CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205834Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NBA 205834 (ledipasvirlsofosbuvir) Fixed Dose Combination Tablet
`
`Cross-Discipline Team Leader Review
`
`Au ust 8, 2014
`
`Kimberl Struble, PharmD
`
`Subject
`Cross-Discipline Team Leader Review
`NDNBLA #
`NDA 205834
`
`. Iement#
`Su .
`
`Gilead Sciences
`Applicant
`Date of Submission
`
`Februa
`
`8, 2014
`
`Recommended:
`
`PDUFA Goal Date
`October 10, 2014
`
`
`Proprietary Name I
`Established USAN names
`
`Dosage forms I Strength
`
`Harvoni (Ledipasvir/Sofosbuvir)
`
`Fixed Dose Combination Tablet (ledipasvir 90
`m o/sofosbuvir 400 m .
`
`Pro oosed Indication 3
`
`Treatment of chronic he oatitis C infection
`
`Approval pending satisfactory outcome from CMC
`insections
`
`1 . Introduction
`
`This cross-discipline team leader review presents the main findings for
`ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) tablet for the
`treatment of chronic hepatitis C (CHC) genotype 1 infection. Ledipasvir (LDV) is a
`hepatitis C virus (HCV) inhibitor targeting the HCV NS5A protein, which is required for
`RNA replication and assembly of HCV virions. Sofosbuvir (SOF) is an inhibitor of the
`HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication.
`SOF was approved on December 6, 2013, as a part of a combination regimen for the
`treatment of CHC genotype 1, 2, 3, and 4 infection and is the only NS5B inhibitor
`approved. LDV is the first direct acting antiviral agent (DAA) in the NS5A drug class
`submitted for marketing approval.
`
`The Applicant submitted data from three Phase 3 trials in subjects with CHC genotype
`1 infection who were treatment-naive and in subjects who previously failed treatment
`with either pegylated interferon alfa and ribavirin (PR) or an HCV protease inhibitor in
`combination with PR. Data from these trials included subjects with and without
`cirrhosis.
`
`This review highlights the safety and efficacy, virology, clinical pharmacology findings
`and overall benefit/risk assessment to support my recommendation for approval of
`this NDA. Brief comments regarding chemistry/manufacturing and controls and
`pharmacology/toxicology are also presented.
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`2. Background
`
`Chronic HCV infection is a serious and life-threatening condition and can lead to
`cirrhosis and hepatocellular carcinoma. Chronic HCV infection is a global health
`problem with an estimated 170 million individuals infected worldwide. In the United
`States, approximately 3 million people have chronic HCV infection.
`
`The majority of cases of chronic HCV infection in the United States are genotype 1
`(70-75%, predominately genotype 1a). The treatment of genotype 1 infection has
`rapidly evolved over the past three years. HCV drug development has focused on
`DAAs, which are designed to target specific steps in the HCV replication cycle. Prior
`to 2011 the standard of care was PR for 48 weeks. A PR regimen is poorly tolerated
`due to associated toxicities such as flu-like illness, depression and cytopenia.
`Sustained virologic response (SVR) rates for PR range 40-45%. Since 2011 four
`different HCV DAAs were approved. The first DAAs approved in 2011 were NS3/4A
`protease inhibitors (PIs), boceprevir and telaprevir. With these approvals the standard
`of care changed from PR to boceprevir or telaprevir in combination with PR. These
`regimens resulted in improved efficacy SVR rates (60-70%); however, tolerability and
`toxicity of this regimen remains because PR is still part of the regimen. The standard
`of care again changed in 2013 with the approvals of simeprevir (NS3/4A protease
`inhibitor) and SOF. Although both were approved in combination with PR in genotype
`1 HCV-infected patients the overall treatment duration was reduced and SVR rates of
`up to 90% were achieved.
`
`As noted the current standard of care still includes treatment with PR for genotype 1
`HCV-infected subjects. Therefore, there is an unmet need for safe and effective
`treatment options that do not contain PR. The LDV/SOF regimen represents some
`important milestones in HCV drug development. Specifically, LDV/SOF FDC is the
`first regimen for genotype 1 HCV infection that does not include PR and combines two
`drugs from different DAA classes, of which LDV is the first in class for NDA
`submission.
`
`Breakthrough therapy designation was granted on July 22, 2013. This NDA received a
`priority review under PDUFA V and was not presented at the Antiviral Products
`Advisory Committee because LDV/SOF received breakthrough designation and the
`benefit/risk assessment did not appear controversial based on the review team’s
`preliminary assessment of the top line trial results.
