CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205834Orig1s007, s008, s009
`
`SUMMARY REVIEW
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`Cross-Discipline Team Leader Review
`NDA 205834/SOO7-009
`
`HARVONI (ledipasvirlsofosbuvir Fixed-Dose Combination)
`
`Cross-Discipline Team Leader Review
`
`Februa
`
`10, 2016
`
`Poonam Mishra, MD, MPH
`De . u Director for Safe
`
`Cross-Disci 0 line Team Leader Review
`
`NDNBLA #
`
`Su .
`
`. Iement#
`
`NDA 205834
`
`8007-009
`
`Gilead Sciences, Inc.
`
`Date of Submission
`August 26, 2015
`Februa
`26, 2016
`
`PDUFA Goal Date
`
`Proprietary Name I
`Established USAN names
`
`HARVONI
`ledi oasvir, sofosbuvir
`
`Dosage forms I Strength
`
`Fixed Dose Combination Tablet (FDC) containing:
`Ledipasvir 90 mg
`Sofosbuvir 400 m
`
`Proposed Indication(s)
`
`To expand the use in patients with chronic hepatitis C
`virus infection with
`
`
`
`Recommended:
`
`1. Genotypes 1 & 4, who are post liver
`transplantation with compensated liver disease
`2. Genotype 1, with decompensated liver disease
`regardless of transplantation status
`A o roval
`
`1. Introduction
`
`The Applicant (Gilead Sciences, Inc.) has submitted three efficacy supplements to
`NDA 205834 (7, 8, & 9) seeking to expand the indication in patients with chronic
`hepatitis C virus (HCV) infection, genotypes 1 & 4 who are posttransplantation with
`compensated liver disease as well as patients with decompensated liver disease with
`genotype 1 HCV infection, regardless of transplantation status. Specifically, these
`efficacy supplements include the following subpopulations:
`0
`8-007: Liver transplant recipients with genotype 1 HCV infection
`
`0 S-008: Liver transplant recipients with genotype 4 HCV infection
`0
`8—009: Patients with decompensated cirrhosis with genotype 1 HCV infection
`
`Harvoni, a fixed dose combination (FDC) tablet containing ledipasvir 90 mg/sofosbuvir
`400 mg, was approved for the treatment of chronic HCV infection in the United States
`(US) on October 10, 2014. Ledipasvir (LDV) is an HCV inhibitor targeting the HCV
`nonstructural protein 5A (NS5A) and sofosbuvir (SOF) is an inhibitor of the HCV
`NS5B RNA-dependent RNA polymerase. SOF was approved for the treatment of
`chronic hepatitis C (CHC) infection in combination with other HCV agents on
`
`Page 1 of 24
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`Reference ID: 3885450
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`December 6, 2013. The LDV/SOF FDC was initially approved for the treatment of
`CHC genotype 1 infection in adults without cirrhosis or with compensated cirrhosis. In
`2015, the indication was extended to adults with compensated cirrhosis with genotype
`4, 5, or 6; and those with HIV-1/HCV genotype 1 or 4 coinfection.
`
`The submission contains data from two Phase 2 trials GS-US-337-0123 (SOLAR-1)
`and GS-US-337-0124 (SOLAR-2) to support the safety and efficacy of LDV/SOF plus
`ribavirin (RBV) for 12 weeks in the proposed patient populations - those with HCV
`genotype 1 or 4 infection who are liver transplant recipients with compensated liver
`disease as well as those with HCV genotype 1 infection with decompensated liver
`disease, regardless of transplantation status.
`
`This CDTL review will provide a brief overview of the clinical safety, efficacy, and
`virology reviews. For detailed assessments, please refer to respective discipline’s
`primary reviews. In particular, this review will focus on the safety and efficacy data in
`decompensated population as well as in the post liver transplant population as data in
`these subpopulations has not been previously submitted and reviewed under this
`NDA.
