CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208341Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
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`
`

`

`DiVision Director’s Review
`Debra Bimkrant. MD
`NDA 208341
`
`Epclusa (sofosbuvir and vclpatasvir)
`
`Decisional Review for NDA 208341
`
`
`From
`Debra Birnkrant, M.D.
`
`Subject
`Division Director’s Summary Review
`N DA#
`NDA 208341
`
`
`
`Gilead Sciences, Inc.
`Applicant Name
`Date of Submission
`October 28, 2015
`
`PDUFA Goal Date
`June 28, 2016
`Epclusa®
`Sofusbuvir SOF and veloatasvir VEL
`
`Proprietary Name I
`Established USAN Name
`
`Fixed dose combination tablet containing 400 mg
`Dosage Forms I Strength
`
`SOF and 100 mg VEL
`Treatment of adult patients with chronic hepatitis
`C virus infection
`
`
`Proposed lndication(s)
`
`Recommended Action
`
`Material Reviewed/Consulted
`Names of discipline reviewers
`
`OND Action Package, including:
`Medical Officer Review
`Drs. Prabha Viswanathan and Sarah Connelly
`
`supervised by Dr. Kim Struble
`Drs. Karen Qi and Thamban Valappil supervised
`by Dr. Dionne Price
`Pharmacology Toxicology
`Dr. John Dubinion supervised by Dr. Hanan
`
`Review
`Ghantous.
`
`Statistical Review
`
`A roval
`
`
`
`
`CMC Review
`
`Drs. Larry Bai, George Lunn, Sithamalli
`Chandramouli, and Ying Wang with Dr. Stephen
`
`Miller, CMC- Lead
`Drs. Lisa Naeger and Eric Donaldson supervised
`Microbiology Review
`
`by Dr. Jules O’Rear
`Drs. Jenny Zheng and Abhay Joshi supervised by
`Dr. Shirley Seo;
`Pharmacology/Pharmacometrics
`Review
`Dr. Fang Li supervised by Dr. Jeffry Florian
`
`
`Clinical
`
`DDMAC
`Kemi Asante, Pharm.D.
`
`OSI
`Dr. Antoine El Hage
`CDTL Review
`Dr. Kim Struble
`
`OSE/DMEPA
`OPM/DMPP
`OSE/DRISK
`
`Menica Calderén, PharmD, BCPS
`Morgan Walker, PharmD, MBA
`Erin Hachey, Pharm.D.
`
`Reference ID: 3947286
`
`
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OSI=Office of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`Reference ID: 3947286
`
`2
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
` Benefit-Risk Assessment
`1.
`I am in agreement with the benefit-risk assessment summarized in the multidisciplinary reviews of this NDA. I am also
`in agreement with the summary contained in the benefit-risk framework that contains an analysis of chronic hepatitis C
`viral infection, current treatment options, and the benefit, risk and risk management for the pangenotypic indication for
`SOF/VEL. My recommendation is for approval of NDA 208341 for the fixed-dose combination of SOF/VEL for the
`treatment of adult patients with chronic hepatitis C viral infection for genotypes 1-6 without cirrhosis or with
`compensated cirrhosis and for SOF/VEL/ribavirin (RBV) for the treatment of adult patients with chronic hepatitis C viral
`infection for genotypes 1-6 with decompensated cirrhosis.
`
`Benefit-Risk Summary and Assessment
`
`Sofosbuvir (SOF) is a hepatitis C virus (HCV) NS5B nucleotide analog polymerase inhibitor and velpatasvir (VEL) is an HCV NS5A inhibitor.
`SOF/VEL is a fixed-dose combination tablet with a proposed indication for treatment of patients with chronic HCV infection. Intended
`subpopulations include treatment-naïve (TN) and treatment-experienced (TE) patients and patients with compensated and decompensated
`cirrhosis.