`
`LDV/SOF FDC tablet has not been marketed outside the United States to date; a
`marketing application is currently under consideration by the EMA.
`
`21 CFR 300.50 describes FDA's policy for the approval of fixed combination
`prescription drugs for humans. The Federal Food, Drug and Cosmetics Act states in
`part, "Two or more drugs may be combined in a single dosage form when each
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`component makes a contribution to the claimed effects and the dosage of each
`component (amount, frequency, duration) is such that the combination is safe and
`effective for a significant patient population requiring such concurrent therapy as
`defined in the labeling for the drug" 21 CFR 300.50(a). The regulations are interpreted
`to require a factorial analysis of proposed combination ingredients to demonstrate the
`combination is more effective than each component of the combination alone. For
`HCV drugs, however, studying the efficacy of an FDC in a clinical study with a
`factorial design in which the entire combination would be compared to its individual
`components is not feasible or ethical. This type of study design requires HCV-infected
`individuals to be exposed to suboptimal regimens that could quickly result in drug
`resistance not only to the drug or drugs under study, but in many cases to other drugs
`from within the same class. Suboptimal therapy may jeopardize the success of future
`therapeutic options for those patients exposed to single treatment or risk disease
`progression.
`
`In this scenario where components of the combination cannot be administered
`individually (more than few days) due to rapid development of resistance, other
`evidence to show the contribution of each agent to the combination is needed. The
`evidence to show the contribution of each agent to the combination comes from (1)
`the approval of SOF 400 mg QD as part of a combination regimen for genotype 1
`subjects (NDA 204671), (2) monotherapy and dose ranging trial results for LDV and
`(3) the comparison of SVR rates between SOF+ PR and LDV/SOF.
`
`The SVR12 rate for genotype 1 subjects receiving SOF + PR in one Phase 3 trial for
`12 weeks was 89%. LDV proof-of-concept was established in a 3-day dose-ranging
`monotherapy trial evaluating LDV doses 1, 3, 10, 30 and 90 mg once daily. Results
`show a dose dependent response (reduction in HCV RNA) for doses 1 mg through 30
`mg. No evidence of additional antiviral activity at 90 mg was seen; however, HCV
`RNA suppression was sustained for a longer period compared to the 30 mg dose. A
`phase 2 dose-ranging trial (GS-US-248-0120) LDV 30 mg and 90 mg in combination
`with two other investigational DAAs (vedroprevir and tegobuvir) with RBV for 12 and
`24 weeks was conducted. LDV 90 mg group for 12 or 24 weeks had numerically
`higher SVR rates compared with LDV 30 mg group for 24 weeks, though not
`statistically different. However, the incidence of virologic breakthrough in the LDV 90
`mg group was approximately half of that observed in the LDV 30 mg group. These
`data show the contribution of LDV to the regimen via dose response.
`
`As mentioned the SVR rate in genotype 1 treatment-naïve subjects with SOF+PR for
`12 weeks is 89%. In comparison, the SVR rate for LDV/SOF in treatment-naïve
`genotype 1 subjects from Phase 3 trials ranges from 94% - 99%. Collectively these
`data (monotherapy, dose ranging and Phase 3 cross-trial comparison results) show
`the contribution of LDV to the LDV/SOF FDC and satisfy 21 CFR 300.50. Based on
`cross trial comparison, SVR rates are numerically improved when LDV is combined
`with SOF compared to SOF+PR, thereby eliminating the need for a PR based
`regimen.
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`3. CMC/Device
`Collectively the CMC review team cannot recommend approval of LDV/SOF at this
`time due to pending facilities review and inspections and agreement to monitor for the
` content of LDV. Addenda to reviews are expected following receipt and
`review of the final outcomes of the inspections.
`
` General product quality considerations
`
`LDV/SOF FDC is a new molecular entity. LDV/SOF is for oral administration and each
`tablet contains 90 mg of LDV and 400 mg of SOF.
`
`According to the CMC reviewer, Dr. George Lunn, the data presented in the NDA and
`amendments are adequate to assure composition, manufacturing process, and
`specifications for LSV/SOF FDC are appropriate. The expiration dating period of 24
`months when stored below 30 degrees Celsius is supported by adequate data. No
`product quality microbiology issues were identified by Dr. Steven Donald. The
`proposed labeling is adequate pending minor revisions. The specified impurities were
`reviewed by Dr. Mark Powley and deemed adequate from a pharmacology/toxicology
`perspective.