`2. Background
`
`CHC is a global public health problem with an estimated 185 million people worldwide
`and 3.2 million persons in the US with HCV infection (Mohd Hanafiah 2013,
`Armstrong, 2006). The natural history of CHC involves progression to cirrhosis,
`hepatocellular carcinoma (HCC), end stage liver disease, and death. CHC is the most
`common reason for liver transplantation in the US. By 2007 there were more yearly
`deaths in the US related to HCV than HIV-1 and, without effective treatment
`interventions, significant increases in CHC-associated morbidity, mortality, and
`healthcare costs were predicted (Ly 2012, Wong 2000).
`
`Evaluating clinical outcomes from prospective, randomized controlled clinical trials in
`patients infected with HCV is challenging and not feasible because of the difficulty of
`maintaining patients on a randomized arm without intervening therapy for a sufficient
`duration (many years) to identify late-occurring clinical events such as HCC;
`therefore, treatment response is defined by virological parameters. The most
`important virologic parameter has been the sustained virologic response (SVR) which
`is defined as undetectable HCV RNA in serum after a predefined number of weeks
`following the completion of therapy.
`
`SVR is an objective endpoint that signifies long-term clearance of hepatitis C and is
`generally regarded as a “virological cure”. Multiple observational cohorts have shown
`strong correlations between achieving SVR and improved clinical outcomes such as
`decreased HCC, end-stage liver complications, and mortality. Attainment of SVR in
`CHC patients has shown to be associated with a decreased progression of fibrosis,
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`and some studies have even suggested reversal of fibrosis or early cirrhosis (Poynard
`2000 & 2002).
`
`With the aging of the infected population, CHC-related complications such as
`decompensated cirrhosis and HCC are increasing and it is estimated that by 2019-
`2020 there will be approximately 145,000 annual cases of decompensated cirrhosis
`and 14,000 cases of HCC (Davis 2010). The ultimate goal of CHC treatment is to
`reduce the occurrence of end-stage liver disease and its complications including
`decompensated cirrhosis, liver transplantation and HCC. Without effective treatment,
`the recurrence of HCV after liver transplantation is universal and is associated with
`accelerated progression of fibrosis and significant morbidity and mortality.
`
`Interferon (IFN)-based regimens have not been recommended for use in patients with
`decompensated liver disease and liver transplantation had been the only treatment
`option. Approval of multiple IFN-free regimens since 2013 has paved the way for
`treatment of these patients who have been awaiting therapy all these years. Currently
`approved IFN-free regimens for the treatment of HCV infection include SOF plus
`RBV; fixed-dose LDV/SOF; simeprevir (SMV, a NS3/4A protease inhibitor) in
`combination with SOF; a co-packaged triple-DAA regimen (Viekira Pak) consisting of
`ombitasvir, paritaprevir/ritonavir, and dasabuvir (NS5A inhibitor, ritonavir-boosted
`NS3/4A PI, and nonnucleoside NS5B-palm polymerase inhibitor, respectively); a
`regimen consisting of ombitasvir, paritaprevir/ritonavir (Technivie); and a regimen of
`daclatasvir (DCV, NS5A inhibitor) in combination with SOF. Recent approval of a fixed
`dose combination of elbasvir, a HCV NS5A inhibitor, and grazoprevir, an HCV
`NS3/4A protease inhibitor has expanded the available treatment options.
`
`Notably, the majority of the above-mentioned regimens are indicated only in patients
`with compensated cirrhosis; with limited therapeutic options available to the specific
`populations such as, those with decompensated cirrhosis or those who are liver
`transplant recipients. Particularly, HCV protease inhibitor based regimens are either
`not recommended or contraindicated for use in patients with decompensated liver
`disease due to risk of liver failure. Specifically, the only approved regimen for
`decompensated patients is daclatasvir in combination with sofosbuvir taken with or
`without RBV. For post-transplant patients, available options include the above-
`mentioned regimen of DCV plus SOF with or without RBV, and Viekira Pak with RBV
`in patients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or
`lower).
`
`The available data showing the long-term benefits of achieving SVR in HCV patients
`who have decompensated liver disease and/or post-liver transplantation is limited and
`needs to be demonstrated in a systematic manner. However, the published data from
`patients with decompensated cirrhosis due to chronic hepatitis B virus infection
`suggests that reversal of decompensation is possible with effective therapeutic
`interventions (Zoulim 2008).
