/kg) Male and Female Mice .... 31
`Table 9. Mean Toxicokinetic Parameters of GS-5885 in the 4-week Oral Gavage Study
`in Wild Type Mice (TX-256-2018) .................................................................................. 33
`Table 10: Toxicokinetic Parameters for GS-5885 in Rat Plasma - Day 1 and Weeks 13
`and 26 ........................................................................................................................... 39
`Table 11: Mean Toxicokinetic Parameters of GS-5885 in Dog Plasma: Day 1 and
`Weeks 13 and 39 .......................................................................................................... 42
`Table 12: Summary of mouse 2-year carcinogenicity study design .............................. 48
`Table 13: Summary of unscheduled mortality of CD-1 mice administered GS-7977,
`vehicle or water for ~92 (female) to 97 (male) weeks .................................................... 50
`Table 14: Cause of death summary of unscheduled mortalities in CD-1 mice
`administered GS-7977, vehicle or water ~92 (female) to 97 (male) weeks ................... 51
`Table 15: Summary of statistical analysis for selected tumor types in male mice
`administered GS-7977, vehicle or water for ~97 weeks ................................................ 52
`Table 16: Incidence and mean severity of nasal turbinate histopathologic changes in
`CD-1 mice administered GS-7977, vehicle or water for ~92 (female) to 97 (male) weeks
` ...................................................................................................................................... 53
`Table 17: Mean plasma TK parameters for the predominant GS-7977 (PSI-7977)-
`related metabolite, GS-331007 (PSI-6206), in mice following single and multiple (Day
`178) GS-7977 administration ........................................................................................ 54
`Table 18: Characteristics of GS-7977 lots used for rat carcinogenicity study ................ 54
`Table 19: Mortality summary of rats administered GS-7977, vehicle or water for ~20 to
`23 months ..................................................................................................................... 59
`Table 20: Cause of death summary of unscheduled mortalities in rats administered GS-
`7977, vehicle or water for ~20 to 23 months ................................................................. 60
`Table 21: Summary of statistical analysis for selected tumor types in male rats
`administered GS-7977, vehicle or water for ~20 months .............................................. 62
`Table 22: Summary of statistical analysis for selected tumor types in female rats
`administered GS-7977, vehicle or water for ~20 to 23 months ..................................... 62
`
`Reference ID: 3540127
`
`4
`
`

`

`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`NDA # 205,834
`
`Table 23: Incidence and mean severity for GS-7977 related histopathologic changes in
`rats ................................................................................................................................ 63
`Table 24: Incidence and mean severity for histopathology findings in heart, skeletal
`muscle and tongue in rats ............................................................................................. 64
`Table 25: Mean plasma TK parameters for the predominant GS-7977 (PSI-7977)-
`related metabolite, GS-331007 (PSI-6206), in rats following single and multiple (Day
`180) GS-7977 administration ........................................................................................ 64
`Table 26: Toxicokinetic Parameters for GS-5885 in Rat Plasma. ................................. 72
`Table 27: Study design summary of rabbit EFD study .................................................. 74
`Table 28: Summary of Unscheduled Deaths in Rabbit EFD Study ............................... 75
`Table 29: Summary of the Mean Toxicokinetic Parameters for GS-5885 in Pregnant
`Rabbit ............................................................................................................................ 76
`Table 30: Summary of the Mean Toxicokinetic Parameters for GS-5885 in the Plasma of
`Pregnant ........................................................................................................................ 77
`Table 31: Offspring allocation of F1 generation ............................................................. 80
`Table 32: Summary of uterine content in F0 dams administered GS-5855 .................... 82
`Table 33: Mean plasma GS-5885 TK parameters in pregnant and lactating F0 rats and
`F1 offspring following maternal GS-5885 administration ................................................ 83
`Table 34: Summary of survival, body weight, clinical and selected developmental
`parameters in the F1 generation ................................................................................... 84
`Table 35: Summary of F1 reproductive performance ..................................................... 85
`Table 36: Summary of uterine content in F1 dams administered GS-5855 .................... 85
`Table 37: Summary of fetal data for F2 generation ....................................................... 85
`Table 38: Experimental design summary of ocular phototoxicity study in male Long
`Evans rats ..................................................................................................................... 89
`Table 39: Mean plasma GS-5885 TK parameters in male Long Evans rats following
` 89
`administration of GS-5885 with or without
`Table 40: Summary of Systemic Exposure Multiples for Ledipasvir Toxicology Studies96
`Table 41: Summary of Systemic Exposure Multiples for Sofosbuvir Toxicology Studies
`(modified from original Table included in NDA-204,671) ............................................... 96
`
`
`Reference ID: 3540127
`
`5
`
`(b) (4)
`
`

