CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205834Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review
`
`Date:
`
`July 18, 2014
`
`Reviewer(s):
`
`Acting Team Leader:
`
`Bob Pratt, Pharm.D.
`Division of Risk Management
`Jamie Wilkins-Parker, Pharm.D.
`Division of Risk Management
`Reema Mehta, Pharm.D., M.P.H.
`Division of Risk Management
`Evaluation to determine if a REMS is necessary
`Ledipasvir/Sofosbuvir Fixed Dose Combination, 90/400 mg
`Hepatitis C virus NS5A inhibitor / Hepatitis C virus NS5B
`polymerase inhibitor
`One tablet taken orally once daily
`Dosage and Route:
`Treatment of chronic hepatitis C virus genotype-1 infection
`Indication:
`Application Type/Number: NDA 205834
`Applicant/sponsor:
`Gilead Sciences, Inc.
`OSE RCM #:
`2014-354
`
`Acting Deputy
`Division Director:
`Subject:
`Drug Name(s):
`Therapeutic Class:
`
`Reference ID: 3595657
`
`

`

`INTRODUCTION
`1
`This review by the Division of Risk Management (DRISK) evaluates if a risk evaluation and
`mitigation strategy (REMS) is needed for the new molecular entity (NME) fixed dose
`combination of ledipasvir/sofosbuvir (LDV/SOF). On February 10, 2014, the Agency received
`an original New Drug Application (NDA) from Gilead Sciences for LDV/SOF for the treatment
`of chronic hepatitis C virus (HCV) genotype 1-infected patients. Ledipasvir is the NME
`component of the application. Sofosbuvir (Sovaldi®, NDA 204671) is approved for use in
`combination with other treatments for HCV and does not have a REMS. The applicant did not
`submit a proposed REMS or risk management plan for LDV/SOF.
`1.1 DISEASE BACKGROUND1-4
`Infection with the single-stranded RNA virus hepatitis C can result in both acute and chronic
`hepatitis. Approximately 20 to 30 percent of newly infected persons develop signs and
`symptoms of an acute illness, which can include fever, fatigue, loss of appetite, and other non-
`specific symptoms. Although the acute disease is usually self-limited, the immune response is
`mostly insufficient to eradicate the virus such that acute infection leads to chronic infection in 60
`to 80 percent of cases. Chronic HCV infection is associated with ongoing liver inflammation
`and often follows a progressive course over years to decades, increasing the risk of liver fibrosis,
`cirrhosis, and hepatocellular carcinoma.
`HCV lacks a proofreading mechanism during replication that leads to frequent viral mutations
`and viral heterogeneity. At least seven distinct HCV genotypes and more than 60 subtypes have
`been identified, with varying geographic distribution. Genotype 1 (GT1) is the most common
`genotype in the United States, with genotypes 2 and 3 less common. The viral diversity and
`heterogeneity have prevented the development of a vaccine and also affect the completeness of
`response to antiviral therapy.
`The goal of antiviral therapy in patients with chronic HCV is to see an absence of HCV RNA 12
`or 24 weeks after the completion of treatment. This is defined as a sustained virologic response,
`which is associated with a very low risk of viral reactivation and reduced risk of disease
`progression. The type and duration of antiviral therapy selected is dependent on the viral
`genotype, the patient’s baseline disease and host factors, the patient’s prior treatment experience
`and response, and other factors.
`HCV has been treated with combinations of indirect acting antivirals and direct acting antivirals.
`The indirect acting agents typically used include interferon alfa and ribavirin, which have broad
`antiviral activity but are associated with many toxicities and modest efficacy against HCV GT1.
`Direct acting antivirals are designed to target specific non-structural HCV proteins. Some agents
`inhibit the NS3/4A serine protease, which cleaves the HCV polyprotein into several polypeptides
`with distinct functions. Other direct acting antivirals target the NS5A protein necessary for viral
`assembly and replication, or inhibit the NS5B RNA-dependent RNA polymerase responsible for
`replication of HCV RNA.
`
`1 Chopra S. Clinical manifestations and natural history of chronic hepatitis C virus infection. In:UpToDate, Di
`Bisceglie AM and Bloom A (Eds), UpToDate, Waltham, MA, 2014.
`2 Chopra S. Characteristics of the hepatitis C virus. In:UpToDate, Edward MS, Di Bisceglie AM, and Bloom A
`(Eds), UpToDate, Waltham, MA 2014.
`3 Feeney ER and Chung RT. Antiviral treatment of hepatitis C. BMJ 2014; 349:g3308.
`4 Liang TJ and Ghany MG. Current and future therapies for hepatitis C virus infection. NEJM 2013; 368:1907-17.
