CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208341Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`June 1, 2016
`Date
`
`From
`Kimberly Struble, PharmD
`
`Subject
`Cross-Discipline Team Leader Review
`
`NDAIBLA #
`208341
`A -
`. licant
`Gilead Sciences
`
`Date of Submission
`PDUFA Goal Date
`
`October 28, 2015
`June 28, 2016
`
`Epclusa [(sofosbuvir (SOF) and velpatasvir (VEL)]
`Proprietary Name I Non-
`
`Proprietary Name
`
`Fixed dose combination tablet containing 400 mg
`Dosage form(s) I Strength(s)
`sofosbuvir and 100 mg velpatasvir
`Treatment of adult patients with chronic hepatitis C virus
`infection
`
`Applicant Proposed
`Indication 5 [Po ulation 5
`
`
`
`Recommendation on
`Re ulato Action
`
`Approval
`
`Recommended
`
`lndication(s)lPopuIation(s) (if
`applicable)
`
`SOFNEL: Treatment of adult patients with chronic
`hepatitis C virus genotype 1, 2, 3, 4, 5 and 6 infection
`without cirrhosis or with compensated cirrhosis
`SOFNEL/ribavirin (RBV): Treatment of adult patients with
`chronic hepatitis C virus genotype 1, 2, 3, 4, 5 and 6
`infection with decom ensated cirrhosis
`
`1 .
`
`Benefit-Risk Assessment
`
`I am in agreement with the Risk-Benefit Assessment as provided in the Clinical Review by Dr.
`Prabha Viswanathan and Dr. Sarah Connelly; therefore this section closely mirrors that found in
`the Clinical Review with the exception of relatively minor revisions that do not substantively
`impact the overall risk-benefit assessment.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9. 2015. For initial rollout (NMEl‘original BLA reviews)
`
`1
`
`Reference ID: 3939476
`
`

`

`Cross Discipline Team Leader Review
`
`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 dates observed to
`date across HCV GT 1-6 in subjects with decompensated cirrhosis.
`
`Consistent with results from other development programs, HCV GT3- infected subjects with cirrhosis and/or prior treatment experience had
`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 SVR12 rate in these GT3 subpopulations remains unclear. A
`PMR is recommended 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:
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 3939476
`
`2
`
`

`

`Cross Discipline Team Leader Review
`(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).
` 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
` 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. 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
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Current
`Treatment
`Options
`
`HCV infection is a significant and growing
`public health concern. If untreated, chronic
`HCV infection is a life-threatening condition,
`one that affects a large population in the US
`and worldwide. Patients can experience
`symptoms that are severe and debilitating.
`
`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
`GT2, 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
`
`3
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`Reference ID: 3939476
`
`

`

`Cross Discipline Team Leader Review
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`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
`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
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Benefit
`
`Reference ID: 3939476
`
`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.
`
`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
`GT3 subjects, particularly those with
`cirrhosis, merit consideration of 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 GT3 infected subjects
`with cirrhosis.
`
`4
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`

`

`Cross Discipline Team Leader Review
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`GT 1, 2, 3, and 4 subjects with decompensated cirrhosis was 85-100%.
`
`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 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.
`
`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%)
`
`SOF/VEL + RBV fills an important unmet
`medical need for subjects with
`decompensated cirrhosis who have few or no
`treatment options.
`
`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.
` 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
`
`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.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 3939476
`
`5
`
`

`

`Cross Discipline Team Leader Review
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`RBV-associated adverse events, at rates consistent with prior HCV
`DAA trials.
`
`Risk
`Management
`
` 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.
`
`Safety concerns associated with SOF or
`RBV are adequately addressed in product
`labeling.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`Reference ID: 3939476
`
`6
`
`