`
`HCV infection is a serious disease, affecting an estimated 3-5 million people in the US and 170 million people worldwide
`(http://www.epidemic.org/theFacts/theEpidemic/worldPrevalence/). Although often asymptomatic in early stages, if untreated, chronic HCV can
`lead to debilitating and life-threatening liver problems, including hepatocellular carcinoma, liver failure, and death. Treatment options for chronic
`hepatitis C (CHC) have changed dramatically over the past 5 years as oral direct-acting antiviral (DAAs) agents have replaced interferon-based
`regimens, resulting in markedly improved efficacy rates. The standard measure of efficacy is the absence of detectable HCV RNA, termed
`sustained virologic response (SVR), documented 12 weeks after the end of treatment (SVR12); SVR12 is considered a virologic cure. Several
`DAA regimens were approved during this NDA review cycle that confer SVR12 rates greater than 93% for HCV genotype (GT) 1, 3, 4, 5, or 6-
`infected patients with compensated liver disease, defined as the absence of cirrhosis or compensated cirrhosis (Child Pugh Turcotte [CPT] A).
`The first approvals of DAA regimens in HCV GT 1 or 3-infected subjects with decompensated cirrhosis or liver transplant were also granted
`during this review cycle, with SVR12 rates ranging from 50-92% among HCV GT1 subjects and 83% for HCV GT3 subjects.
`
`While great progress has been made in improving SVR12 rates among patients with all stages of hepatic dysfunction, better treatment options
`for patients with non-GT1 HCV are needed, especially for HCV GT3. The need for better treatment options is even greater among subjects with
`decompensated cirrhosis regardless of HCV GT. SOF/VEL demonstrated SVR12 rates ranging from 83-100% depending on the Phase 3 trial
`regimen, HCV GT, cirrhosis stage, and prior treatment history. In addition, SOF/VEL is the first DAA regimen with potent activity across HCV
`GT 1, 2, 3, 4, 5 and 6. SOF/VEL is a highly effective, RBV-free, single tablet, once daily treatment option for TN and TE patients with
`compensated liver disease, regardless of HCV GT. Similarly, treatment with SOF/VEL + RBV confers the highest SVR12 rates observed to
`date across HCV GT 1-6 in subjects with decompensated cirrhosis.
`
`3
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Consistent with results from other development programs, HCV GT3- infected subjects with cirrhosis and/or prior treatment experience had only
`slightly lower SVR rates than subjects with any other HCV GT studied. SVR12 rates are 89% for HCV GT3 TE cirrhotic subjects, 91% for HCV
`GT3 cirrhotics and 90% for HCV GT3 TE subjects. The optimal strategy for improving the SVR12 rate in these GT3 subpopulations remains
`unclear. The Applicant has agreed to a PMR to obtain the results from Trial GS-US-342-2097 to assess the role of RBV in HCV GT3 infected
`subjects with cirrhosis.
`
`No major safety issues unique to SOF/VEL were identified in this review. The most frequent adverse drug reactions were headache, fatigue,
`and nausea. SOF has been associated with serious bradycardia when co-administered with amiodarone and another DAA; amiodarone
`treatment was prohibited in the four pivotal trials and no cases of serious bradycardia were observed. RBV is associated with common adverse
`reactions and serious risks, but these safety issues are well known and are not exacerbated by concomitant administration with SOF/VEL.
`
`Approval of SOF/VEL for treatment of adult patients with CHC infection is fully supported by the available evidence of efficacy and safety. The
`following regimens are recommended based on thorough analysis of efficacy, safety, and virology data overall, and in each subpopulation:
`(1) SOF/VEL for 12 weeks: Subjects with HCV GT 1, 2, 3, 4, 5, or 6 infection and without cirrhosis or with compensated cirrhosis
`(2) SOF/VEL + RBV for 12 weeks: Subjects with HCV GT 1, 2, 3, 4, 5, or 6 infection and decompensated cirrhosis
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Analysis of
`Condition
`
` Chronic infection with hepatitis C virus (HCV) causes inflammation of the
`liver that can lead to long-term health problems or death.
` Globally, an estimated 170 million people are infected with HCV, including
`approximately 3 to 5 million people in the United States (US) (Edlin, et al,
`Hepatology, 2015 .
` At least seven distinct HCV genotypes (GTs) exist. GT 1 is the most
`common among US patients (72%), followed by GT 2 (11%), GT 3 (9%),
`and GT 4 (6%). GTs 5 and 6 occur uncommonly (< 1%) in the US but may
`predominate in other parts of the world.
` HCV infection is typically asymptomatic in its early stages. However, if
`left untreated, HCV infection can lead to cirrhosis, hepatocellular
`carcinoma, liver failure, and death. HCV infection is a leading cause
`of chronic liver disease in the US.