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Clinical protocols submitted under IND were reviewed by the review team throughout
`the course of the product’s development, with feedback provided as appropriate. In
`addition, a pre-NDA meeting was held with the sponsor including the hepatology
`expert panel convened by the sponsor.
`3. CMC/Device
`
`No changes to the chemistry, manufacturing, and controls for the HARVONI tablet are
`proposed with this application.
`4. Nonclinical Pharmacology/Toxicology
`
`No nonclinical safety studies were submitted with these supplements. Refer to original
`Pharmacology/Toxicology Review for NDA 205834.
`
`Sections 8.1 and 8.2 of the Prescribing Information (PI) were updated to be consistent
`with the Pregnancy and Lactation Labeling Final Rule. Please refer to
`Pharmacology/Toxicology Review by Christopher Ellis, Ph.D. for details.
`5. Clinical Pharmacology/Biopharmaceutics
`
`No new information for pharmacology; in vitro or nonclinical data; absorption,
`distribution, metabolism, and elimination (ADME); or pharmacokinetics (PK) profile
`studies or analyses between healthy and HCV-infected subjects is included with these
`supplements. New data for population PK analyses was submitted. Please refer to
`Clinical Pharmacology Review by Dr. Florian for a detailed assessment. In addition,
`in-depth Clinical Pharmacology/Biopharmaceutics Reviews were conducted during
`original NDA reviews for sofosbuvir and ledipasvir/sofosbuvir. No new
`biopharmaceutics information is included within this submission.
`
`As noted in Dr. Florian’s review, “The Office of Clinical Pharmacology has determined
`that there is sufficient clinical pharmacology information provided in this supplement
`NDA to support a recommendation of approval of LDV/SOF in patients with
`decompensated cirrhosis and patients who have received a liver transplant.”
`
`Key points from Dr. Florian’s review are noted below:
`
`
`• PK for LDV, SOF, and the predominant circulating metabolite of SOF (GS-
`331007) were evaluated in SOLAR trials. The data from the SOLAR trials was
`compared with observations from the original LDV/SOF NDA submission.
`• No difference in PK was observed based on liver transplantation status, but
`differences were observed based on degree of hepatic impairment.
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`• Based on population PK analyses, the observed changes in LDV, SOF, and
`GS-331007 exposures based on hepatic impairment are not considered
`clinically relevant and no dose adjustments are recommended.
`• No dose adjustments are recommended in posttransplant patients on a
`cyclosporine containing regimen.
`• Decreased SOF, GS-331007, and LDV AUCτ were observed (15-40%) in
`subjects who relapsed compared to those subjects achieving SVR. However,
`exposures of SOF, GS-331007, and LDV were not significant predictors of
`response from multivariate analyses. No dose adjustments are proposed
`based on this observation.
`6. Clinical Microbiology
`
`Please refer to Clinical Virology Review by Dr. Lisa Naeger for a detailed assessment.
`
`Key points from Dr. Naeger’s review are noted below:
`
`
`•
`
`In SOLAR-1 and SOLAR-2 trials, the overall prevalence of NS5A resistance-
`associated polymorphisms (RAPs) in genotype 1 (GT1) subjects was 25%.
`• The virologic failure rates in HCV GT1 subjects were comparable for subjects
`with NS5A RAPs and subjects without NS5A RAPs at 3.4% (5/146) vs. 4.3%
`(19/443).
`• For subjects with baseline NS5A RAPs, virologic failure rates were slightly
`higher for GT1a subjects compared to GT1b subjects (5.3% vs. 1.4%).
`• Relapse rates were 7% (5/71) and 5% (10/217) in GT1 subjects with and
`without baseline NS5A polymorphisms, respectively, treated with 12 weeks of
`HARVONI and RBV.
`• For subjects with baseline NS5A RAPS, there were no virologic failures in the
`24-week duration arms.
`• For subjects with genotype 4 (GT4) HCV infection, the presence of baseline
`NS5A RAPs resulted in higher virologic failure rates for Child-Pugh-Turcotte
`(CPT) B (33%; 1/3) and CPT C (67%; 2/3) groups in the 12-week duration arm,
`although the subgroups were very small.