`

`Cross Discipline Team Leader Review
`
`2.
`
`Background
`
`Chronic hepatitis C virus (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 to
`5 million people have chronic HCV infection
`(http://www.epidemic.org/theFacts/theEpidemic/worldPrevalence/).
`
`The majority of cases of chronic HCV infection in the United States are HCV genotype (GT) 1
`(70-75%, predominately GT 1a). Approximately 20% are infected with HCV GT 2 or 3,
`approximately 5% with HCV GT 4, and less than 1% with HCV GT 5 or 6.
`
`The treatment of HCV infection has rapidly evolved since the approval of the first direct acting
`agents (DAAs) in 2011, boceprevir and telaprevir, both NS3/4A protease inhibitors, followed by
`the approvals of simeprevir (NS3/4A protease inhibitor) and sofosbuvir, an NS5B nucleotide
`analog polymerase inhibitor, in 2013. Boceprevir, telaprevir, sofosbuvir and simeprevir required
`the use of interferon (IFN) and ribavirin (RBV) for HCV GT1. Since 2013 several other
`interferon-free DAA regimens were approved for GTs 1-6, many of which offer SVR12 rates in
`excess of 90% for most GTs and exceeding 95% for certain populations and GTs.
`Recommended regimens for CHC treatment for all GTs no longer require the use of IFN;
`however, RBV is still recommended for certain GTs or subpopulations.
`Approved interferon-free regimens for specific GTs include:
` Sofosbuvir/ledipasvir (GT 1,4,5,6)
` Sofosbuvir+daclatasvir (GT 1,3)
` Sofosbuvir+simeprevir (GT 1)
` Sofosbuvir+ribavirin (GT 2,3)
` Dasabuvir, ombitasvir, paritaprevir/ritonavir (GT1)
` Ombitasvir, paritaprevir/ritonavir (GT4)
` Elbasvir/grazoprevir (GT1,4)
`
`This New Drug Application (NDA), submitted by Gilead Sciences, contains information to
`support the approval of Epclusa, an interferon-free, complete regimen proposed for the
`treatment of chronic HCV infection GTs 1, 2, 3, 4, 5, and 6 in adults. Epclusa is comprised of
`sofosbuvir (SOF), an NS5B nucleotide analog polymerase inhibitor, and velpatasvir (VEL), an
`HCV NS5A inhibitor, coformulated as a fixed dose combination (FDC) tablet and administered
`with or without RBV. SOF is an approved product and if approved VEL would represent the 5th
`approved HCV NS5A inhibitor to date.
`
`The regulatory history was also notable for fast track designation for HCV GT 1, 2, 3, 4, 5 and 6
`in September 2013. Breakthrough designation was granted in April 2014 for HCV GT 1, 3, 4, 5,
`and 6 infection in treatment-naïve (TN) patients. The Breakthrough Therapy Designation was
`rescinded on April 1, 2015 due to approval of treatment regimens demonstrating high SVR rates
`and favorable safety profiles for HCV GT 1 infection. A new Breakthrough Therapy Designation
`was granted in May 2015 for HCV GT 3, 4, 5 and 6 infection in TN patients.
`
`This NDA received a priority review under PDUFA V and was not presented at the Antimicrobial
`Advisory Committee because SOF/VEL received breakthrough designation and the benefit/risk
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`7
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`Reference ID: 3939476
`
`

`

`Cross Discipline Team Leader Review
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`assessment did not appear controversial based on the review team’s preliminary assessment of
`the top line trial results.
`
`SOF/VEL 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 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". 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) monotherapy and dose ranging trial results for
`VEL, (2) the comparison of SVR rates between SOF+IFN+RBV or SOF+RBV and SOF/VEL and
`(3) the approval of SOF 400 mg QD as part of a combination regimen for HCV GT 1 subjects
`(NDA 204671).
`
`VEL monotherapy and dose ranging
`
`
` VEL proof-of-concept was established in a 3-day dose-ranging monotherapy trial in HCV
`GT1, 2, 3 and 4 infection evaluating VEL doses 5 to 150 mg once daily. The median
`maximal decline in HCV RNA across all HCV GTs for all VEL doses evaluated was
`greater than 3 log10 IU/mL.
` The Phase 2 trials (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 HCV GT 1 to 6 infection. Based on results from the 8 week and
`12 week regimens, a duration response was observed. Therefore, the 12 week regimen
`was considered the preferred regimen for all genotypes for the Phase 3 trials.
`
`Specifically, two treatment durations (8 and 12 weeks), two VEL doses (25 and 100 mg),
`and the contribution of RBV to efficacy and safety were evaluated in GS-US-342-0102.
`o Treatment groups 7-14 evaluated SOF/VEL with or without RBV for 8 weeks in
`HCV GT 1 and 2 infected subjects. SVR12 rates in this group ranged from 77%
`to 89%.
`o In contrast, the 12 week regimens resulted in higher SVR12 rates compared to
`the 8 week regimens. The SVR12 rates were 91-96% for HCV GT 1 and GT2,
`93% for HCV GT3, 88-100% for HCV GT4, and 100% for HCV GT 5 and 6.
`
`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
`
`8
`
`Reference ID: 3939476
`
`