`

`NDA # 205,834
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`Table of Figures
`Figure 1: Proposed biotransformation pathway of LDV ................................................. 25
`Figure 2: Mean Body Weight Data – Males ................................................................... 35
`Figure 3: Mean Body Weight Data - Females ............................................................... 36
`Figure 4: Mean Food Consumption Data - Males .......................................................... 37
`Figure 5: Mean Food Consumption Data - Females...................................................... 37
`Figure 6: Kaplan-Meier survival estimates in male mice administered GS-7977, vehicle
`or water for ~97 weeks .................................................................................................. 49
`Figure 7: Kaplan-Meier survival estimates in female mice administered GS-7977,
`vehicle or water for ~92 weeks ...................................................................................... 50
`Figure 8: Kaplan-Meier survival estimates in male rats administered GS-7977, vehicle or
`water for ~20 months .................................................................................................... 58
`Figure 9: Kaplan-Meier survival estimates in female rats administered GS-7977, vehicle
`or water for up to ~20 to 23 months .............................................................................. 59
`
`
`Reference ID: 3540127
`
`6
`
`

`

`NDA # 205,834
`
`
`1
`
`Executive Summary
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`Introduction
`1.1
`Harvoni™, a once daily fixed-dose combination (FDC) tablet containing ledipasvir
`
`and sofosbuvir, is intended to be indicated for treatment of chronic hepatitis C virus
`(HCV) genotype 1 infection in adult patients. Ledipasvir (LDV, GS-5885) is a specific
`inhibitor of nonstructural protein 5A (NS5A) of HCV that has displayed potent inhibition
`of HCV replication in vitro. Sofosbuvir (SOF, GS-7977) is a nucleotide prodrug of 2’-
`deoxy-2’-fluoro-2’-C-methyluridine monophosphate that is converted intracellularly to
`the active uridine triphosphate (GS-461203) within tissues. GS-461203 is a specific
`inhibitor of nonstructural protein 5B (NS5B) of HCV that has displayed potent inhibition
`of HCV replicon ribonucleic acid (RNA) replication in vitro. SOF (as a component of a
`combination antiviral treatment regimen) was approved for marketing in the U.S. in
`December 2013 (refer to NDA-204,671).
`The nonclinical safety profile of LDV has been evaluated in: safety pharmacology
`studies in rats and dogs; repeat-dose toxicology studies in mice, rats and dogs for up to
`1, 6 and 9 months duration, respectively; up to 2-week repeat-dose toxicology studies to
`qualify impurities; phototoxicity studies in mice and rats; fertility and pre- and post-natal
`developmental studies in rats; embryo-fetal developmental studies in rats and rabbits;
`and genetic toxicology studies (Ames, in vitro chromosomal aberration and in vivo rat
`micronucleus assays). In addition, numerous in vitro and in vivo nonclinical
`pharmacokinetic studies evaluating the absorption, distribution, metabolism and
`excretion of LDV have been conducted, while rat and mouse carcinogenicity studies
`with LDV are currently in progress. With the exception of rodent 2-year carcinogenicity
`studies that were reviewed with this application, nonclinical safety studies for SOF to
`support the FDC were reviewed previously. Refer to the Pharmacology/Toxicology
`review for NDA-204,671 for a detailed summary of SOF nonclinical data (as well as
`Table 41 in this review for updated exposure multiples).
`1.2 Brief Discussion of Nonclinical Findings
`LDV had moderate oral bioavailability (~30-50% in rats, monkeys and dogs) with
`Tmax values of ~4-5 hours, despite low intrinsic aqueous solubility and saturation of
`absorption that nonetheless resulted in adequate circulating LDV exposure levels in
`toxicology studies. LDV was bound highly to plasma protein (>99.8%) and was
`distributed widely to tissues including gall bladder (and bile), liver, adrenal, salivary,
`thyroid, pituitary, pancreas, adipose tissue (brown), kidney (in mice and/or rats) and the
`uveal tract of the eye in pigmented rats, but did not accumulate to any great extent in
`tissues (mean residence times ~6-13 hours). Although several minor metabolites were
`identified, unchanged parent drug is the predominant circulating component (in mice,
`rats, dogs and human subjects) as well as the primary component in feces, with a major
`route of LDV elimination occurring as biliary excretion of unchanged parent (in rats and
`dogs).
`No clear target organs of toxicity were identified in repeat-dose toxicology studies
`in mice, rats and dogs administered LDV doses of up to 300, 100 and 30 mg/kg/day for
`1, 6 and 9 months, respectively. Therefore, no specific overlapping toxicity of potential
`
`Reference ID: 3540127
`
`7
`
`