`
`The dissolution method and dissolution acceptance criterion were acceptable for both
`LDV and SOF. Adequate data were provided to support the discriminating ability of
`the dissolution method. The Applicant agreed to monitor for the
` content of
`the LDV component.
`
` Facilities review/inspection
`
`The facilities review and inspections are pending.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The preclinical evaluation of SOF was conducted for NDA 204671. This review
`focuses on the preclinical evaluation of LDV and the 2-year SOF carcinogenicity
`studies. The preclinical evaluation includes over 44 studies to assess the safety,
`pharmacology, pharmacokinetics, general toxicity, carcinogenicity, reproductive and
`developmental toxicology, genetic toxicology and local tolerance, in mice, rats, dogs,
`rabbits and monkeys. Repeat dose studies were conducted in mice (4 weeks), rats
`(26 weeks), and dogs (39 weeks). Dr. Christopher Ellis recommended approval for
`this NDA based on the nonclinical pharmacology/toxicology findings.
`
` General nonclinical pharmacology/toxicology considerations
`
`According to Dr. Ellis’s assessment, no clear target organs of toxicity were identified
`in repeat-dose toxicology studies in mice, rats and dogs for 1, 6, and 9 months
`respectively. No overlapping toxicities between LDV and SOF were noted. A potential
`LDV-related mild hepatobiliary signal was noted as evident by increases in ALT or
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`ALT associated with increased liver/gallbladder weight without corresponding
`histopathology changes in mice. In rats, minimal to slight random foci of hepatocyte
`necrosis and bile duct hyperplasia were noted. For these findings an 8-30 fold safety
`margin is available for the expected human exposure for LDV 90 mg once daily. In
`dogs, no clear clinically relevant findings were seen.
`
`Additionally slight increases in cholesterol and triglycerides were noted in rats at 100
`mg/kg/day.
`
`LDV accumulates in the uveal tract of the eye in pigmented (but not albino) rats. LDV
`also absorbs ultraviolet light. An in vivo study with pigmented rats assessed potential
`ocular phototoxicity risk. Results of this study showed the phototoxicity risk was
`negative at up to the highest dose level tested (8 fold higher than the recommended
`LDV dose in humans)
`
` Carcinogenicity and Mutagenesis
`
`LDV and SOF are not genotoxic following testing in bacterial mutagenicity,
`chromosome aberration and in vivo rat and mouse micronucleus assays.
`
`Carcinogenicity studies of LDV in mice and rats are ongoing.
`
`In mice and rats, no increases in the incidence of drug-related neoplasms were
`observed at the highest doses tested resulting in SOF metabolite GS-331007
`exposures of approximately 4- and 18-fold (in mice) and 8- and 10 fold (rats) higher
`than those in humans at the recommended 400 mg once daily dose.
`
`Additionally, no heart degeneration or inflammation was observed in rats following
`SOF doses of up to 750 mg/kg/day in the 2-year carcinogenicity study at GS-331007
`AUC exposure approximately 9-fold the exposure in humans at the recommended
`400 mg once daily dose.
`
` Reproductive toxicology
`
`In rats, no effects on mating or fertility were seen with LDV at exposures
`approximately 5 and 2 fold higher, in males and females respectively than the
`exposure in humans at the recommended dose. The mean number of corpora lutea
`and implantation sites were slightly reduced at maternal exposures approximately 3
`fold the exposure in humans at the 90mg once daily dose.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Approval is recommended from the clinical pharmacology and pharmacometrics
`review team.
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
` General clinical pharmacology/biopharmaceutics considerations,
`including absorption, metabolism, half-life, food effects
`
`The pharmacokinetic properties of LDV, SOF and the predominant circulating
`metabolite GS-331007 were evaluated in healthy and HCV infected subjects. Mean
`peak concentrations of LDV, SOF and GS-331007 were observed at 4-4.5 hours, 0.8-
`1 hour and 3.5-4 hours post-dose respectively. Following administration of LDV/SOF,
`the median terminal half-lives of LDV, SOF and GS-331007 were 47 hours, 0.5 hours
`and 27 hours, respectively.
`
`Following a single dose of LDV/SOF FDC with a moderate fat meal and compared to
`fasting condition, SOF AUC was increased by approximately 2-fold (no significant
`effect on Cmax). LDV and GS-331007 were not affected by meal type. These data
`support dosing without regard to food. Phase 3 trials were conducted in this manner.