`
`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`
`
`Virologic Failures and Treatment-emergent Substitutions
`
`As noted by Dr. Naeger, “There were 27 virologic failure subjects with GT1 (n=24)
`and GT4 HCV (n=3): 23 subjects relapsed and 4 subjects discontinued on treatment
`with a detectable viral load and were included in the FDA virologic failure analysis.
`Most of the virologic failures were in the 12-week duration arms (n=18) and most had
`GT1a HCV (n=17). Eight of the virologic failures (30%) had baseline NS5A RAPs.
`The remaining subjects had no pretreatment RAPs, but most developed treatment-
`emergent NS5A RAPs at the time of relapse.”
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Furthermore, “Seventy-eight percent (21/27) of the virologic failures had emergent
`NS5A resistance substitutions, including one of the virologic failures who discontinued
`on treatment with detectable viral load. Fourteen virologic failures developed 1 NS5A
`substitution and 7 developed ≥2 substitutions. Of the virologic failures who relapsed,
`91% (21/23) had emergent NS5A resistance substitutions. Emergent NS5A
`resistance-associated substitutions included K24K/R, M28T, Q30H/R, R30Q, M31V,
`H58D, and Y93H/C. The most prevalent NS5A substitutions that emerged at failure
`were Q30H/R or R30Q (33%; n=9) and Y93H (41%; n=11). The majority of
`treatment-emergent substitutions conferred >1000-fold reduced susceptibility to LDV
`in cell culture.”
`7. Clinical/Statistical- Efficacy
`
`Please refer to the Statistical Review by Wen Zeng, PhD, Clinical Review by Charu
`Mullick, MD and Virology Review by Lisa Naeger, PhD for a complete review of
`efficacy.
`
`The Applicant conducted two Phase 2 trials which were randomized, open-label,
`multicenter studies and were identical in study design (Table 1). The only difference
`between the trials was the location of the clinical sites (US versus ex-US sites).
`SOLAR-2 trial was not conducted under an IND. The Applicant provided adequate
`justification for the applicability of the data generated from SOLAR-2 trial to the US
`HCV-infected population.
`
`Table 1: Clinical Trials included in the sNDA
`Na Region
`Trial
`Treatment
`GS-US-337-
`LDV/SOF+RBV
`337 US
`0123
`for 12 or 24
`weeks
`(SOLAR-1)
`
`Trial Population
`Treatment-naive and
`treatment-experienced adult
`subjects with
`chronic genotype 1 or 4 HCV
`infection, who were
`posttransplantation with
`compensated liver disease or
`with decompensated liver
`disease regardless of
`transplantation status
`Same as above
`
`GS-US-337-
`0124
`(SOLAR-2)
`
`LDV/SOF+RBV
`for 12 or 24
`weeks
`
`
`
`333 Europe,
`Canada,
`Australia,
`New
`Zealand
`
`a Subjects who received at least 1 dose of LDV/SOF
`Source: Adapted from Applicant’s Clinical Overview (Table 1)
`
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`Page 6 of 24
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Subjects were enrolled into Cohort A or B based on liver transplantation status and
`into 1 of the following 7 groups based on severity of hepatic impairment.
`
`In Cohort A, subjects with cirrhosis who had not undergone transplantation were
`enrolled into one of the following two groups based on severity of hepatic impairment
`at their screening visit:
`• Group 1: subjects with cirrhosis and moderate hepatic impairment (CPT B;
`score of 7 to 9 [decompensated])
`• Group 2: subjects with cirrhosis and severe hepatic impairment (CPT C; score
`of 10 to 12 [decompensated])
`
`
`In Cohort B, posttransplantation subjects with or without cirrhosis were enrolled into
`one of the following five groups based on severity of hepatic impairment at their
`screening visit.
