CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208341Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`CLINICAL PHARMACOLOGY REVIEW MEMO
`
`NDA:
`
`208341
`
`Brand Name
`
`Submission Date(s): February 10, 2014
`
`EPCLUSATM
`
`Generic Name
`
`SofosbuvirNelpatasvir
`
`Clinical Pharmacology
`Reviewers
`
`Jenny H. Zheng, Ph.D.
`
`Secondary Reviewer
`
`Shirley K. Seo, Ph.D.
`
`OCP Division
`
`0ND division
`
`Division 4
`
`DAVP
`
`Applicant
`
`Gilead Sciences
`
`Formulation; Strength(s)
`
`Fixed dose combination tablets; 400 mg/100 mg
`
`Indication
`
`laiitsment of chronic hepatitis C (CHC)
`
`"’"4’ infection in
`
`The Clinical Pharmacology Review for NDA208341 was completed at March 25, 2016. When
`the review was completed, a Clinical Pharmacology issue was pending:
`
`. Can proton-pump inhibitors (PPls) be coadministered with EPCLUSATM?
`
`Based on the rationales provided by the applicant and consultation with the gastroenterology
`products team leader in the Office of Clinical Pharmacology (OCP), the Agency ultimately
`revised the proposed labeling recommendation as follows (final, agreed-upon wording):
`
`“Coadministration of omeprazole or other proton pump inhibitors is not recommended. If it is
`considered medically necessary to coadminister, EPCLUSA should be administered with food
`and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not
`been studied. ”
`
`As stated in the original NDA review, the applicant’s original labeling proposal was
`
`“M"
`
`The Agency did not agree with the applicant’s
`proposal because of the concern that coadministration of SofosbuvirNelpatasvir (SOFNEL)
`with proton-pump inhibitors under the proposed conditions decreases the concentration of
`velpatasvir (VEL), which may lead to reduced therapeutic effect of SOFNEL; therefore,
`coadministration is not recommended.
`
`Because SOFNEL+ribavirin (RBV) is a highly effective treatment for HCV infected patients with
`decompensated cirrhosis, and PPls are commonly prescribed in patients with decompensated
`cirrhosis for prophylaxis of variceal hemorrhage, the applicant insisted
`(m4)
`
`Reference ID: 3947635
`
`