`In vitro, no detectable metabolism of LDV was observed by human CYP1A2,
`CYP2C8, CYP2C9, CYP 2C19, CYP2D6 and CYP3A4. Evidence of slow oxidative
`metabolism via an unknown mechanism has been observed.
`
`SOF is extensively metabolized in the liver to form the pharmacologically active
`nucleoside analog triphosphate GS-461203. The metabolic activation pathway
`involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human
`cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by
`histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the
`pyrimidine nucleotide biosynthesis pathway.
`
`Biliary excretion is the major route of elimination for LDV with renal excretion being a
`minor pathway (approximately 1%). Renal clearance is the major elimination pathway
`for GS-331007.
`
` Dose Selection
`
`The dose selection for SOF 400 mg once daily is based on the safety and efficacy
`established during the review of NDA 204671. Section 2: Background provides a
`summary for the LDV 90 mg once daily dose selection. In sum, the LDV 90 mg once
`daily dose was selected based on results from a three day monotherapy trial and a
`phase 2 dose-ranging trial. Overall the 90 mg dose had numerically higher SVR rates
`and lower incidence of virologic breakthrough compared to a 30 mg once daily dose.
`
` Drug-drug interactions
`
`LDV is an inhibitor of drug transporter P-gp and breast cancer resistance protein
`(BCRP); therefore, LDV may increase the intestinal absorption of coadministered
`substrates for these transporters. LDV also inhibits OATP1B1, OATP1B3 and BSEP
`but only at concentrations exceeding those achieved in humans. The drug-drug
`interaction potential of LDV is primarily limited to intestinal inhibition of P-gp and
`BCRP. Clinically relevant transporter inhibition by LDV in the systemic circulation is
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`not expected due to LDV high protein binding. SOF and GS-331007 are not inhibitors
`of drug transporters. LDV, SOF and GS-331007 are not inhibitors or inducers of CYP
`or UGT1A1 enzymes.
`
`LDV and SOF are substrates of P-gp and BCRP but GS-331007 is not. Therefore, P-
`gp inducers may decrease LDV and SOF exposures and affect efficacy. As a result
`coadministration of LDV/SOF with rifampin, rifapentine and St. John’s wort is not
`recommended. SOF is not a substrate for CYP or UGT1A1 enzymes. Clinically
`significant drug interactions with LDV/SOF FDC mediated by CYP or UGT1A1
`enzymes are not expected.
`
`Drug interaction trials were conducted with LDV as a single agent, SOF as a single
`agent or LDV/SOF in combination with several antiretrovirals, H2 receptor
`antagonists, proton pump inhibitors, oral contraceptives, cyclosporine, rifampin and
`verapamil. Some potentially clinically significant interactions were noted. Please refer
`to Dr. Jenny Zheng’s review for full details and rationale for recommendations despite
`changes in LDV, SOF or concomitant medication exposures. Below is the proposed
`table for the package insert and still under discussion. Two outstanding issues
`remain: use with acid reducing agents and tenofovir based regimens.
`
`Acid-reducing agents:
`
`LDV solubility decreases as pH increases; therefore drugs that increase gastric pH
`are expected to decrease LDV exposures. As a result separation of antacid intake
`and LDV/SOF by four hours is recommended. The data support simultaneous
`administration of proton-pump inhibitor doses comparable to omeprazole 20 mg or
`lower and LDV/SOF under fasted conditions. The Applicant recommends H2-receptor
`antagonists are administered simultaneously with or 12 hours apart from LDV/SOF at
`a dose that does not exceed doses comparable to famotidine 40 mg twice daily. We
`had concerns whether the results from the famotidine trials can be extended to all H2-
`receptor antagonists because some H2-receptor antagonists such as ranitidine may
`have a faster onset of action. The Applicant provided information from the Phase 2/3
`trials, 231 out of 2120 HCV-infected patients on LDV/SOF reported the use of H2-RAs
`as concomitant medications with 10 subjects reporting the use of two agents within
`the H2-RA class. Thirteen subjects reported the use of cimetidine, 76 subjects
`reported the use of famotidine and 152 subjects reported the use of ranitidine. The
`Applicant evaluated the PK of LDV/SOF in subjects on H2 receptor antagonists and
`subjects not on H2 receptor antagonists using Phase 2/3 population PK analyses.