`• Group 3: posttransplantation subjects without cirrhosis (fibrosis stage F0-F3)
`and with no evidence of hepatic decompensation
`• Group 4: posttransplantation subjects with cirrhosis and mild hepatic
`impairment (CPT A; score of 5 to 6 [compensated])
`• Group 5: posttransplantation subjects with cirrhosis and moderate hepatic
`impairment (CPT B; score of 7 to 9 [decompensated])
`• Group 6: posttransplantation subjects with cirrhosis and severe hepatic
`impairment (CPT C; score of 10 to 12 [decompensated])
`• Group 7: posttransplantation subjects with fibrosing cholestatic hepatitis
`
`
`Within each of the 7 treatment groups, subjects were randomized in a 1:1 ratio to
`receive LDV/SOF+RBV for 12 or 24 weeks.
`
`The primary efficacy endpoint in both clinical trials was the proportion of subjects
`achieving SVR12 (HCV RNA < lower limit of quantitation [LLOQ] 12 weeks after last
`dose of study drug).
`
`Overall, the clinical and statistical reviewer’s independent analyses confirmed the
`Applicant’s primary efficacy findings and relevant secondary endpoint analyses for the
`two clinical trials. The following sections summarize the key findings of the FDA’s
`clinical and statistical reviewers.
`
`The intent-to-treat population (ITT) included 670 subjects; out of which 455 subjects
`were post-liver transplant. A total of 329 subjects with decompensated cirrhosis were
`enrolled including 78 subjects with baseline MELD scores greater than 15. The
`majority of subjects had genotype 1 infection (94%); and 6% of subjects had genotype
`4 infection. Across all groups, the majority of subjects were male (77%) and white
`(91.5%). The median age was 59 years (range: 21 to 81). Majority of subjects (78%)
`had failed a prior HCV therapy.
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`The trial demographics and baseline disease characteristics were comparable
`between the treatment arms. Of the 670 subjects, 628 subjects (94%) completed the
`trial and 42 subjects (6%) discontinued LDV/SOF treatment prematurely. The
`common reasons for treatment discontinuations were due to an adverse event (n=19,
`3%), death (n=8, 1%), liver transplantation (n=7, 1%), and investigator’s discretion
`(n=3, <1%).
`
`Efficacy in Genotype 1 Subjects
`
`This section will discuss the demonstrated efficacy results in genotype 1 subjects
`evaluated in SOLAR-1 and SOLAR-2 trials. The section is further divided based on
`the baseline disease stage.
`
`Post-transplant Subjects without Cirrhosis or with Compensated Cirrhosis
`
`The SVR12 rates in post-transplant groups without cirrhosis (F0-F3 Fibrosis) and in
`those with compensated cirrhosis (CPT A) were 95% and 98% respectively with 12
`weeks of LDV/SOF in combination with RBV. The observed SVR12 rates are
`consistent with those demonstrated in previous clinical trials of LDV/SOF conducted in
`patients without cirrhosis or with compensated cirrhosis.
`
`Table 2: SVR12 for Genotype 1 Post-transplant Subjects without Cirrhosis or
`with Compensated Cirrhosis – SOLAR-1 and SOLAR-2 (pooled data)
`LDV/SOF + RBV
`LDV/SOF + RBV
`12 weeks
`24 weeks
`SVR12 n/N (%)
`SVR12 n/N (%)
`[95% CI]
`[95% CI]
`94.9% (94/99)
`99.0% (99/100)
`[88.6%, 98.3%]
`[94.6%, 100.0%]
`98.2% (55/56)
`96.2% (51/53)
`[90.5%, 100%]
`[87.0%, 99.5%]
`Source: Adapted from Efficacy Analyses by Dr. Zeng and Clinical Review by Dr. Mullick
`
`Similar SVR12 rates were observed with 12 and 24 weeks durations hence extending
`the treatment duration was not indicated in this subpopulation based on these trial
`results.
`
`Subjects with Decompensated Cirrhosis irrespective of Transplantation status
`
`The SVR12 rates in those with decompensated cirrhosis (CPT B & C) were lower
`compared to subjects without cirrhosis or compensated cirrhosis and ranged from
`89% to 57% with 12 weeks of LDV/SOF in combination with RBV.