`

`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`NDA # 205,834
`
`significant clinical concern was identified in animals administered LDV or SOF alone.
`However, a potential LDV-related mild hepatobiliary toxicity signal (not considered
`adverse and not clearly dose dependent) was noted, with slight increases in ALP and/or
`ALT associated with increased liver/gall bladder weight (high-dose males only) without
`correlating histopathology changes observed in mice following oral administration of
`LDV at up to 300 mg/kg/day (AUC0-24hr~164 & 271 µg.h/ml for GS-5885 in females and
`males, respectively). In addition, minimal to slight random foci of hepatocyte necrosis
`(males) and bile duct hyperplasia (males and females) were noted in rats following oral
`administration of LDV at up to 100 mg/kg/day (AUC0-24hr~56 µg.h/ml for GS-5885).
`These non-adverse hepatobiliary findings were observed at GS-5885 AUC exposure
`~8- and 30-fold higher, in rats and mice respectively, than that in humans at the
`recommended LDV dose. In addition, slight increases in cholesterol and triglycerides
`were noted in rats at 100 mg/kg/day. In dogs, no clear clinically relevant LDV-related
`findings were observed following oral administration of LDV at up to 30 mg/kg/day
`(AUC0-24hr~41.3 & 80.3 µg.h/ml for GS-5885 in males and females, respectively),
`resulting in GS-5885 AUC exposure ~9-fold higher than that in humans at the
`recommended LDV dose.
`
`The average number of corpora lutea, implantations and viable embryos were
`reduced slightly in rats following administration of LDV at 100 mg/kg/day (estimated
`AUC0-24hr~25.1 µg.h/ml for GS-5885) and were associated with non-adverse maternal
`toxicity findings consisting of slight body weight loss and reduced food consumption.
`The NOEL for female fertility and early embryonic development is considered to be 30
`mg/kg/day (estimated AUC0-24hr~12.1 µg.h/ml for GS-5885). At 30 and 100 mg/kg/day,
`GS-5885 AUC exposure is estimated to be ~2 and 3.4-fold higher, respectively, than
`that in humans at the recommended LDV dose.
`
`1.3 Recommendations
`1.3.1 Approvability
`
`Yes, the sponsor provided sufficient nonclinical safety information on ledipasvir in
`support of approval for marketing in the U.S. Sofosbuvir (as a component of a
`combination antiviral treatment regimen) was approved for marketing in the U.S. in
`December 2013.
`1.3.2 Additional Non Clinical Recommendations
`
`None
`1.3.3 Labeling
`
`The Pharmacology/Toxicology portion of the sponsor’s draft product label with
`reviewer suggested modifications (designated by strikethrough or bold italics) is
`included below.
`
`8.1 Pregnancy
`Pregnancy Category B
`
`Reference ID: 3540127
`
`8
`
`