`

`In the absence of a large clinical dataset for the use of SOF/VEL with PPI, a more cautious
`approach may be warranted. The Agency and the applicant have reached the following
`agreements:
` Allow coadministration of omeprazole with SOF/VEL only when it is medically necessary.
`o In ASTRAL 3, VEL AUC exposures were 30% lower in relapsers compared to
`non-relapsers. Thus, even this degree of decrease in VEL AUC may be
`problematic.
`o Since SOF/VEL is administered under fed conditions and omeprazole should be
`administered under fasted conditions (based on recommendations in the
`omeprazole label), there is concern over the practicality of dosing in the real
`world when a patient needs to consider the dose of omeprazole to take (20 mg),
`time of day to take two different drugs (SOF/VEL 4 hours before omeprazole),
`and prandial condition of each drug administration. In considering the worst case
`scenario, there were significant decreases in exposure for both SOF and VEL
`that could impact efficacy for patients with any HCV genotype.
` SOF/VEL should not be used with other PPIs, because the use of SOF/VEL with other
`proton pump inhibitors has not been studied.
` SOF/VEL should be administered with food and taken 4 hours before omeprazole 20
`mg, because the impact of omeprazole on VEL is relatively less as compared to when
`omeprazole is administered 2 hours ahead of SOF/VEL as shown in the following table.
`There is 33% and 28% reduction on VEL Cmax and AUC, respectively, as compared to
`that when SOF/VEL is administered under fasted conditions without omeprazole.
`Because administration of SOF/VEL with a high-fat/high-calorie or a moderate-
`fat/moderate-calorie meal resulted in a 21% and 34% increase in VEL AUC, and
`SOF/VEL can be given with or without food, for patients who take SOF/VEL under fed
`conditions, the true effect of omeprazole on VEL exposures could actually be more.
`
`Therefore, use of omeprazole or other PPIs with SOF/VEL is not recommended unless
`medically necessary.
`
`Drug Interactions: Changes in Pharmacokinetic Parameters for Velpatasvir in the
`Presence of Omeprazole
`
`Mean Ratio (90% CI) of Velpatasvir PK
`With/Without Coadministered Drug
`No Effect=1.00
`
`SOF Dose
`(mg)a
`
`VEL Dose
`(mg)a
`
`400 single
`dose fed
`
`100 single
`dose fed
`
`N
`
`40
`
`Cmax
`
`0.52 (0.43, 0.64)
`
`Dose of
`Omeprazole
`(mg)
`20 once daily 2
`hours prior to
`SOF/VEL
`20 once daily 4
`hours after
`SOF/VEL
`a SOF/VEL was administered under fasted conditions in the reference arms.
`
`400 single
`dose fed
`
`100 single
`dose fed
`
`38
`
`0.67 (0.58, 0.78)
`
`Reference ID: 3947635
`
`AUC
`
`0.62 (0.51, 0.75)
`
`0.74 (0.63, 0.86)
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HUIMIN ZHENG
`06/17/2016
`
`SHIRLEY K SEO
`06/17/2016
`
`Reference ID: 3947635
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`
` 208341
`NDA:
`Brand Name
`Generic Name
`Primary 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): October 28, 2015
`To be Determined
`Sofosbuvir/Velpatasvir (GS-7977/GS-5816)
`Jenny H. Zheng, Ph.D.
`Abhay Joshi, Ph.D.
`Shirley K. Seo, Ph.D.
`Fang Li, Ph.D.
`Jeffry Florian, Ph.D.
`Division 4
`DAVP
`Gilead Sciences
`INDs 118605, 106739, 115670 and NDAs 204671, 205834
`Priority
`Fixed dose combination tablets; 400 mg/100 mg
`Treatment of chronic hepatitis C (CHC) infection in adults
`
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ............................................................................................................................... 1
`1. EXECUTIVE SUMMARY ......................................................................................................................... 2
`1.1
`Recommendation ........................................................................................................................ 3
`1.2
`Phase IV Commitments .............................................................................................................. 3
`1.3
`Summary of Important Clinical Pharmacology Findings ....................................................... 3
`2. QUESTION BASED REVIEW .................................................................................................................. 8
`2.1 General Attributes ............................................................................................................................. 8
`2.1.1 What are the highlights of the chemistry and physico-chemical properties of the drug substance
`and the formulation of the drug product as they relate to clinical pharmacology review? ............ 8
`2.1.2. What are the proposed mechanism(s) of action and therapeutic indication(s)? ......................... 9
`2.1.3. What are the proposed dosage(s) and route(s) of administration? ............................................. 9
`2.2 General Clinical Pharmacology ..................................................................................................... 10
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to support
`dosing or claims? ........................................................................................................................ 10
`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? ............................................................................................ 11
`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?....... 11
`2.2.4 Exposure-response ..................................................................................................................... 12
`
`
`Reference ID: 3908046
`
`1
`
`