`
`Reference ID: 3595657
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`1.2 PRODUCT BACKGROUND
`Ledipasvir is a novel HCV NS5A inhibitor that has demonstrated potent anti-HCV activity
`against genotype 1a and 1b HCV infection. Sofosbuvir is a nucleotide NS5B polymerase
`inhibitor that inhibits HCV RNA replication and has been approved for use in combination with
`other agents for the treatment of chronic HCV infection in adults. The recommended dosage is
`one tablet once daily for 12 weeks (without cirrhosis). For patients, with cirrhosis, the treatment
`duration is 24 weeks.
`1.3 REGULATORY HISTORY
`On February 10, 2014, the Agency received an original New Drug Application (NDA) from
`Gilead Sciences for LDV/SOF for the treatment of chronic hepatitis C virus genotype 1-infected
`patients. The Applicant previously received Breakthrough Therapy designation for the treatment
`on July 22, 2013. The review classification for the application is Priority. The Applicant did not
`submit a proposed REMS.
`
`2 MATERIALS REVIEWED
`July 3, 2013, Division of Antiviral Products (DAVP) Breakthrough Therapy Designation
`
`Request Memorandum, IND 115268
` February 10, 2014, Original NDA 205834 submission
`o Section 2.5, Clinical Overview
` May 8, 2014, slides from NDA 205834 Mid-Cycle Meeting
`June 3, 2014, Mid-Cycle Communication Meeting Minutes
`
`July 10, 2014, DAVP Clinical Review NDA 205834, Sarah Connelly, M.D.
`
`July 11, 2014, Draft Prescribing Information LDV/SOF
`
`
`3 RESULTS OF REVIEW
`3.1 OVERVIEW OF CLINICAL PROGRAM
`The Applicant completed three phase 3, randomized, open-label clinical trials (ION-1, ION-2,
`ION-3) of LDV/SOF in patients with chronic HCV GT1 infection in support of the proposed
`indication. The primary efficacy endpoint was sustained virologic response (SVR) 12 weeks
`after discontinuation of treatment. Pre-specified historical control rates were used to determine
`comparative statistical significance.
`In ION-1, the efficacy and safety of LDV/SOF with or without ribavirin for 12 to 24 weeks
`
`was evaluated in 865 treatment naïve patients, including those with cirrhosis. Patients in
`each of the 12-week treatment groups achieved SVR (99% LDV/SOF; 97% LDV/SOF plus
`ribavirin) compared to a pre-specified historical control rate of 60% (p<0.001). Relapse rates
`were 0.5% in the LDV/SOF arm and 0% in the LDV/SOF plus ribavirin arm.
` The ION-2 study compared LDV/SOF with or without ribavirin for 12 to 24 weeks in 440
`patients who had failed prior therapy with an interferon-based regimen of which 53%
`included an HCV protease inhibitor. Patients in each of the four treatment groups achieved
`SVR (94% LDV/SOF 12-week; 96% LDV/SOF plus ribavirin 12-week; 99% LDV/SOF 24-
`week; 99% LDV/SOF plus ribavirin 24-week) compared to a pre-specified historical control
`rate of 25% (p<0.001). Relapse rates were 6.5% in the LDV/SOF 12-week arm, 3.6% in the
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`Reference ID: 3595657
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`
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`LDV/SOF plus ribavirin 12-week arm and 0% in each of the LDV/SOF plus ribavirin 24-
`week arms.
`ION-3 evaluated 8 weeks of treatment with LDV/SOF with or without ribavirin, and 12
`weeks of treatment with LDV/SOF in 647 treatment naïve non-cirrhotic patients. Patients in
`each treatment group achieved SVR12 (94% LDV/SOF 8-week; 93% LDV/SOF plus
`ribavirin 8-week; 96% LDV/SOF 12-week) compared to a pre-specified historical control
`rate of 60% (p<0.001). Relapse rates were 5.1% in the LDV/SOF 8-week arm, 4.2% in the
`LDV/SOF plus ribavirin 8-week arm, and 1.4% in the LDV/SOF 24-week arm.
`In summary, ION-1 demonstrated the efficacy of LDV/SOF with or without ribavirin for 12
`weeks in treatment naïve patients (including patients with cirrhosis) and ION-2 demonstrated the
`efficacy of those regimens for 12 or 24 weeks in treatment-experienced patients. ION-3
`demonstrated the efficacy of LDV/SOF with or without ribavirin for 8 weeks and LDV/SOF for
`12 weeks in treatment naïve patients without cirrhosis.
`3.2
`SAFETY CONCERNS
`For the purpose of this review, serious adverse events associated with LDV/SOF are defined by
`the regulatory definition of a serious outcome, such as death, a life-threatening reaction, or
`hospitalization (among other outcomes). Severe adverse events associated with LDV/SOF are
`defined as Grade 3-4 using the Applicant’s Toxicity Grading Scale for Severity of Adverse
`Events and Laboratory Abnormalities.