`The post-hoc comparison revealed comparable exposures for all analytes between
`the two groups. These findings are consistent with the results from the drug-drug
`interaction with famotidine. Similar high response rates were observed in subjects
`who received and did not receive H2 receptor antagonists in Phase 3 trials. The PK
`and efficacy data demonstrate that LDV/SOF may be administered with different
`agents within H2 receptor antagonist class and supports the proposed language in the
`package insert.
`
`Page 7 of 31
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`Tenofovir:
`
`Based on results from a drug interaction trial with efavirenz/emtricitabine/tenofovir
`(Atripla) and LDV/SOF, LDV/SOF increases tenofovir AUC, Cmax and Ctau by 98%,
`79% and 163%. The magnitude of the increase in tenofovir exposures is higher
`compared to other drug interaction trials with tenofovir and the concern is for
`tenofovir- associated toxicities, specifically renal events. Therefore, to support the
`safety of this magnitude of increase in tenofovir exposures, we requested the
`Applicant provide safety data for this combination. Currently data were only available
`for 15 subjects receiving efavirenz/tenofovir/emtricitabine and LDV/SOF from trial
`ERADICATE. All subjects completed 12 weeks of treatment and no discontinuations
`due to AEs were reported. No clinically significant changes in creatinine were
`observed. The review team is currently reviewing the summary safety data provided
`by the Applicant on August 7, 2014. The submission includes safety data from 175
`subjects who received LDV/SOF + Atripla and includes safety data from 94 subjects
`receiving LDV/SOF for 12 weeks. These data will be reviewed to support LDV/SOF+
`Atripla coadministration. Of note, the outstanding issue is use of LDV/SOF with an
`HIV protease inhibitor/ritonavir and tenofovir. The tenofovir exposures from a
`combination of LDV/SOF+ HIV protease inhibitor/ritonavir + tenofovir are higher than
`with LDV/SOF+ Atripla. To date, no safety data are available to support the increased
`tenofovir exposures from this combination. Currently the review team is considering a
`recommendation to avoid use with LDV/SOF + HIV protease inhibitor/ritonavir and
`tenofovir. However, if coadministration is necessary, monitor for tenofovir associated
`toxicities. Tenofovir associated toxicities are well characterized and could be
`managed with additional monitoring. Given the high SVR rates with LDV/SOF and the
`limited treatment duration (12-24 weeks), the opportunity to cure HCV in a co-infected
`patient is important. Additionally, there may be clinical circumstances where an
`alternative HIV treatment options that do not contain tenofovir with an HIV protease
`inhibitor/ritonavir is not possible and we wanted to provide an option. Therefore, if
`coadministration is necessary, we propose monitoring recommendations consistent
`with the tenofovir package insert.
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`Concomitant Drug
`Class: Drug Name
`Acid Reducing
`Agents:
`
`Effect on
`Concentrationb
` ledipasvir
`
`Antacids (e.g.
`aluminum and
`magnesium
`hydroxide)
`H2-receptor
`antagonists
`
`Proton-pump
`inhibitors
`
`Antiarrhythmics:
`digoxin
`
`↑ digoxin
`
`Anticonvulsants:
` ledipasvir
`carbamazepine
` sofosbuvir
`phenytoin
` GS-331007
`phenobarbital
`oxcarbazepine
`
`Antimycobacterials:
`rifabutin
`rifampin
`rifapentine
`
` ledipasvir
` sofosbuvir
` GS-331007
`
`Antiretrovirals:
`elvitegravir/cobicistat/
`emtricitabine/tenofovir
`disoproxil fumarate
`
` tenofovir
`
`Clinical Comment
`
`Ledipasvir solubility decreases as pH increases. Drugs
`that increase gastric pH are expected to decrease
`concentration of ledipasvir.
`
`Separate antacid and [TRADENAME] administration by
`4 hours
`
`Recommendation pending
`
`Proton-pump inhibitor doses comparable to omeprazole
`20 mg or lower can be administered simultaneously with
`[TRADENAME] under fasted conditions.
`Coadministration of [TRADENAME] with digoxin may
`increase the concentration of digoxin. Caution is
`warranted and therapeutic concentration monitoring of
`digoxin is recommended when coadministered with
`[TRADENAME].
`Coadministration of [TRADENAME] with
`carbamazepine, phenytoin, phenobarbital or
`oxcarbazepine is expected to decrease the
`concentration of ledipasvir and sofosbuvir, leading to
`reduced therapeutic effect of [TRADENAME].