`

`Cross Discipline Team Leader Review
`
` Trial GS-US-342-0109 evaluated SOF/VEL 400/25 mg and SOF/VEL 400/100 mg with
`or without RBV, administered for 12 weeks in HCV GT 1 and 3 treatment-experienced
`(TE) subjects with or without cirrhosis. Results from Trial GS-US-342-0109 show a dose
`response in HCV GT 3 subjects. Therefore, the 100 mg VEL dose was selected for the
`Phase 3 trials.
`o For HCV GT 3 subjects, SVR12 rates were higher for the groups treated with
`100mg VEL, regardless of RBV.
`o For cirrhotics and noncirrhotics combined the SVR12 was 71% for the 25 mg
`VEL group without RBV (37/52) and 96% for the 100mg VEL group without RBV
`(50/52).
`
`
`Overall, the Phase 2 data show the contribution of VEL to the regimen via dose response (GT3
`SOF/VEL 400/25 mg vs 400/100 mg in TE subjects) and duration response (8 vs 12 weeks).
`The Phase 2 data were used to select one dosage regimen (SOF/VEL 400/100 mg) and one
`duration (12 weeks) for all HCV GTs.
`
`SVR rates for SOF-containing regimens
`
` The SVR rate for SOF + IFN and RBV for 12 weeks in HCV GT 1 TN subjects is 90%. In
`comparison, the SVR rate for VEL/SOF for 12 weeks in TN and TE HCV GT 1 subjects
`in the ASTRAL-1 trial is 98%.
` The SVR rates for SOF/RBV for 12 weeks in HCV GT 2 TN + TE subjects range from
`82-95% and the SVR rates for SOF/RBV for 24 weeks in HCV GT3 TN + TE subjects
`with SOF/RBV is 84%. In comparison the SVR rate for SOF/VEL for 12 weeks in HCV
`GT2 and GT3 TN + TE subjects is 99-100% and 95%, respectively.
`
`Collectively these data (monotherapy, dose ranging and Phase 3 cross-trial comparison results)
`show the contribution of VEL to the SOF/VEL FDC and satisfy 21 CFR 300.50. Based on cross
`trial comparison, SVR rates are numerically improved when VEL is combined with SOF
`compared to SOF+IFN and RBV or SOF+RBV and eliminates the need for an IFN and RBV
`based regimen.
`
`This cross-discipline team leader review presents the major findings from the NDA review. For
`a more comprehensive assessment, please refer to the specific discipline reviews.
`
`Product Quality
`3.
`At this time evaluation of all manufacturing facilities is not complete. Additionally, the
`acceptance criteria for VEL impurities in the drug substance and product specifications were
`under discussion with Gilead when the initial review was finalized. That issue was resolved with
`the April 6, 2016 amendment. The recommendation from the Product Quality perspective is
`PENDING at this time because of the on-going final inspection (May 16-20, 2016).
`
`•
`
`General product quality considerations
`
`SOF/VEL is for oral administration and each tablet contains 400 mg of SOF and 100 mg of VEL.
`
`According to the product quality reviewers, Dr. George Lunn and Mouli Chandramouli, the data
`presented in the NDA and amendments are adequate to assure composition, manufacturing
`process, and specifications for SOF/VEL FDC are appropriate, with the exception of the ongoing
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`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
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`review discussion about drug substance and drug product specifications for VEL impurity
`acceptance criteria. 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. Ying Wang. The proposed labeling is adequate pending minor revisions. Adequate data
`were provided to support the discriminating ability of the dissolution method. The dissolution
`method and dissolution acceptance criteria, as amended, were found to be acceptable for both
`SOF and VEL by Dr. Ge Bai.
`
`•
`
`Facilities review/inspection
`
`The facilities review and inspections are pending.
`
`4.
`
`Nonclinical Pharmacology/Toxicology
`
`The nonclinical pharmacology/toxicology evaluation of SOF was conducted during the review for
`NDA 204671. Please refer to previous reviews and SOF product labeling for details. This review
`focuses on the nonclinical evaluation of VEL. The nonclinical evaluation includes over 58
`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. John Dubinion recommended approval for this NDA based on
`the nonclinical pharmacology/toxicology findings.
`
` General nonclinical pharmacology/toxicology considerations
`
`According to Dr. Dubinion’s assessment, 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. No specific overlapping toxicity of
`clinical concern was identified in animals administered VEL or SOF alone. VEL related effects