`

`NDA # 205,834
`
`Reviewer: Christopher Ellis, Ph.D.
`
`There are no adequate and well-controlled studies with [TRADENAME] in pregnant
`women. Because animal reproduction studies are not always predictive of human
`response, [TRADENAME] should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`
`Animal Data
`
`Ledipasvir: No effects on fetal development have been observed in rats and rabbits at
`the highest dose; tested. In the rat and rabbit, AUC exposure to ledipasvir was
`approximately (04- and 2-fold, respectively, the exposure in humans at the
`recommended clinical dose.
`
`(5) (4)
`
`Sofosbuvir: No effects on fetal development have been observed in rats and rabbits at
`the highest doses tested. In the rat and rabbit, AUC exposure to the predominant
`circulating metabolite GS—331007 incrbeased over the course of gestation from
`approximately 3- to 6-fold and 7- to (37-fold the exposure in humans at the
`recommended clinical dose, respectively.
`
`8.3
`
`Nursing Mothers
`
`It is not known whether [TRADENAME] and its metabolites are present in human
`breast milk. When administered to lactating rats, ledipasvir was detected in the plasma
`of suckling rats likely due to
`M" the presence of ledipasvir‘m" in milk. Ledipasvir
`had no clear effects on the nursing pups. The predominant circulating metabolite of
`sofosbuvir (GS—331007) was the primary component observed in the milk of lactating
`rats, without effect on nursing pups.
`“m
`
`The developmental and health benefits
`of breastfeeding should be considered along with the mother's clinical need for
`[TRADENAME] and any potential adverse effects on the breastfed child from the
`drug or from the underlying maternal condition.
`0"“)
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Reference ID: 3540127
`
`

`

`NDA # 205,834
`
`Reviewer: Christopher Ellis, Ph.D.
`
`Carcinogenesis and Mutagenesis
`
`Ledipasvir: Ledipasvir was not genotoxic in a battery of in vitro or in vivo assays,
`including bacterial mutagenicity, chromosome aberration using human peripheral blood
`lymphocytes and in vivo rat micronucleus assays.
`
`Carcinogenicity studies of ledipasvir in mice and rats are ongoing.
`
`Sofosbuvir: Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays,
`including bacterial mutagenicity, chromosome aberration using human peripheral blood
`lymphocytes and in vivo mouse micronucleus assays.
`
`(b) (4)
`
`-Two-year
`carcinogenicity studies in mice and rats were conducted with sofosbuvir. Mice
`were administered doses of up to 200 mg/kg/day in males and 600 mg/kg/day in
`females, while rats were administered doses of up to 750 mg/kg/day in males and
`females. No increase in the incidence of drug-related neoplasms were observed
`at the highest doses tested in mice and rats, resulting in AUC exposure to the
`predominant circulating metabolite GS-331007 of approximately 4- and 18-fold (in
`mice) and 8- and 10-fold (in rats), in males and females respectively, the exposure
`in humans at the recommended clinical dose.
`
`Impairment of Fertility
`
`Ledipasvir: Ledipasvir had no adverse effects on mating and fertility. In female rats, the
`mean number of corpora lutea and implantation sites were
`0”“) reduced slightly at
`maternal exposures approximately gb-fold the exposure in humans at the
`effects
`recommended clinical dose. At the highest dose levels withobyt
`level, AUC exposure to ledipasvir was approximately «)5- and (02-fold, in males and
`females7 respectively, the
`“M" exposure in humans at the recommended clinical
`dose.
`
`(5) (4)
`
`Sofosbuvir: Sofosbuvir had no effects on embryo—fetal viability or on fertility when
`evaluated in rats. At the highest dose tested, AUC exposure to the predominant
`circulating metabolite GS-331007 was approximately 5-fold the exposure in humans at
`the recommended clinical dose.
`
`13.2 Animal Toxicology and/or Pharmacology
`
`00(4)
`
`Reference ID: 3540127
`
`1 0
`
`