`Coadministration is not recommended.
`Coadministration of [TRADENAME] with rifabutin or
`rifapentine is expected to decrease the concentration of
`ledipasvir and sofosbuvir, leading to reduced
`therapeutic effect of [TRADENAME]. Coadministration
`is not recommended.
`Coadministration of [TRADENAME] with rifampin (a P-
`gp inducer) is not recommended [see Warnings and
`Precautions (5.1)].
`There are insufficient data to make a dosing
`recommendation for coadministration of [TRADENAME]
`with elvitegravir/cobicistat/emtricitabine/tenofovir
`disoproxil fumarate.
`
`tipranavir/ritonavir
`
`HCV Products:
`simeprevir
`
` ledipasvir
` sofosbuvir
` GS-331007
`
` ledipasvir
` simeprevir
`
`Coadministration of [TRADENAME] with
`tipranavir/ritonavir is expected to decrease the
`concentration of ledipasvir and sofosbuvir, leading to
`reduced therapeutic effect of [TRADENAME].
`Coadministration is not recommended.
`Concentrations of ledipasvir and simeprevir are
`increased when simeprevir is coadministered with
`ledipasvir. Coadministration of [TRADENAME] with
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`Herbal
`Supplements:
`St. John’s wort
`(Hypericum
`perforatum)
`HMG-CoA
`Reductase
`Inhibitors:
`rosuvastatin
`
` ledipasvir
` sofosbuvir
` GS-331007
`
` rosuvastatin
`
`simeprevir is not recommended.
`Coadministration of [TRADENAME] with St. John’s wort,
`a P-gp inducer is not recommended[See Warnings and
`Precautions (5.1)].
`
`Coadministration of [TRADENAME] with rosuvastatin
`may significantly increase the concentration of
`rosuvastatin which is associated with increased risk of
`myopathy, including rhabdomyolysis. Coadministration
`of [TRADENAME] with rosuvastatin is not
`recommended.
`
` Critical intrinsic factors: age, gender, hepatic and renal impairment
`
`Based on population pharmacokinetic analyses, age, race, BMI, treatment status,
`presence of RBV, and cirrhosis status had no clinically relevant effects on the
`exposure of LDV, SOF or GS331007. LDV AUC, Cmax and Ctau were approximately
`77%, 58%, and 75% higher in females compared to males. The relationship between
`sex and LDV exposures was not considered clinically relevant given the high
`response rates (>93%) and the lack of related safety issues in the clinical trials.
`
`The effect of renal impairment was evaluated for LDV and SOF as individual agents.
`No clinically relevant differences in LDV pharmacokinetics were seen between healthy
`subjects and subjects with severe renal impairment, thus supporting that LDV can be
`given to patients with mild, moderate or severe renal impairment. However, the SOF
`component of the FDC cannot be given to patients with severe renal impairment.
`Higher exposures (up to 20 fold) for GS-331007 were seen in subjects with severe
`renal impairment. Safety and efficacy have not been established for GS-331007
`exposures; therefore, dosing recommendations in patients with severe renal
`impairment cannot be made for LDV/SOF FDC.
`
`No clinically relevant effect on the exposure of LDV, SOF and GS-331007 was seen
`in subjects with severe hepatic impairment. Therefore LDV/SOF FDC can be given to
`patients with mild, moderate and severe hepatic impairment. Data in subjects with
`decompensated cirrhosis are not available.
`
` Thorough QT study or other QT assessment
`
`A thorough QT trial was not conducted for LDV/SOF FDC. The individual products
`were evaluated in a thorough QT trial. LDV or SOF did not prolong QTc to any
`clinically relevant extent compared to an active control (moxifloxacin 400 mg).
`
` Exposure-response and Exposure-safety analyses
`
`A numeric trend of increased response with respect to increased LDV, SOF, and GS-
`331007 exposures was seen for the LDV/SOF +/- RBV-treated, treatment-naïve, non-
`
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`Cross Discipline Team Leader Review
`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
`
`cirrhotic subjects in ION-3. SVR rates in subjects administered LDV/SOF +/- RBV for
`8 weeks were numerically higher in subjects in the highest exposure quartile
`compared to the lowest exposure quartile. Dose adjustment or therapeutic drug
`monitoring is not recommended based on this finding because overall SVR12 rates
`were greater than 93%.