`
`HCV monoinfection and HCV/HIV-1
`coinfection are a significant and growing
`public health concern. CDC reported an
`increase in new cases of hepatitis C in
`Appalachia and Scott County, Indiana related
`to injection drug use (CDC.gov).
`
`If untreated, chronic HCV infection is a life-
`threatening condition that affects a large
`population in the US and worldwide.
`Patients can experience symptoms that are
`severe and debilitating.
`
`4
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Once cirrhosis is established, complications such as jaundice, ascites,
`variceal hemorrhage, and encephalopathy may develop which
`defines decompensated cirrhosis, or end-stage liver disease. In
`patients with decompensated cirrhosis, the 5-year survival rate is
`approximately 50%.
` The current standard-of-care treatments for CHC are interferon-free, all-oral
`DAA regimens (AASLD Treatment Guidelines, April 2016). Treatment
`options vary based on HCV GT:
`o GT1: ledipasvir/sofosbuvir; elbasvir/grazoprevir;
`paritaprevir/ombitasvir/ritonavir + dasabuvir; daclatasvir +
`sofosbuvir; and simeprevir + sofosbuvir
`o GT2: sofosbuvir + ribavirin
`o GT3: daclatasvir + sofosbuvir; sofosbuvir + ribavirin
`o GT4: ledipasvir/sofosbuvir; elbasvir/grazoprevir; ombitasvir/
`paritaprevir/ritonavir + RBV
`o GT5: ledipasvir/sofosbuvir
`o GT6: ledipasvir/sofosbuvir
` Treatment with DAAs can result in sustained virologic response determined
`12 weeks after the end of treatment (SVR12), considered a virologic cure, in
`greater than 93% of CHC patients with compensated liver disease. However,
`SVR12 rates were lower for certain subpopulations, and some of these
`regimens require the addition of RBV or longer treatment durations for
`subjects with cirrhosis and/or prior treatment failure.
` During this NDA review cycle, two regimens were approved for treatment of
`HCV GT 1 or GT 3-infected subjects with decompensated cirrhosis (Child-
`Pugh-Turcotte [CPT] score B or C) or liver transplant:
`o Treatment with ledipasvir/sofosbuvir + RBV for 12 weeks resulted
`in SVR12 rates of 87-88% among GT1-infected pre-transplant
`subjects with decompensated cirrhosis and SVR12 rates of 89%
`and 57% for post-transplant CPT B and C subjects, respectively.
`o Treatment with daclatasvir + sofosbuvir + RBV for 12 weeks
`resulted in SVR12 rates 92% for CPT B subjects and 50% of CPT
`
`Patients with chronic HCV infection would
`greatly benefit from new therapeutic options
`that are well tolerated and equally or more
`efficacious than current interferon-free DAA
`options.
`
`Only one approved regimen for subjects with
`GT 2, 5 and 6 HCV is available. These
`subjects would benefit from a treatment
`alternative.
`
`RBV-free regimens with shorter treatment
`durations (< 16 weeks) are needed for
`populations that are traditionally harder to
`treat; such regimens may improve treatment
`adherence and minimize safety and
`tolerability issues associated with RBV.
`
`DAA regimens for subjects with
`decompensated cirrhosis, particularly for
`those infected with HCV GT 2, 4, 5, or 6 is an
`unmet medical need population because no
`approved regimens are available.
`
`5
`
`Current
`Treatment
`Options
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`C subjects with GT1; 83% of subjects with GT3 achieved SVR12.
` At the time of this review, no DAA regimens are approved for patients
`with decompensated cirrhosis and HCV GT 2, 4, 5, or 6 infection.
`
` The efficacy of SOF/VEL was established in four Phase 3 clinical trials
`which cumulatively evaluated 1302 subjects in the SOF/VEL treatment
`arms. The trial populations varied based on HCV GT and cirrhosis
`status.
`o ASTRAL-1: TN and TE subjects with compensated liver
`disease and HCV GT 1, 2, 4, 5, or 6. Subjects received
`SOF/VEL x 12 weeks or placebo x 12 weeks.
`o ASTRAL-2: TN and TE subjects with compensated liver
`disease and HCV GT2. Subjects received SOF/VEL x 12
`weeks or SOF + RBV x 12 weeks.