`

`2.2.5 What are the PK characteristics of the drug and its major metabolite? ...................................... 14
`2.3 Intrinsic Factors ............................................................................................................................... 19
`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? .......................................... 19
`2.4 Extrinsic Factors ............................................................................................................................. 24
`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? ....... 24
`2.4.2 Drug-Drug Interactions ............................................................................................................... 25
`2.5 General Biopharmaceutics ............................................................................................................. 34
`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?
` .................................................................................................................................................... 34
`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? ............................................ 34
`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
`2.6 Analytical Section............................................................................................................................ 35
`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? ........................................................................................................................... 35
`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 .................................................................................... 36
`4. APPENDICES ......................................................................................................................................... 37
`4.1 Individual Study Review ................................................................................................................. 37
`4.1.1 Biopharmaceutics ....................................................................................................................... 37
`4.1.2 General Pharmacokinetics/Pharmacodynamics ......................................................................... 41
`4.1.3 Intrinsic Factors (by Abhay Joshi) ............................................................................................... 68
`4.1.4 Extrinsic Factors ......................................................................................................................... 77
`4.1.5 In vitro Studies .......................................................................................................................... 125
`4.1.6 Pharmacometric Review (Fang) ............................................................................................... 154
`
`
`
`1. EXECUTIVE SUMMARY
`
`Gilead Sciences is seeking approval of sofosbuvir (SOF, GS-7977) and velpatasvir (VEL, GS-
`5816) together as an oral fixed-dose combination (FDC) tablet (SOF/VEL 400 mg/100 mg) for
`the treatment of chronic hepatitis C virus (HCV) infection. SOF/VEL was granted Breakthrough
`Therapy Designation on May 18, 2015.
`
`VEL is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV activity against
`genotypes 1 through 6 HCV infection. SOF is a nucleotide NS5B polymerase inhibitor that
`inhibits HCV RNA replication in vitro, and has been approved for use in combination with other
`agents for the treatment of chronic HCV infection in adults (Sovaldi®, NDA 204671 and
`Harvoni® [ledipasvir (LDV)/SOF], NDA 205834).
`
`The proposed SOF/VEL dosage regimen is one 400 mg/100 mg tablet, taken orally, once daily
`with or without food. The following treatment regimens are proposed by the applicant,
`regardless of HCV genotype:
`
`
`Reference ID: 3908046
`
`2
`
`

`

`
`
`Patient Population
`Patients without cirrhosis and
`patients with compensated cirrhosis
`Patients with decompensated
`cirrhosis
`
`Proposed Treatment Regimen
`SOF/VEL for 12 weeks
`
`SOF/VEL + ribavirin for 12 weeks
`
`Recommendation
`
`Phase IV Commitments
`
`
`The consideration for approval of this NDA is based on efficacy data from three Phase 3 trials
`(ASTRAL-1, ASTRAL-2, and ASTRAL-3) in subjects with genotypes 1 through 6 HCV infection
`with or without compensated cirrhosis and one Phase 3 trial (ASTRAL-4) in subjects with
`genotypes 1 through 6 HCV infection with decompensated cirrhosis.
`
`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
`SOF/VEL.
`
`1.2
`
`Post Marketing Requirement (PMR): The sponsor will be asked to conduct a drug interaction
`study to evaluate the interaction between sofosbuvir/velpatasvir and atorvastatin.
`
`Rationale: The results from the rosuvastatin study indicate that velpatasvir can significantly
`increase the concentration of substrates of organic anion transporting polypeptides (OATP)
`and breast cancer resistance protein (BCRP), such as atorvastatin. Although the results
`from the rosuvastatin drug interaction study cannot be directly extrapolated to atorvastatin,
`there is a mechanistic basis for a potentially clinically significant interaction with this
`commonly used statin. Furthermore, a serious safety event (rhabdomyolysis) has been
`identified in postmarketing reports with use of ledipasvir/sofosbuvir and atorvastatin. Based
`on the evidence from in vitro studies, ledipasvir and velpatasvir may have similar drug
`interaction potential for inhibition of OATP1B and BCRP transport, so the potential exists for
`sofosbuvir/velpatasvir to increase atorvastatin exposures, leading to serious adverse events.
`Thus, a PMR is needed to study the interaction between sofosbuvir/velpatasvir and
`atorvastatin in order to derive appropriate dosing recommendations for concomitant use.
`
`
`1.3
`
` A
`
`Summary of Important Clinical Pharmacology Findings
`
` comprehensive program of Phase 1 and Phase 2 clinical studies and in vitro studies
`characterized the PK of SOF, its predominant inactive metabolite GS-331007, and VEL when
`administered either as single agents or as the FDC. Additionally, both intensive and sparse
`plasma concentration data from 331 healthy subjects and 1694 HCV-infected subjects who
`received SOF/VEL FDC, SOF and VEL administered together as single agents, or VEL as a
`single agent from 11 clinical studies (four Phase 1, three Phase 2, and four Phase 3 studies)
`were used for population PK evaluation of SOF, its predominant circulating metabolite GS-
`331007, and VEL.
`
`
`Reference ID: 3908046
`
`3
`
`