`
`For treatment-naïve cirrhotic subjects and treatment-experienced cirrhotic and non-
`cirrhotic subjects no clinically relevant differences were observed in SVR12 between
`the highest and lowest exposure quartiles.
`
`No exposure-response relationships were identified between LDV, SOF, GS-331007
`AUC and the most commonly observed adverse events in Phase 3 trials.
`
`6. Clinical Microbiology
`
`Please refer to the reviews by Dr. Lisa Naeger and Dr. Eric Donaldson for a detailed
`assessment of the cell culture and in vivo clinical virology data. Dr. Naeger
`recommended an approval action.
`
`The results from baseline NS5A resistance-associated polymorphism and outcome
`(SVR12 and relapse rate) are presented in section 7 Clinical/Statistical Efficacy. This
`section will focus on the virologic failures from the Phase 3 trials. Additionally a brief
`summary is presented from the next generation sequencing (NGS) analyses.
`
`Overall 50 subjects experienced virologic failure from the Phase 2 and Phase 3
`submitted trials. Two subjects experienced breakthrough and the remaining 48 were
`relapsers (41 genotype 1a subjects and 7 genotype 1b subjects). The comments
`below focus on the 37 virologic failures from the Phase 3 trials (29 with genotype 1a
`and 8 with genotype 1b; 35 relapsers and 2 breakthroughs due to documented non-
`adherence).
`
`Overall 62% (23/37) of the failures in Phase 3 had emergent NS5A resistance
`substitutions. Notably more treatment-experienced subjects developed an NS5A
`substitution at failure (75%) compared to treatment-naïve subjects (56%).
`Of the 29 genotype 1a virologic failure subjects, 55% (16/29) of subjects had virus
`with emergent NS5A resistance-associated substitutions K24R, M28T/V, Q30R/H/K/L,
`L31M, or Y93H/N at failure. Five of these 16 subjects also had baseline NS5A
`polymorphisms at resistance-associated positions. The most common substitutions
`detected at failure were Q30R, Y93H or N, and L31M.
`Of the 8 genotype 1b virologic failure subjects, 88% (7/8) had virus with emergent
`NS5A resistance-associated substitutions L31V/M/I or Y93H at failure. Three of these
`7 subjects also had baseline NS5A polymorphisms at resistance-associated positions.
`The most common substitution detected at failure was Y93H.
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`NDA 205834 (ledipasvir/sofosbuvir) Fixed Dose Combination Tablet
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`At failure, 38% (14/37) of virologic failure subjects had 2 or more NS5A resistance-
`associated substitutions.
`In phenotypic analyses, post-baseline isolates from subjects who harbored NS5A
`resistance-associated substitutions at failure showed 20- to >243-fold reduced
`susceptibility to LDV.
`The SOF-associated resistance substitution S282T in NS5B was not detected in any
`failure isolate from the Phase 3 trials. However, the NS5B S282T substitution in
`combination with NS5A substitutions L31M, Y93H and Q30L was detected in one
`subject at failure following 8 weeks of treatment from a Phase 2 trial.
`
`Data on the retreatment strategy for subjects failing LDV/SOF is limited. Data from
`nine subjects who did not achieve SVR12 after receiving an LDV/SOF based regimen
`(LDV/SOF x 8 weeks or LDV/SOF+RBV x 6 weeks) were available for review. Only
`one subject from the Phase 2 trial LONESTAR was retreated with LDV/SOF+RBV for
`24 weeks following virologic failure after receiving LDV/SOF for 8 weeks. This subject
`had multiple NS5A substitutions and an NS3 substitution (Q30L, L31M, Y93H and
`S282T). This subject achieved SVR12. The remaining eight subjects were all
`retreated with LDV/SOF+ RBV for 12 weeks. Of note only three of the eight subjects
`had NS5A resistance substitutions at relapse. All subjects achieved SVR12. In
`summary the optimal regimen (LDV/SOF, LDV/SOV+RBV or other DAA combination)
`or optimal duration (12 or 24 weeks) for retreatment for subjects failing LDV/SOF is
`unknown. Additional data are needed to make labeling recommendations for
`retreatment regimens; however, the limited data available appears encouraging for
`future retreatment options.
`
`Dr. Donaldson concluded there was good agreement between his independent
`analysis of the NGS data and the analysis done by the Applicant despite different
`criteria used. Based on his review, LDV/SOF has a high barrier to resistance.
`Additional NS5B s