`o ASTRAL-3: TN and TE subjects with compensated liver
`disease and HCV GT3. Subjects received SOF/VEL x 12
`weeks or SOF + RBV x 24 weeks.
`o ASTRAL-4: TN and TE subjects with decompensated liver
`disease (CPT B at screening) with HCV GT 1-6. Subjects
`received SOF/VEL x 12 weeks, SOF/VEL+RBV x 12 weeks,
`or SOF/VEL x 24 weeks
` The primary efficacy endpoint was SVR12, or virologic cure. As displayed in
`the tables below, SVR12 results for SOF/VEL for 12 weeks in HCV GT 1,
`2, 3, 4, 5, and 6 subjects without cirrhosis or with compensated cirrhosis
`were 95-100%. The SVR12 rates for SOF/VEL+RBV for 12 weeks in HCV
`GT 1, 2, 3, and 4 subjects with decompensated cirrhosis were 85-100%.
`
`Benefit
`
`Four clinical trials provide substantial
`evidence of effectiveness of SOF/VEL for
`treatment of CHC GT1-6.
` The recommended regimen for subjects
`with compensated liver disease is
`SOF/VEL for 12 weeks irrespective of
`HCV GT or prior treatment experience.
` The recommended regimen for subjects
`with decompensated cirrhosis is
`SOF/VEL + RBV for 12 weeks,
`irrespective of HCV GT or prior treatment
`status.
`
`The lower SVR12 rates observed among GT
`3 subjects, particularly those with cirrhosis,
`merit consideration of the utility of adding
`RBV to optimize treatment success. A PMR
`is recommended to obtain the results from
`Trial GS-US-342-2097 to assess the role of
`RBV in HCV GT 3 infected subjects with
`cirrhosis.
`
`SOF/VEL fills an important unmet medical
`need for a 12 week, RBV-free regimen for
`subjects with GT 1-6 infection and
`compensated liver disease, irrespective of
`prior treatment status.
`
`6
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Pooled Analysis of ASTRAL-1, ASTRAL-2, and ASTRAL-3: SVR12 by HCV
`GT Among Subjects Treated with SOF/VEL Subjects for 12 Weeks n (%)
`GT1
`GT2
`GT3
`GT4
`GT5
`GT6
`Total
`323/328
`237/238
`264/277
`116/116
`34/35
`41/41
`1015/1035
`(99%)
`(100%)
`(97%)
`(100%)
`(98%)
`(99%)
`(95%)
`
`SOF/VEL + RBV fills an important unmet
`medical need for subjects with
`decompensated cirrhosis who have few or no
`treatment options.
`
`ASTRAL-4: SVR12 by Treatment Arm and HCV GT n (%)
`GT1
`GT2
`GT3
`GT4
`GT6
`60/68
`4/4
`7/14
`4/4
`-
`(88%)
`(100%)
`(50%)
`(100%)
`65/68
`4/4
`11/13
`2/2
`(96%)
`(100%)
`(85%)
`(100%)
`
`-
`
`SOF/ VEL
` x 12 wks
`SOF/
`VEL+RBV x
`12 wks
`6/12
`3/4
`65/71
`SOF/ VEL
`(50%)
`(75%)
`(92%)
`x 24 wks
`No GT5 subjects were enrolled in ASTRAL-4
`
`2/2
`(100%)
`
`1/1
`(100%)
`
`Total
`75/90
`(83%)
`82/87
`(94%)
`
`77/90
`(86%)
`
` SVR12 rates were comparable across GT with the exception of GT3;
`subjects with GT 3 in ASTRAL-3 and ASTRAL-4 had higher rates of
`virologic failure relative to other GTs. Subgroup analyses demonstrated
`cirrhosis, prior treatment failure, and the presence of baseline NS5A
`resistance-associated polymorphisms were associated with numerically
`higher rates of treatment failure.
` Overall, demographic factors did not impact SVR12 rates.
` The safety database for SOF/VEL includes 1302 subjects from the four
`aforementioned clinical trials and is considered adequate.
` ASTRAL-1 included a placebo-controlled comparison for safety with
`deferred treatment in subjects who were randomized to placebo.
` Additional safety data included subjects who received SOF/VEL at
`doses of at least SOF 400 mg and VEL 25 mg in Phase 2 trials.
` No major safety issues were identified during this review.