`

`Mechanism of Action (MOA)I General Pharmacokinetics (PK) and Pharmacodynamics (PD)
`
`MOA: SOFNEL is a fixed-dose combination of SOF (an inhibitor of the HCV NSSB RNA-
`dependent RNA polymerase) and VEL (an inhibitor of the HCV NSSA protein) which are direct-
`acting antiviral agents against the hepatitis C virus.
`
`Pharmacokinetics: The following table characterizes the absorption, distribution, metabolism,
`and excretion (ADME) of the components of SOFNEL
`
`:—~:elpatasvir
`Absorption
`
`
`
`Distribution
`
`% Bound to human plasma proteins _ 99.5%
`Blood-to-plasma ratio
`I 52-06?
`Metabolism
`Metabolism
`
`
` athepsin A
`
`ES1
`
`
`HINT1
`
`
`Elimination
`
`Major route of elimination
`
`t1/2 (h)c
`
`% Of dose excreted in urine
`
`0F: metabolism
`GS-331007": glomerular
`Iltration and active tubular
`~ ecretion
`
`
`
`OF: 0.5
`(as—331007": 25
`
`= iliary excretion as parent
`77%)
`
`15
`
`| .4%
`
`% Of dose excreted in feces' — . %
`CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1
`a Values refer to mean systemic exposure. Moderate meal = ~600 kcal, 30% fat; high fat meal = ~800
`kcal, 50% fat. SOFNEL can be taken with or without food.
`b GS—331007 is the primary circulating nucleoside metabolite of SOF.
`° tm values refer to median terminal plasma half-life.
`d Single dose administration of [“C] SOF or [14C] VEL in mass balance studies.
`9 Predominantly as GS-331007.
`
`Pharmacodynamics: At a dose three times the maximum recommended dose for SOF and a
`dose five times the maximum recommended dose for VEL, neither SOF nor VEL prolong QTc to
`a clinically relevant extent. Please refer to the review conducted by Interdisciplinary Review
`Team for QT Studies Consultation (IND 115670, 4/15/2015) for details.
`
`Exposure-Response: No exposure-response relationships for safety or efficacy were identified
`for either of the components of SOFNEL at the recommended dosage. No dose-response was
`identified between SOF 400 mg + VEL 25 mg and SOF 400 mg + VEL100 mg for treatment-
`na'ive, non—cirrhotic subjects. However, higher efficacy was observed with SOF 400 mg + VEL
`100 mg (SVR12 (sustained virologic response at 12 weeks following completion of all
`
`Reference ID: 3908046
`
`