`were limited to the highest dose examined in rats and dogs and were not considered adverse.
`No significant neurological, cardiovascular, or pulmonary findings in the safety pharmacology
`studies of VEL were observed.
`
` Genetic toxicology and carcinogenicity
`
`VEL is not mutagenic or clastogenic following testing in bacterial mutagenicity, chromosome
`aberration and in vivo rat micronucleus assays.
`
`Carcinogenicity studies of VEL in mice and rats are ongoing
`
` Reproductive toxicology
`
`VEL is not associated with effects on fertility or on embryo-fetal development. At the highest
`dose tested, VEL exposure was approximately 6 times the exposure in humans at the
`recommended human dose.
`
`VEL maternal exposure was not associated with effects on pre-and postnatal development.
`Maternal systemic exposure (AUC) to VEL was approximately 5 times the exposure in humans
`at the recommended human dose.
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`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
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`Clinical Pharmacology
`5.
`Approval is recommended from the clinical pharmacology and pharmacometrics review team
`(Drs. Jenny Zheng, Abhay Joshi, Shirley Seo, Fang Li and Jeffry Florian). Specific labeling for
`use with proton pump inhibitors is ongoing (see below for further discussion). This section
`focuses predominantly on VEL. Please refer to previous reviews (NDA 204671) and SOF
`product labeling for details.
`
` General clinical pharmacology considerations
`
`The pharmacokinetic properties of SOF and the predominant circulating metabolite GS-331007
`and VEL were evaluated in healthy and HCV infected subjects. Mean peak concentrations of
`SOF and VEL were observed at 0.5-1 hour and 3 hours, respectively.
`
`Following administration of SOF/VEL, the median terminal half-lives of SOF, GS-331007 and
`VEL were 0.5 hours, 25 hours and 15 hours, respectively. Ninety-four percent of VEL is
`excreted in feces and 0.4% is excreted in urine compared to 14% and 80% for SOF,
`respectively. The major route of elimination for VEL is biliary excretion (77%).
`
`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, with no change to 31% increases in VEL
`Cmax. Food slowed the rate of absorption of SOF within SOF/VEL, with only modest alterations
`in bioavailability, as evidenced by less than 2-fold higher mean AUC and no change in mean
`Cmax. For GS-331007, an approximately 25% to 37% lower Cmax was observed following
`SOF/VEL administration with food, with no change in AUC (Study GS-US-342-0104). These
`changes in exposure are not considered clinically significant for any moiety. Accordingly,
`SOF/VEL can be administered without regard to food.
`
`SOF and GS-331007 AUC0-24 and Cmax were similar in healthy adult subjects and subjects
`with HCV infection. Relative to healthy subjects (N=331), VEL AUC0-24 and Cmax were 37%
`lower and 41% lower, respectively in HCV-infected subjects.
`
` Critical intrinsic factors: age, race, gender, hepatic impairment, and renal impairment
`
`Age, race, gender:
`
`No clinically relevant effects on the exposure of SOF, GS-331007 or VEL were found for age,
`race or BMI. Based on the population PK analyses, gender was a statistically significant
`covariate for SOF, GS-331007 and VEL PK. Female subjects had 27-28% higher AUC and
`Cmax for GS-331007 compared to male subjects. Female subjects also had 47%, 43% and
`69% higher AUC, Cmax and Ctau, respectively, for VEL compared to male subjects. Based on
`the favorable safety profile (see Section 8), the noted differences in PK between females and
`males for GS-331007 and VEL were not considered clinically relevant.
`
`Hepatic impairment:
`
`No clinically relevant effect on the exposure of SOF, GS-331007 or VEL was seen in subjects
`with severe hepatic impairment. SOF/VEL can be given to patients with mild, moderate and
`severe hepatic impairment.
`
`Renal impairment:
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`CDER Cross Discipline Team Leader Review Template 2015 Edition
`Version date: June 9, 2015. For initial rollout (NME/original BLA reviews)
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`The effect of renal impairment was evaluated for SOF and VEL as individual agents. No
`clinically relevant differences in VEL pharmacokinetics were seen between healthy subjects and
`subject