`
`Risk
`
`SOF/VEL with or without RBV demonstrated
`an overall favorable safety profile.
`
`The safety issues with RBV are well known
`and are not exacerbated by SOF/VEL.
`
`7
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` Headache, fatigue, and nausea were the three most commonly
`reported adverse drug reactions reported across trials.
` Subjects who received RBV with SOF/VEL experienced higher rates of
`RBV-associated adverse events, at rates consistent with prior HCV
`DAA trials.
` Although no significant safety signals were detected in this review, the
`SOF/VEL prescribing information will include safety information
`contained in the current SOF label, even if the events occurred rarely
`in the SOF/VEL trials:
`o Though no cases were reported in the Phase 3 SOF/VEL
`trials, Section 5 of the SOF/VEL label will include a warning
`regarding the risk of serious symptomatic bradycardia related
`to co-administration of sofosbuvir with amiodarone and
`another DAA.
`o Rash and depression are recommended for inclusion in
`Section 6 of the SOF/VEL label.
` Section 5 will also include a warning regarding risks associated with
`RBV therapy.
`
`Risk
`Management
`
`Safety concerns associated with SOF or
`RBV are adequately addressed in product
`labeling.
`
`Reference ID: 3947286
`
`8
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`This Division Director’s memorandum provides a topline summary of NDA 208341 for
`Gilead Sciences, Inc.’s New Drug Application (NDA) for the fixed-dose combination of
`of two direct-acting antivirals (DAAs), sofosbuvir (SOF), a nucleotide analog NS5B
`polymerase inhibitor and velpatasavir (VEL) a hepatitis C virus (HCV) NS5A inhibitor
`indicated for the treatment of adults with genotypes 1- 6 chronic hepatitis C viral
`infection. This decisional review summarizes pertinent findings from the NDA
`submission, FDA’s multidisciplinary reviews, and product labeling.
`
`2. Background
`Chronic hepatitis C (CHC) viral infection remains a public health challenge despite
`recent approvals of highly potent direct-acting antivirals. CHC affects millions
`domestically of whom almost 50% are unaware of their infection (Yehia, et al, PLoS
`One, 2014). Recent death rate estimates with hepatitis C as an underlying or
`contributing cause have surpassed those related to 60 nationally notifiable infections
`reported to CDC (LY, et al, CID, 2016).
`
`Hepatitis C virus is classified into at least seven distinct genotypes and many
`subtypes. Hepatitis C genotype 1 is responsible for approximately 70-75% of HCV
`infections domestically; whereas GT 2 comprises approximately 11%, GT 3, 9%, and
`GT 4, 6% of infections. GTs 5 and 6 occur uncommonly (< 1%) in the US but
`predominate in other parts of the world. (Gower et al, J. Hepatology, 2014; Messina et
`al, Hepatology, 2015).
`Sustained virologic response (SVR), a measure of virologic cure used as an endpoint
`in clinical trials and in clinical practice is a validated surrogate endpoint that is
`measured 12 weeks after treatment. SVR correlates with clinically important
`outcomes such as histologic benefit, a decrease in all-cause and liver-related
`mortality, and decreases in rates of HCC and hepatic decompensation (Backus, et al,
`Clin. Gastroenterol Hepatol 2011; Singal, et al, Clin Gastroenterol Hepatol, 2010; van
`der Meer, et al JAMA, 2012; Veldt, et al, Ann Intern Med, 2007; Mishra, et al,
`Hepatology, 2015).
`
`Treatment of CHC has improved over the years, especially with the approval of potent
`direct-acting antivirals (DAA). Treatment regimens are well tolerated and yield cure
`rates of at least 90% for most genotypes with 8-12 week interferon-free regimens.