`
`
`Cohort
`
`Group/Stage
`
`Posttransplantation 3: F0-F3 Fibrosis
`
`4: CPT A
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Table 3: SVR12 for Genotype 1 Subjects with Decompensated Cirrhosis –
`SOLAR-1 and SOLAR-2 (pooled data)
`
`Cohort
`
`Group/Stage
`
`LDV/SOF + RBV
`LDV/SOF + RBV
`24 weeks
`12 weeks
`SVR12 n/N (%)
`SVR12 n/N (%)
`[95% CI]
`[95% CI]
`92.0% (46/50)
`86.5% (45/52)
`[80.8%, 97.8%]
`[74.2%, 94.4%]
`82.6% (38/46)
`87.5% (35/40)
`[68.6%, 92.2%]
`[73.2%, 95.8%]
`95.6% (43/45)
`89.1% (41/46)
`[84.9%, 99.5%]
`[76.4%, 96.4%]
`77.8% (7/9)
`57.1% (4/7)
`[40.0%, 97.2%]
`[18.4%, 90.1%]
`Source: Adapted from Efficacy Analyses by Dr. Zeng and Clinical Review by Dr. Mullick
`
`Pretransplantation 1: CPT B
`
`2: CPT C
`
`Posttransplantation
`
` 5: CPT B
`
`6: CPT C
`
` I
`
` agree with Dr. Mullick’s dosing recommendations for post-transplant CPT C patients
`in spite of limited data in this subgroup. The dosing recommendation for this subgroup
`is supported by available SVR12 data in CPT B patients irrespective of transplant
`status as well as data in CPT C patients who did not undergo liver transplant. There
`was no consistent trend in SVR12 rates to suggest the need for longer treatment
`duration of 24 weeks for patients with decompensated cirrhosis; for example, SVR12
`rates for pretransplant CPT C group were 87.5% with a 12 week regimen compared to
`82.6% with 24 weeks duration. The number of subjects enrolled in the post-transplant
`CPT C group was very limited to draw any conclusions about the treatment duration
`based on these data. In summary, although the trial data in post-transplant CPT C
`subjects was limited, the totality of data in the CPT B and C subgroups was
`considered. The demonstrated efficacy in the pretransplant CPT B and C subgroups
`was leveraged to derive the dosing recommendation for post-transplant CPT C
`patients.
`
`As noted earlier, the clinical impact of achieving SVR12 in patients with advanced
`liver disease is not well documented. Patients with decompensated liver disease who
`are awaiting liver transplant may benefit by delaying the need for liver transplant or
`eliminating the need for the liver transplant at all. Certain patients may still need a
`transplant due to their advanced disease or deteriorating liver function and having an
`undetectable HCV RNA at the time of transplant may prevent HCV recurrence in the
`new graft. Historically, liver transplant recipients with chronic HCV have a significantly
`lower 5-year survival compared to other recipients due to a higher rate of graft failure
`from recurrent disease.
`
`
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`Pretransplantation
`(decompensated)
`
`G1: CPT B
`
`G2: CPT C
`
`Posttransplantation G3: F0-F3 Fibrosis
`
`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Efficacy in Genotype 4 Subjects
`
`Table 4 below shows SVR12 rates for genotype 4 subjects including post-transplant
`subjects without cirrhosis or with compensated cirrhosis and those with
`decompensated Cirrhosis irrespective of transplantation status in SOLAR-1 and
`SOLAR-2 trials.