`

`•
`
`treatment): 94%) compared to SOF 400 mg + VEL 25 mg (SVR12: 71%) in Genotype 3,
`treatment-experienced subjects (Phase 2 study GS-US-342-0109).
`
`Drug Interaction Potential
`• VEL solubility decreases as pH increases. Drugs that increase gastric pH are expected
`to decrease systemic concentrations of VEL.
`• SOF and VEL are substrates of drug transporters P-glycoprotein (P-gp) and breast
`cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are inducers of P-
`gp may decrease plasma concentrations of SOF and VEL leading to reduced therapeutic
`effect of SOF/VEL.
`In vitro, slow metabolic turnover of VEL by CYP2B6, CYP2C8, and CYP3A4 was
`observed. Drugs that are moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4
`may decrease plasma concentrations of VEL leading to reduced therapeutic effect of
`SOF/VEL.
`• VEL is an inhibitor of drug transporters P-gp, breast cancer resistance protein (BCRP),
`OATP1B1 and OATP1B3. Coadministration of SOF/VEL with drugs that are substrates
`of these transporters may increase the exposure of such drugs.
`• Serious symptomatic bradycardia has been observed when amiodarone is
`coadministered with a SOF-containing regimen (with another HCV direct acting antiviral).
`Therefore, coadministration of amiodarone with SOF/VEL may also result in serious
`symptomatic bradycardia. The mechanism of this effect is unknown.
`
`The following table provides a listing of reviewer-proposed changes (in blue) to established or
`potentially clinically significant drug interactions. The table is not all inclusive.
`
`
`Concomitant Drug
`Class: Drug Name
`Acid Reducing
`Agents:
`
`Effect on
`Concentrationa
`↓ VEL
`
`Antacids (e.g.,
`aluminum and
`magnesium hydroxide)
`H2-receptor antagonistsb
`(e.g., famotidine)
`
`Proton-pump inhibitorsb
`(e.g., omeprazole)
`
`Antiarrhythmics:
`amiodarone
`
`digoxinb
`
`Effect on
`amiodarone,
`SOF, and VEL
`concentrations
`unknown
`↑ digoxin
`
`Clinical Comment
`
`VEL solubility decreases as pH increases. Drugs that
`increase gastric pH are expected to decrease
`concentration of VEL.
`Separate antacid and SOF/VEL administration by 4 hours.
`
`H2-receptor antagonists may be administered
`simultaneously with or 12 hours apart from SOF/VEL at a
`dose that does not exceed doses comparable to famotidine
`40 mg twice daily.
`Coadministration of SOF/VEL with proton-pump inhibitors
`decrease the concentration of velpatasvir, which may lead
`to reduced therapeutic effect of SOF/VEL.
`Coadministration is not recommended.
`Coadministration of amiodarone with SOF/VEL may result
`in serious symptomatic bradycardia. The mechanism of
`this effect is unknown. Coadministration of amiodarone
`with SOF/VEL is not recommended; if coadministration is
`required, cardiac monitoring is recommended.
`Measure serum digoxin concentrations before initiating
`SOF/VEL. Reduce digoxin concentrations by decreasing
`the dose by approximately 15-30% or by modifying the
`dosing frequency and continue monitoring.
`
`
`Reference ID: 3908046
`
`5
`
`

`

`
`
`Coadministration is not recommended.
`T topotecan
`Anticancers:
`
`topotecan
`
`J, SOF
`
`J, VEL
`
`Anticonvulsants:
`
`carbamazepine
`
`phenytoin
`phenobarbital
`
`oxcarbazepine
`
`Coadministration is not recommended.
`
`J, SOF
`J, VEL
`
`Coadministration is not recommended.
`
`
`
`Antimycobacterials:
`rifabutin
`rifampinb
`rifapentine
`HIV Antiretrovirals:
`
`efavirenzb
`J, VEL
`Coadministration of SOFNEL with efavirenz—containing
`regimens is not recommended.
`
`Regimenscontalnlng
`tenofovir DF W"
`
`"""""""""""
`""i"'t'é"ri$i6§ii""""""""""""ii'Sfii’t'éi’isi"i'é’iié’iéiiil飧3€i§£§82€i§éi§€Fé’ééiiéfiéi'fi
`patients receiving SOFNEL concomitantly with a regimen
`containing tenofovir DF. Refer to
`(”"0
`prescribing information for recommendations on renal
`monitoring.
`
`(hm)
`
`tipranavirlritonavir
`
`J, SOF
`i VEL
`
`Coadministration is not recommended.
`
`Herbal Supplements:
`St. John’s wort
`(Hypericum perforatum)
`
`J, SOF
`J, VEL
`
`Coadministration is not recommended.
`
`10 mg.
`
`HMG-CoA Reductase
`Inhibitors:
`
`T rosuvastatin
`
`rosuvastatinb
`
`Coadministration of SOFNEL with rosuvastatin may
`significantly increase the concentration of rosuvastatin
`which is associated with increased risk of myopathy,
`including rhabdomyolysis. Rosuvastatin may be
`administered with SOFNEL at a dose that does not exceed
`
`atorvastatin
`
`T atorvastatin
`
`Coadministration of SOFN EL with atorvastatin is expected
`to increase the concentrations of atorvastatin, which is
`associated with increased risk of myopathy, including
`rhabdomyolysis. Monitor closely for HMG-CoA reductase
`inhibitor-associated adverse events, such as myopathy,
`a. l = decrease, f = increase
`b. These interactions have been studied in healthy adults.
`
`Although the drug interaction potential was not studied between SOFNEL and atorvastatin,
`atorvastatin is a sensitive substrate of OATP1 B1, and has been reported as a substrate of P-gp
`
`Reference ID: 3908046
`
`