`3.2.1 Serious Adverse Events
`Nonfatal serious adverse events (SAEs) of any nature were reported in 51/1952 patients (2.6%)
`in the pooled phase 3 safety population. No trends were identified, as each SAE occurred in only
`one or two patients in any given treatment group. The LDV/SOF 24-week group had a higher
`SAE rate (7.4%) compared with the other LDV/SOF groups (1.9% and 1.1% in the 8-week and
`12-week groups, respectively) but the majority of these events occurred during the first 12 weeks
`of treatment.
`One death occurred in the post-treatment period in the ION-1 trial, but was considered not
`related to study treatment by the investigator. The case involved fatal hepatic failure on post-
`treatment day 121 in a 63 year-old patient with a history of alcoholism, alcoholic liver disease,
`and ascites, among other conditions. The DAVP clinical reviewer agreed with the investigator
`that the events were unlikely related to treatment. Nine other fatal cases have occurred in
`ongoing studies of LDV/SOF plus ribavirin; one patient died of a cardiac arrest in a foreign trial,
`and eight patients died in a study of patients who have received liver transplants or have
`advanced liver disease. The DAVP clinical reviewer noted there was no clustering of events in
`these fatal outcome cases, and the decompensated liver disease/post-transplant population has
`known associated comorbidities and is overall a sicker population.
`3.2.2 Severe adverse events
`The most frequently reported Grade ≥ 3 adverse events (AEs) were fatigue (0.7%), headache
`(0.6%), and anemia (0.3%). All Grade 3 AEs of anemia occurred in patients in treatment groups
`receiving ribavirin. Grade 4 AEs were reported in four patients and included events related to a
`traffic accident; unstable angina; an anaphylactic reaction on post-treatment Day 9; and
`hypoglycemia. All Grade 4 AEs were considered unrelated to study treatment by the
`investigator. These assessments seemed reasonable to the clinical reviewer.
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`Reference ID: 3595657
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`3.2.3 Hepatic events
`Hepatic adverse events were experienced by 16/1952 (0.8%) patients in the pooled safety
`population. The most commonly reported event was jaundice, which occurred in eight cases;
`seven of the eight cases (and all three cases of hyperbilirubinemia) occurred in ribavirin-treated
`patients. One serious AE case of severe jaundice (≥ Grade 3) in the LDV/SOF 12-week arm
`occurred in the setting of a bile duct stone. None of the other events were SAEs and there were
`no Grade 4 events.
`3.2.4 Postmarketing Requirements
`At this time, pediatric trials to assess safety and efficacy of sofosbuvir for the treatment of
`chronic hepatitis C in pediatric subjects will be required under Pediatric Research Equity Act.
`
`4 DISCUSSION
`Based on the results of the phase 3 pivotal trials, LDV/SOF provides substantial efficacy in the
`treatment of chronic HCV GT1 in treatment-naïve and treatment-experienced patients with or
`without cirrhosis. The once-daily, orally administered LDV/SOF combination also offers an
`improved safety profile compared to interferon-based and ribavirin-based HCV regimens, which
`are difficult for patients to tolerate because of the associated toxicities.
`DRISK does not recommend a REMS as necessary to ensure the benefits of LDV/SOF outweigh
`the risks. HCV is a serious and life-threatening disease that infects an estimated 3 million people
`in the U.S. There are no serious clinical risks described under the Warnings and Precautions
`section of the LDV/SOF draft Prescribing Information. Additionally, based on the currently
`available data, there is an absence of new safety signals unique to the LDV/SOF combination.
`None of the currently approved antiviral drugs for HCV infection – including interferon,
`ribavirin, and sofosbuvir as a single-entity – require a REMS to ensure the benefits of treatment
`outweigh the risks, and the most frequently reported severe AEs associated with LDV/SOF are
`also associated with interferon and ribavirin.
`The most likely prescribers of LDV/SOF are specialists who are familiar with the management
`of chronic HCV and who understand the risks of treatment using antiviral therapies that have
`more serious risk profiles. Like the HCV antiviral agents already approved, the risks of
`LDV/SOF may be managed by the Prescribing Information and routine pharmacovigilance.
`
`5 CONCLUSION
`In conclusion, risk mitigation measures beyond professional labeling are not warranted for
`LDV/SOF. LDV/SOF has proven efficacy in the treatment of chronic HCV genotype 1-infected
`patients. There were no serious or severe safety issues which warrant a boxed warning for
`LDV/SOF. Thus, the benefit-risk profile for LDV/SOV is acceptable and the risks can be
`mitigated through professional labeling.
`Should DAVP have any concerns or questions, feel that a REMS may be warranted for this
`product, or new safety information becomes available, please send a consult to DRISK.
`
`Reference ID: 3595657
`
`4
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT G PRATT
`07/18/2014
`
`REEMA J MEHTA
`07/18/2014
`
`Reference ID: 3595657
`
`