`
`Table 4: SVR12 for Genotype 4 Subjects– SOLAR-1 and SOLAR-2 (pooled data)
`
`
`LDV/SOF + RBV
`LDV/SOF + RBV
`
`
`12 weeks
`24 weeks
`Cohort
`Group/stage
`SVR12 n/N (%)
`SVR12 n/N (%)
`[95% CI]
`[95% CI]
`75% (3/4)
`100% (2/2)
`[19.4%, 99.4%]
`[15.8%, 100.0%]
`33% (1/3)
`50% (1/2)
`[0.8%, 90.6%]
`[1.3%, 98.7%]
`100% (8/8)
`100% (5/5)
`[63.1%, 100.0%]
`[47.8%, 100.0%]
`75% (3/4)
`100% (5/5)
`[19.4%, 99.4%]
`[47.8%, 100.0%]
`100% (2/2)
`75% (3/4)
`[15.8%, 100.0%]
`[19.4%, 99.4%]
` 0 (0/1)
`0
`[0.0%, 97.5%]
`Source: Adapted from Efficacy Analyses by Dr. Zeng and Clinical Review by Dr. Mullick
`
`The efficacy was demonstrated in post-transplant genotype 4 subjects without
`cirrhosis or with compensated cirrhosis (Groups 3 & 4). LDV/SOF + RBV for 12 weeks
`resulted in high efficacy rates of 100% and 75%. The subject who did not achieve
`SVR12 in Group 4 did not experience virologic relapse. I concur with Dr. Mullick’s
`conclusion to recommend a 12 week LDV/SOF + RBV treatment regimen for post-
`transplant CPT A patients based on findings in Group 4, and supporting data from
`Group 3. This recommendation also takes into consideration the approved 12-week
`duration of LDV/SOF treatment in genotype 4 patients with compensated cirrhosis.
`
`Although genotype 4 subjects with decompensated disease were enrolled in the trial,
`the available data in each subgroup is limited to make a determination about an
`optimal duration to support an indication in the HCV GT4 infected population with
`decompensated cirrhosis. The Applicant has not requested to expand the indication in
`this subpopulation of genotype 4 patients.
`
`
`G4: CPT A
`
`G5: CPT B
`
`G6: CPT C
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`Efficacy in Subjects with Fibrosing Cholestatic Cirrhosis (FCH)
`
`There were a total of eleven subjects with FCH enrolled in the SOLAR trials, 7
`subjects in the 12 week treatment arm and 4 subjects in the 24 week treatment arm.
`All subjects achieved SVR12.
`
`Relapse Rates
`
`Overall, 20 of 589 subjects (3.4%) with genotype 1 HCV infection relapsed and 3 of
`36 subjects (8.3%) with genotype 4 HCV infection relapsed. A pooled analysis was
`done to assess the role of treatment duration in decompensated subjects (Groups 1,
`2, 5, and 6) with genotype 1 HCV infection, irrespective of transplantation status.
`Relapse rates were 8.1% and 4.3% in subjects who received LDV/SOF+RBV for 12 or
`24 weeks, respectively, and the difference in relapse rates was 3.8% with 95% CI of
`[−2.1%, 10.2%].
`
`Analysis of Changes in CPT and MELD Scores
`
`Pre-specified secondary efficacy endpoints in both trials include changes in CPT and
`Model for End-Stage Liver Disease (MELD) scores from Day 1 of study treatment to
`12 weeks and 24 weeks posttreatment. As noted in the protocol, the objective was to
`determine the therapeutic efficacy as measured by the change of CPT score and
`MELD score. MELD and the CPT scores are used to assess chronic liver disease
`severity.
`
`The CPT score is widely used. It was originally developed for the assessment of the
`outcome of patients with cirrhosis and portal hypertension. The CPT score is derived
`using following 5 variables: albumin, total bilirubin, international normalized ratio for
`prothrombin time (INR), presence and degree of ascites, and presence and degree of
`encephalopathy. Higher CPT scores correlate with increased mortality. The use of
`CPT score has limitations due to inclusion of variables such as ascites and
`encephalopathy, which are subjective and influenced by medical therapy (Gotthardt
`2009).
`
`MELD is a scoring system for the severity of liver disease initially developed as a
`model in predicting poor survival in patients after transjugular intrahepatic porto-
`systemic shunt (TIPS). A modification of this score was developed to predict mortality
`in patients with cirrhosis of different etiologies and severities of liver disease. The
`MELD score is calculated using 3 objective parameters: serum creatinine, serum total
`bilirubin, and INR. This MELD score was found to be superior to the CPT score in
`predicting 3-month mortality and therefore the MELD score was implemented in 2002
`in the US for the prioritization of liver transplant recipients (Gotthardt 2009).