`

`and BCRP. There have been postmarketing reports of rhabdomyolysis cases associated with
`the coadministration of Harvoni® (LDV/SOF) and atorvastatin. VEL and LDV have similar drug
`interaction potential profiles. Therefore, there is a potential for a clinically relevant drug
`interaction (DDI) between SOF/VEL and atorvastatin. Because it is difficult to extrapolate the
`results from one statin to another, a postmarketing requirement (PMR) is necessary to study the
`interaction between SOF/VEL and atorvastatin.
`
` Use in Specific Populations
`
`
`• No dosage adjustment is recommended based on gender, race, or age (≥18 to ≤82
`years).
`• Renal Impairment: No dosage adjustment of SOF/VEL is required for patients with mild
`or moderate renal impairment. The safety and efficacy of SOF/VEL have not been
`established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m2)
`or ESRD requiring hemodialysis. No dosage recommendation can be given for patients
`with severe renal impairment or ESRD.
`• Hepatic Impairment: No dosage adjustment of SOF/VEL is required for patients with
`mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C). Safety and
`efficacy of SOF/VEL have been established in patients with decompensated cirrhosis.
`
`Safety and Efficacy
`
`The SOF/VEL pivotal studies consisted of three randomized Phase 3 trials (ASTRAL-1,
`ASTRAL-2, and ASTRAL-3) in subjects with genotypes 1 through 6 HCV infection with or
`without compensated cirrhosis and one Phase 3 trial (ASTRAL-4) in subjects with genotypes 1
`through 6 HCV infection with decompensated cirrhosis. Overall, 1035 subjects were treated with
`SOF/VEL for 12 weeks in Studies GS-US-342-1138, GS-US-342-1139, and GS-US-342-1140
`including 328, 238, 277, 116, 35, and 41 subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection,
`respectively. In Study GS-US-342-1137, 267 subjects with genotype 1, 2, 3, 4, or 6 HCV
`infection with decompensated cirrhosis were treated with SOF/VEL±RBV for 12 weeks or
`SOF/VEL for 24 weeks.
`
`For all subjects, regardless of cirrhosis status, SVR12 rates > 95% (range: 95.3% to 100.0%
`across genotypes) were achieved across all HCV genotypes. Among subjects with cirrhosis, the
`SVR12 rates were > 91% (range: 91.3% to 100.0% across HCV genotypes) and among
`subjects with prior treatment experience, the SVR12 rates also were > 90% (range: 90.1% to
`100.0% across HCV genotypes). For subjects with decompensated cirrhosis, numerically higher
`SVR 12 rates were achieved following treatment with SOF/VEL+RBV for 12 weeks (SVR12:
`94.3) as compared to treatment with SOF/VEL for 12 weeks (SVR 83.3%) or 24 weeks (SVR12:
`85.6%). The most common adverse reaction (incidence at least 5%) were headache, fatigue,
`and nausea in subjects treated with 12 weeks of SOF/VEL. The most common adverse
`reactions (all grades with frequency of at least10% in subjects with decompensated cirrhosis
`who received SOF/VEL plus RBV for 12 weeks were fatigue (32%), anemia (26%), nausea
`(15%), headache (11%), insomnia (11%), and diarrhea (10%).
`
`
`
`Reference ID: 3908046
`
`7
`
`