`See table 1 excerpted from the clinical NDA review:
`
`Page 9 of 31
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Table 1. Summary of Approved Interferon-Free Treatments for Chronic HCV
`Infection
`Product (s)
`Name
`Elbas ir and
`grazoprevir
`(Zepatier®)
`
`Product
`Class
`NS5A
`inhibitor,
`NS3/4A
`protease
`inhibitor (PI)
`
`Year of
`HCV
`Approval
`GT
`1, 4 2016
`
` Efficacy
`Information
`SVR 94-
`97%
`
`Dosing/
`Administration
`1 tablet orally
`once daily with
`or without RBV
`for 12 or 16
`weeks
`
`Ombitasvir,
`paritaprevir
`and ritonavir
`(Technivie®)
`
`NS5A
`inhibitor,
`NS3/4A PI,
`PK
`enhancer
`
`Daclatasvir
`
`(Daklinza®)
`
`NS5A
`inhibitor
`
`4
`
`2015
`
`2 tablets orally
`once daily with
`RBV for 12
`weeks
`
`SVR
`100%
`
`1, 3 2015
`
`SVR 82-
`97%
`
`SVR 93-
`99%
`
`SVR 95-
`99%
`
`1 tablet orally
`with sofosbuvir
`and with or
`without RBV for
`12 weeks
`1 tablet orally
`once daily with
`or without RBV
`for 8, 12, or 24
`weeks
`
`2 FDC tablets
`once daily + 1
`dasabuvir tablet
`twice daily (+/-
`RBV) for 12 or
`24 weeks
`
`Important Safety and
`Tolerability Issues
`Contraindicated for
`patients with
`decompensated liver
`disease; Risk of ALT
`elevations in all
`patients
`Hepatic
`decompensation and
`hepatic failure in
`cirrhotics; ALT
`elevation in all
`patients
`No serious drug-
`specific toxicity
`identified
`
`Serious symptomatic
`bradycardia when
`coadministered with
`amiodarone and
`another DAA
`(daclatasvir, ledipasvir
`or simeprevir)
`Contraindicated for
`patients with
`decompensated liver
`disease; Risk of ALT
`elevations in all
`patients
`
`Serious symptomatic
`bradycardia when
`coadministered with
`amiodarone and
`another DAA
`(daclatasvir, ledipasvir
`or simeprevir)
`Hepatic
`decompensation and
`hepatic failure;
`photosensitivity; rash
`
`Ledipasvir
`and
`sofosbuvir
`
`(Harvoni®)
`
`NS5A
`inhibitor/
`NS5B
`inhibitor
`(nucleotide)
`
`2014
`
`1,
`4,
`5, 6
`
`1
`
`2014
`
`Dasabuvir,
`ombitasvir,
`paritaprevir
`and ritonavir
`(Viekira
`Pak®)
`Sofosbuvir*
`
`(Sovaldi®)
`
`NS5B
`inhibitor
`(non-
`nucleoside),
`NS5A
`inhibitor,
`NS3/4A PI
`NS5B
`inhibitor
`(nucleotide)
`
`2, 3 2013 One tablet
`orally once daily
`with RBV for 12
`or 24 weeks
`
`SVR 82-
`95%
`
`NS3/4 PI
`
`1
`
`2013
`
`Simeprevir
`
`(Olysio®)
`
`*Excludes FDC containing sofosbuvir
`
`1 capsule orally
`once daily (with
`sofosbuvir) for
`12 or 24 weeks
`
`SVR 93-
`97%
`
`Page 10 of 31
`
`Reference ID: 3947286
`
`

`

`DiVision Director’s Review
`Debra Bimkrant. MD
`NDA 208341
`
`Epclusa (sofosbuvir and vclpatasvir)
`
`SOF was first approved for GTs 2 and 3 with ribavirin in 2013. More recently, SOF in
`a FDC with ledipasavir (LDV) as Harvoni, with or without ribavirin was approved for
`GT3 1, 4, 5 and 6 in 2014. SOFNEL is a FDC that was studied in four phase 3 clinical
`trials, ASTRAL 1-4 in multiple patient populations. SOF is a nucleotide analog inhibitor
`of HCV NSSB polymerase and VEL is a NS5A inhibitor. The pangenotypic
`combination received fast track designation on September 30, 2013. Breakthrough
`Therapy Designation was originally granted April 22, 2014 for SOFNEL FDC
`treatment of chronic HCV GT 1, 3, 4, 5, and 6 infection in TN patients. However, due
`to the approval and availability of other safe and effective therapies to treat HCV GT 1
`infection, the Agency rescinded Breakthrough Therapy Designation April 1, 2015, and
`the Applicant submitted a new request for Breakthrough Therapy for the treatment of
`GT3 3, 4, 5, and 6 infection in TN patients. This request was granted May 15, 2015.