`
`Although a substantial proportion of subjects who attained SVR12 showed an
`improvement in MELD and CPT scores at 12 weeks posttreatment, few subjects
`remained stable and a small percentage of subjects worsened. Improvement in CPT
`
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`Cross-Discipline Team Leader Review
`NDA 20583418007-009
`
`HARVONI (ledipasvirlsofosbuvir Fixed-Dose Combination)
`
`score was driven by improvement in albumin and bilirubin. Improvement in MELD
`score was driven primarily by improvement in bilirubin. For detailed analyses, please
`refer to Dr. Wen’s review.
`
`(I!) (4)
`
`Recognizing the importance
`of clinical outcome findings in patients with cirrhosis, including decompensated
`cirrhosis, who are sustained responders, the Division has reached an agreement with
`the Applicant on a postmarketing commitment to submit 5 year follow-up data.
`
`8. Safety
`
`Please refer to Clinical Review by Dr. Mullick for a detailed assessment of safety.
`
`This section will provide a focused summary of the safety data from the two SOLAR
`trials. The safety profile of LDV/SOF has been well-characterized in multiple previous
`clinical trials and has generally been safe and well-tolerated. Please refer to clinical
`reviews by Dr. Sarah Connelly dated July 10, 2014 for original NDA and dated
`October 20, 2015 for efficacy supplements (S 2-6). The two clinical trials being
`evaluated under the current efficacy supplements were conducted to demonstrate
`safety and efficacy in patient populations not previously studied.
`
`The safety evaluation in the patient population specifically enrolled in two SOLAR
`trials is challenging for numerous reasons related to baseline disease characteristics
`of the enrolled subjects. Subjects with advanced liver disease (Child-Pugh B and C
`cirrhosis) represent a highly vulnerable patient population with other coexisting factors
`such as portal hypertension leading to esophageal varices/bleeding, immune
`dysfunction predisposing to increased risk of infections, hemodynamic derangements
`leading to renal dysfunction including hepatorenal syndrome (HRS), and synthetic
`liver dysfunction leading to complications. Spontaneous bacterial peritonitis (SBP),
`sepsis, hyponatremia and hepatic encephalopathy are common clinical presentations
`in patients with decompensated cirrhosis. Other systemic complications of chronic
`liver disease include hepatopulmonary syndrome and portopulmonary syndrome. The
`1-year mortality for patients with decompensated cirrhosis ranges from approximately
`20% for patients with CPT B cirrhosis to greater than 50% for patients with CPT C
`cirrhosis (D'Amico 2006).
`
`In addition, SOLAR trials included subjects who were post liver transplantation. Liver
`transplant recipients are on chronic immunosuppressive therapy to prevent graft
`rejection and are prone to side effects related to immunosuppressants drugs.
`Nephrotoxicity is a well-recognized side effect of calcineurin inhibitors (Cle). It has
`been reported that approximately 20% of liver transplant recipients experience chronic
`renal failure within 5 years (Ojo 2003).
`
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`Cross-Discipline Team Leader Review
`NDA 205834/S007-009
`HARVONI (ledipasvir/sofosbuvir Fixed-Dose Combination)
`
`In such populations, careful evaluation is needed to distinguish adverse drug
`reactions due to the treatment regimen being evaluated versus the expected events
`secondary to the natural progression of disease, and/or worsening of other comorbid
`conditions, and/or the effects secondary to toxicity of concomitant medications. The
`comprehensive safety assessment also took into consideration the established safety
`profile based on data in other LDV/SOF trials reviewed under the LDV/SOF NDA, the
`ongoing and completed postmarketing assessments, published literature reports and
`any relevant available data provided by the Applicant from real-world observational
`cohort study (HCV-TARGET database).
`
`The integrated clinical safety review provided by Dr. Mullick describes pooled data
`from the two trials. Overall, 336 subjects received LDV/SOF+RBV for 12 weeks and
`334 subjects received LDV/SOF+RBV for 24 weeks. A total of 329 subjects (49%)
`had decompensated cirrhosis (either pre- or posttransplantation), of whom 78
`subjects (24%) had a MELD score >15 (a threshold us