`

`2. QUESTION BASED REVIEW
`
`2.1 General Attributes
`
`2.1.1 What are the highlights of the chemistg and physico-chemical progrties of the drug
`substance and the formulation of the drug product as they relate to clinical pharmacology
`review?
`
`Sofosbuvir/velpatasvir (SOFNEL) fixed-dose combination tablets contain 400 mg of sofosbuvir
`(SOF) and 100 mg of velpatasvir (VEL).
`
`Please refer to the Clinical Pharmacology Review for NBA 204671 for additional details on the
`physico-chemical properties of SOF. The following shows physico-chemical properties of VEL.
`
`Empirical Formula: C49H54N808
`Molecular Weight: 883.0glmol
`pKa: pKa1 = 3.2; pKa2 = 4.6
`
`Solubility of VEL in Aqueous Media at 25 °C
`Aqueous Media
`~ olubility (mgImL)
`
`SPIPh. Eur. Solubility Description
`
`Water, pH 1.23
`
`Water, pH 2.02'
`
`Sodium acetate buffer, pH 5.0
`
`Phosphate buffer, pH 6.8
`
`FeSSIF, pH 5.0
`
`FaSSlF, pH 6.5c
`
`> 36
`
`oluble
`
`s lightly soluble
`
`' ractically insoluble
`
`' ractically insoluble
`
`ery slightly soluble
`
`' ractically insoluble
`
`a pH established using HCI
`b FeSSIF, Fed-state simulated small intestine fluid contains 15 mM bile salts (1:1 aurocholate:
`glycocholate, 3.75 mM lecithin)
`° FaSSlF, Fasted-state simulated small intestine fluid contains 5 mM bile salts (1 :1 taurocholate:
`glycocholate, 0.75 mM lecithin)
`
`The quantitative composition of SOFNEL tablets is shown in the following table. SOFNEL
`tablets contain
`“’"4’ (400 mg) SOF and
`W" (100 mg) VEL. The tablet formulation
`utilizes
`M“).
`
`Reference ID: 3908046
`
`

`

`Function
`
`Composition
`(“o w w)
`
`[‘uit Formula
`(mg tablet)
`
`Quality
`Standard
`
`( omponent
`
`Intragranular
`‘
`, 3
`Sotosbux-u-
`
`Yelpatasvirb'c
`b c d
`('0pm'1do1ie '
`'
`
`Microcrystallme Cellulmea c
`Croscamlellme Sodium
`
`Magnesium Slearate
`
`(b)(4I
`
`0’)“:
`
`(MG)
`
`_
`,
`
`400.0
`Ill-house
`Active Ingredient
`
`‘ Active Ingredient
`(b) (4)
`
`100.0
`
`‘
`(b) (4)
`
`Ill-ilothe
`
`,
`.\F. Ph. Eur.
`vL SP. P11. Eur.
`
`NF. Ph. Eur.
`.\'I-‘. Ph. Eur.
`
`NF. Pl]. Elu'.
`
`
`
`_\'F. Ph. Eur.
`
`100.0
`
`1000
`
`—
`
`(DIM)
`
`Ill-house
`
`Fllm-coat
`
`. .
`I SP. Ph. Eur.
`
`(WW
`
`(0)“)
`
`Total Tablet Core Weight
`Film-Coat
`
`a
`
`bC de f
`
`8h
`
`2.1.2. What are the ro osed mechanism 5 of action and thera eutic indication s ?
`
`SOF is a HCV NSSB polymerase nucleotide inhibitor that displays potent inhibition of HCV RNA
`replication in vitro. SOF is a nucleotide prodrug that undergoes intracellular metabolism to form
`the pharmacologically active uridine analog triphosphate (GS-461203). VEL is a novel HCV
`NSSA inhibitor that has displayed potent in vitro inhibition of HCV RNA replication. VEL exhibits
`broad genotypic (genotypes 1-6) potency and selectivity in multiple cell-based replicon assays
`and specificity for HCV. The proposed indication for SOFNEL FDC tablet is the treatment of
`chronic HCV infection in adults.
`
`2.1.3. What are the proposed dosagegs) and routegs) of administration?
`
`The proposed dose of SOFNEL is 400 mg/100 mg, taken orally, once daily with or without food.
`The proposed treatment regimen is based on patient population:
`0
`For patients without cirrhosis and patients with compensated cirrhosis the recommended
`treatment regimen is SOFNEL for 12 weeks.
`For patients with decompensated cirrhosis the recommended treatment regimen is
`SOFNEL +ribavirin for 12 weeks.
`
`0
`
`Reference ID: 3908046
`
`