`

`NDA # 205,834
`
`Sofosbuvir: Heart degeneration and inflammation were observed in rats following GS-
`9851 (a stereoisomeric mixture containing approximately 50% sofosbuvir) doses of
`2,000 mg/kg/day for up to 5 days. At this dose, AUC exposure to the predominant
`circulating metabolite GS-331007 is approximately 1 7-fold higher than human
`exposure at the recommended clinical dose. No heart degeneration or inflammation was
`observed in mice, rats or dogs in studies up to 3 months, 6 months or 9 months at GS-
`331007 AUC exposures approximately 2 4-, 5- or 1 7-fold higher, respectively,
`than human exposure at the recommended clinical dose. In addition, no heart
`degeneration or inflammation was observed in rats following sofosbuvir doses of up
`to 750 mg/kg/day in the 2-year carcinogenicity studyies at GS-331007 AUC exposures
` 9-fold the exposure in humans at the recommended clinical
`approximately
`dose.
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`
`
` 2
`
` Drug Information
`
`2.1 Drug
`
`2.1.1 Ledipasvir
`CAS Registry Number
`
`Generic Name
`
`Code Name
`
`Chemical Name
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1256388-51-8
`
`Ledipasvir (LDV)
`
`GS-5885
`
`Methyl [(2S)-1-{(6S)-6-[5-(9,9-difluoro-7-{2-
`[(1R,3S,4S)-2-{(2S)-2-[(methoxycarbonyl)
`amino]-3-methylbutanoyl}-2-azabicyclo
`[2.2.1]hept-3-yl]-1H-benzimidazol-6-yl}-9H-
`fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro
`[2.4]hept-5-yl}-3-methyl-1-oxobutan-2-yl]
`carbamate (IUPAC)
`
`
`Molecular Formula/Molecular Weight C49H54F2N8O6//889.00 g/mol
`
`Structure
`
`
`
`
`Reference ID: 3540127
`
`
`
`11
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b
`)
`(4)
`
`

`

`NDA # 205,834
`
`Pharmacologic Class
`
`2.1.2 Sofosbuvir
`CAS Registry Number
`
`Generic Name
`
`Code Name
`
`Chemical Name
`
`
`
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HCV NS5A inhibitor
`
`1190307-88-0
`
`Sofosbuvir (SOF)
`
`GS-7977 (PSI-7977)
`
`(S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-
`dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-
`hydroxy-4-methyltetrahydrofuran-2-
`yl)methoxy)(phenoxy) phosphorylamino)
`propanoate (IUPAC)
`
`
`Molecular Formula/Molecular Weight C22H29FN3O9P/529.46 g/mol
`
`Structure
`
`
`
`Pharmacologic Class
`
`
`
`HCV nucleotide analog NS5B polymerase
`inhibitor
`
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`IND-
` IND-106,739 and NDA-204,671 (for SOF)
`and IND-115,268 (for LDV & SOF FDC).
`2.3 Drug Formulation
` film-
`
`LDV/SOF fixed dose combination (FDC) tablets are orange,
`coated, diamond shaped tablets containing 90 mg of LDV and 400 mg of SOF (refer to
`Sponsor Table below).
`
`
`Reference ID: 3540127
`
`12
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 205,834
`
`Reviewer: Christopher Ellis, Ph.D.
`
`Table 1: Composition of LDVISOF FDC tablets
`
`Component
`
`Intragranular
`
`Sofosbuvir‘
`
`Copovidone“e
`
`Function
`
`Unit Formula
`(mg/tablet)
`
`Composition
`(% w/w)
`
`Active Ingredient
`
`‘
`
`‘
`
`USP, Ph. Eur.
`
`USP, Ph. Eur.
`
`Lactose Monohydmte‘“d
`
`Miorocrystalline Cellulose
`
`Croscarmellose Sodium
`
`Collodial Silicon Dioxide
`
`Magnesium Stea'mte
`
`NF, Ph. Eur.
`
`NF, Ph. Eur.
`
`NF, Ph. Eur.
`
`NF, Ph. Eur.
`
`NF, Ph. Eur.
`
`NF, Ph. Eur.
`
`USP, Ph. But.
`
`NF, Ph. Eur. NF, Ph. Eur.
`
`Reference ID: 3540127
`
`1 3
`
`