`
`Per Dr. El-Hage, Office of Scientific Investigations (OSI), FDA inspected eight clinical
`sites, both domestic and foreign. Two sites were selected from each phase 3 clinical
`trial based on enrollment, number of protocol deviations, or results that were
`dissimilar from overall trends. Based on the inspection findings, the data generated
`were found to be reliable and acceptable in support of this application.
`
`The application was not presented before the Antimicrobial Drugs Advisory
`Committee because a preliminary review of the NDA, including labeling did not reveal
`any significant clinical or safety issues that would benefit from an advisory committee
`discussion. In addition, SOF was previously approved and VEL is the fifth NS5A
`inhibitor in its class.
`
`3. CMC
`
`CMC reviewers were Dr. Larry Bai, Dr. George Lunn, Dr. Sithamalli Chandramouli,
`and Dr. Ying Wang; Dr. Stephen Miller served as CMC Lead. The CMC team
`reviewed data to assure the identity, strength, purity, and quality of SOFNEL. The
`commercial product is an immediate-release FDC containing SOF 400 mg and VEL
`100 mg.
`mu)
`
`Long-term and accelerated stability data demonstrate that the packaging is
`appropriate to maintain the quality of the drug product.
`
`An overall recommendation of Acceptable has been made by the Office of Process
`and Facilities. Therefore, from a CMC perspective, NDA 208341 is recommended for
`approval.
`
`4. Nonclinical Pharmacology/Toxicology
`Please see review of submitted nonclinical toxicology studies by Dr. John Dubinion,
`supervised by Dr. Hanan Ghantous. Nonclinical SOF safety studies to support the
`SOFNEL FDC were reviewed previously: please refer to the
`
`Page 11 of3l
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Pharmacology/Toxicology reviews for NDA 204671 and NDA 205834 for detailed
`summary of SOF nonclinical data.
`Per Dr. Dubinion’s review, the nonclinical safety profile of VEL has been satisfactorily
`evaluated in the following studies: safety pharmacology, PK/ADME, single-dose and
`repeat-dose toxicity, phototoxicity, genotoxicity, and reproductive toxicity. No
`significant safety pharmacology signals were detected in studies evaluating
`cardiotoxicity (including effects on the hERG channel), CNS toxicity, and respiratory
`toxicity. No clear target organs of toxicity were identified in repeat-dose toxicology
`studies in mice, rats, and dogs administered VEL doses up to 1500, 200, and 100
`mg/kg/day for 1, 6 and 9 months, respectively. Specifications for impurities were
`deemed acceptable, see review by Dr. Mark Powley.
`
`VEL was rapidly eliminated from most tissues and mainly excreted in the bile within
`24 hours, except from the eye which maintained VEL exposure at 168 hours
`postdose. Additional studies in rats and rabbits suggested VEL was not an ocular
`irritant. Several minor metabolites were identified; however, unchanged parent drug
`was the predominant circulating component (in mice, rats, dogs, and human subjects)
`as well as the primary drug component in feces.
`
`Per Dr. Dubinion’s review, VEL was not genotoxic in standard testing. Further, VEL
`had no effects on reproduction or development in multiple species. Carcinogenicity
`studies in rats and transgenic mice are ongoing.
`
`There are no adequate and well-controlled trials of SOF/VEL in pregnant women to
`inform a drug-associated risk. Therefore, the benefits and risks of SOF/VEL should be
`considered when prescribing SOF/VEL to a pregnant woman.
`
`5. Clinical Pharmacology
`Drs. Jenny Zheng and Fang Li reviewed dedicated in vitro and clinical pharmacology
`trials that were conducted in healthy volunteers and HCV-infected subjects to
`characterize the pharmacokinetics (PK) of SOF, its principal metabolite, GS-331007
`and VEL. The following table from their review characterizes the absorption,
`distribution, metabolism, and excretion (ADME) of the components of SOF/VEL.