`

`When administered with SOF/VEL the recommended dose of ribavirin is based on weight: 1000
`mg per day for patients less than 75 kg and 1200 mg for those weighing at least 75 kg, divided
`and administered twice daily with food.
`
`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 program of Phase 1 and Phase 2 studies characterized the PK of SOF/VEL,
`VEL, and SOF. Additionally, intensive and/or sparse plasma concentration data from 331
`healthy subjects and 1694 HCV-infected subjects who received SOF/VEL, VEL, or SOF from 11
`clinical studies (4 Phase 1, 3 Phase 2, and 4 Phase 3 studies) were used for population PK
`evaluations of VEL and SOF and its predominant circulating metabolite GS-331007, as
`appropriate.
`
`Dose Selection: SOF 400 mg is the approved marketed dose of SOF (Sovaldi®) for the
`treatment of HCV infection and, as such, was selected for coformulation with VEL in an FDC
`tablet for evaluation in the SOF/VEL development program.
`
`VEL:
`The Phase 1b Study GS-US-281-0102 evaluated the antiviral and safety activity of
`administration of VEL for 3 days at doses ranging from 5 to 150 mg in subjects with genotype 1,
`2, 3, or 4 HCV infection. The median maximal decline in HCV RNA across all HCV genotypes at
`all VEL doses evaluated was > 3 log10 IU/mL. The Phase 2 studies (Studies GS-US-342-0102,
`GS-US-342-0109, and GS-US-337-0122 [ELECTRON-2, Cohort 4]) evaluated the efficacy and
`safety of coadministration of SOF and VEL in subjects with genotype 1 to 6 HCV infection; 2
`treatment durations (8 and 12 weeks), 2 VEL doses (25 and 100 mg), and the contribution of
`RBV to efficacy and safety were assessed. Results of the Phase 2 studies indicated that a
`regimen of SOF 400 mg with VEL 100 mg for 12 weeks was well tolerated and resulted in the
`highest SVR12 rates in subjects with genotype 1 to 6 HCV infection including subjects with prior
`treatment failure and compensated cirrhosis, while a regimen of SOF 400 mg with VEL 25 mg
`for 12 weeks resulted in a lower SVR12 rate for treatment-experienced subjects with genotype 3
`(see Section 2.2.4.1 for detailed discussion).
`
`Phase 3 Clinical Efficacy and Safety Evaluation:
`
`The SOF/VEL Phase 3 clinical development program included four Phase 3 studies: GS-US-
`342-1138 (ASTRAL-1), GS-US-342-1139 (ASTRAL-2), GS-US-342-1140 (ASTRAL-3), and GS-
`US-342-1137 (ASTRAL-4).
`
`Study GS-US-342-1138 evaluated 12 weeks of SOF/VEL in subjects with chronic genotype 1, 2,
`4, 5, or 6 HCV infection; Study GS-US-342-1139 compared SOF/VEL with SOF+RBV for 12
`weeks in subjects with chronic genotype 2 HCV infection; Stu