`

`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`NDA # 205,834
`
`2.4 Comments on Novel Excipients
`
`Not applicable. All excipients are compendial.
`2.5 Comments on Impurities/Degradants of Concern
`Qualification assessment of residual solvents, metals and LDV-related impurities
`(specified and unspecified process intermediates, degradants, starting materials etc.)
`was conducted by Dr. Mark Powley. Refer to the Pharmacology/Toxicology review of
`NDA-204,671 for the qualification assessment of SOF. The qualification of specified
`impurities in the LDV drug substance is based on results from general repeat-dose
`toxicology studies, assessment of potential mutagenicity using (quantitative) structure-
`activity relationship [(Q)SAR] models and/or phototoxicity evaluation (for
`
`Repeat-dose toxicology studies in rats were conducted using multiple LDV batches
`containing various levels of LDV-related impurities, with no indication that the impurities
`present in these batches altered the toxicity profile of LDV. In addition, numerous LDV
`impurities were evaluated by (Q)SAR analyses and are expected to be non-mutagenic.
`Finally, a 3-day multiple dose ocular phototoxicity study was conducted in male Long
`Evans (LE) rats administered LDV or LDV (spiked w/ %
` given a specific
`cause for concern identified regarding the presence of a potentially reactive impurity/
`photodegradant (
` that (like LDV) absorbs ultraviolet (UV) light and (likely)
`accumulates in the uveal tract of the eye in pigmented LE rats. This study was
`considered negative (refer to Section 10). Overall, the proposed LDV specifications are
`considered acceptable from a pharmacology/toxicology perspective.
`2.6 Proposed Clinical Population and Dosing Regimen
`
`LDV/SOF FDC is to be indicated for treatment (single tablet once a day) of
`chronic hepatitis C (CHC) genotype 1 infection for 12 to 24 weeks in adult patients.
`2.7 Regulatory Background
`
`NDA-204,671 (for SOF in combination w/ other agents) was approved on
`December 6, 2013, while
` IND-115,268 (for LDV/SOF FDC)
`were opened on April 23, 2010 and July 1, 2012, respectively.
`3
`Studies Submitted
`
`3.1 Studies Reviewed
`
`
`Study Title
`
`
`Safety Pharmacology
`
`Effects of GS-5885 on Cloned hERG Potassium Channels
`Expressed in Human Embryonic Kidney Cells
`
`
`Study #
`
`PC-256-2008
`
`Reference ID: 3540127
`
`14
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`NDA # 205,834
`
`
`
`
` Reviewer: Christopher Ellis, Ph.D.
`
`Cardiovascular Safety Pharmacology Evaluation of GS-5885
`Administered by Oral Gavage to Male Telemetry-Instrumented
`Conscious Dogs
`Respiratory Safety Pharmacology Evaluation of GS-5885
`Using Head-Out Plethysmography following Oral Gavage
`Administration to Male Rats
`Central Nervous System Safety Pharmacology Evaluation of
`GS-5885 Following Oral Gavage Administration to Male Rats
`
`Analytical Method Validation
`
`Abbreviated Validation of a Method for the Determination of
`GS-5885 in Mouse Plasma by HPLC with MS/MS Detection
`Validation of a Method for the Determination of GS-5885 in
`Mouse Plasma by HPLC with MS/MS Detection
`Validation of a Method for the Determination of GS-5885 in Rat
`Plasma by HPLC with MS/MS Detection
`Partial Validation of a Method