`
`Page 12 of 31
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`Table 2. ADME Components of SOF/VEL
`Sofosbuvir
`
`Absorption
`0.5-1
`Tmax (h)
`Effect of moderate meal (relative to fasting)a ↑ 60%
`Effect of high fat meal (relative to fasting)a
`↑ 78%
`Distribution
`% Bound to human plasma proteins
`Blood-to-plasma ratio
`Metabolism
`Metabolism
`
`61-65%
`0.7
`
`Cathepsin A
`CES1
`HINT1
`
`Velpatasvir
`
`3
`↑ 34%
`↑ 21%
`
`>99.5%
`0.52-0.67
`
`CYP2B6 (minor)
`CYP2C8 (minor)
`CYP3A4 (minor)
`
`Elimination
`Major route of elimination
`
`t1/2 (h)c
`
`Biliary excretion as parent
`(77%)
`
`SOF: metabolism
`GS-331007b: glomerular
`filtration and active tubular
`secretion
`SOF: 0.5
`15
`GS-331007b: 25
`0.4%
`80%e
`% Of dose excreted in urined
`94%
`14%
`% Of dose excreted in fecesd
`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. SOF/VEL can be taken with or without food.
`b GS-331007 is the primary circulating nucleoside metabolite of SOF.
`c t1/2 values refer to median terminal plasma half-life.
`d Single dose administration of [14C] SOF or [14C] VEL in mass balance studies.
`e Predominantly as GS-331007.
`
`Dose exploration for SOF had been previously conducted and SOF 400 mg is the
`marketed dose. VEL dose selection was based on a phase 1b Study GS-US-281-
`0102 that evaluated the antiviral activity and safety of VEL for 3 days at doses ranging
`from 5 to 150 mg in subjects with GTs 1, 2, 3, or 4 HCV viral infection. The median
`maximal decline in HCV RNA across all HCV genotypes at all VEL doses evaluated
`was > 3 log10 IU/mL. 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/VEL in subjects with GTs 1 to 6 HCV viral infection. Two
`treatment durations (8 and 12 weeks), two VEL doses (25 and 100 mg), and the
`contribution of RBV to efficacy and safety were also assessed. 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 compared to regimen with VEL at 100 mg (71%
`compared to 94%).
`
`Page 13 of 31
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`No exposure-response relationships for safety were identified for either of the
`components of SOF/VEL at the recommended dosage. Neither SOF nor VEL
`prolonged the QTc to a clinically relevant extent at a dose three times the maximum
`recommended dose for SOF and five times the maximum recommended dose for
`VEL. Please see the review conducted by Interdisciplinary Review Team for QT
`Studies Consultation (IND 115670 dated 4/15/2015) for details.
`
`Other pertinent PK data include the following and appear in product labeling:
` - No dosage adjustment of SOF/VEL is required for patients with mild or moderate
`renal impairment, however 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. Healthcare providers are referred to
`ribavirin prescribing information regarding use of ribavirin in patients with renal
`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), however
`clinical and hepatic laboratory monitoring (including direct bilirubin), as clinically
`indicated, is recommended for patients with decompensated cirrhosis receiving
`treatment with SOF/VEL and ribavirin.
`
`- SOF/VEL can be dosed without regard to food.
`- Based on population pharmacokinetic analyses in HCV-infected subjects, gender
`had no clinically relevant effect on exposure of SOF, GS-331007 or VEL.
`- Population pharmacokinetics analysis in HCV-infected subjects indicated that race
`had no clinically relevant effect on the exposure of SOF, GS-331007 or VEL.
`- Population pharmacokinetic analysis in HCV-infected subjects showed that within
`the age range (18 to 82 years) analyzed, age did not have a clinically relevant effect
`on exposure of SOF, GS-331007 or VEL.
`
`SOF and VEL are substrates of drug transporters P-gp and BCRP. In vitro, slow
`metabolic turnover of VEL by CYP2B6, CYP2C8, and CYP3A4 was also observed.
`Drugs that are inducers of P-gp and/or moderate to potent inducers of CYP2B6,
`CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamazepine) may decrease
`plasma concentrations of SOF/VEL leading to reduced therapeutic effect. The use of
`these agents with SOF/VEL is not recommended in labeling[see Warnings and
`Precautions (5.2), Drug Interactions (7) and Clinical Pharmacology (12.3)]; however,
`SOF/VEL may be coadministered with P-gp, BCRP, and CYP inhibitors.
`
`Page 14 of 31
`
`Reference ID: 3947286
`
`

`

`Division Director’s Review
`Debra Birnkrant, MD
`NDA 208341
`Epclusa (sofosbuvir and velpatasvir)
`
`There is also potential for SOF/VEL to affect other drugs. Labeling contains wording
`that VEL is an inhibitor of drug transport