CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
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`205834Orig1s000
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`OFFICE DIRECTOR MEMO
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`

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`NDA 205834
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`Page 1 of4
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`Office Director Decisional Memo
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`
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`Edward Cox, MD NIPH
`From
`m_—
`
`Proprietary Name
`Established S Name
`
`Harvoni
`lediasvir D /sofosbuvir SOF
`
`Dosage Forms / Strength
`
`fixed dose combination tablet
`LDV 90m SOF400 m
`
`Indication
`
`Harvoni is indicated for the treatment of chronic
`
`Action:
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`hepatitis C (CHC) genotype 1 infection in adults.
`Approval
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`
`
`Material Reviewed/Consulted
`0ND Action Package, including:
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`Names of discipline reviewers
`
`George Lunn, Rapti Madurawe 7/ 10/2014; George
`Lunn, Ste hen Miller 9/26/2014
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`Biopharmaceutics Review
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`Sandra Suarez, Angelica Dorantes, Richard Lostritto——
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`Statistical Review
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`Karen 0 i, Fraser Smith, Tsae Yun Lin
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`Pharmacology Toxicology Reviews Christopher Ellis, Hanan Ghantous, Abigail Jacobs
`Clinical Virolo 3
`Lisa Nae ' er, Eric Donaldson, Julian O’Rear
`Clinical Pharmacology Review
`Jenny Zheng, Leslie Chinn, Shirley Seo, Jeffry Florian,
`Yaning Wang
`Antoine El-Ha . e, Susan Thomson, Kassa A alew
`Kim Struble
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`CDTL Review
`
`De 11 Division Director’s Review Debbie Bimkrant
`OND=0fice ofNew Drugs
`OSI=Omce of Scientific Investigations
`CD'IIFCross-Discipline Team Leader
`
`Harvoni is a fixed-dose combination tablet of ledipasvir and sofosbuvir developed for the
`treatment of patients with chronic hepatitis C (CHC) genotype 1 infection. Ledipasvir is a
`hepatitis C Virus NSSA inhibitor. Sofosbuvir is a nucleotide analog hepatitis C virus NSSB
`inhibitor. Sofosbuvir has been previously approved (December 6, 2013) as Sovaldi
`(sofosbuvir), a single active ingredient tablet under Gilead’s NDA 204671. The ledipasvir
`component of Harvoni has not been previously approved in the US. The combination of
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`Reference ID: 3642277
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`NDA 205834
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`Page 2 of 4
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`ledipasvir and sofosbuvir received breakthrough therapy designation on July 22, 2013 for
`treatment of CHC genotype 1 and was granted a priority review.
`
`CHC infection causes a significant burden of disease in the United States and globally. In the
`U.S. 3.2 million people are estimated to be infected with hepatitis C virus. New therapies to
`treat CHC offer the promise of important advances in the care of patients with CHC. The
`development of direct acting antiviral agents has led to significant advances in the treatment of
`patients with CHC. The new treatments and treatment regimens are yielding sustained
`virologic response rates considerably higher than what has historically been possible prior to
`the advent of direct acting antiviral agents for the treatment of CHC.
`
`The review team has reviewed the issues in detail in their respective disciplines with regard to
`the safety and efficacy of ledipasvir / sofosbuvir. For a detailed discussion of NDA 205834,
`the reader is referred to the individual discipline specific reviews. In addition, the Cross-
`Discipline Team Leader’s review and the Division Director’s review summarize key issues in
`the NDA submission. This memorandum will focus on select issues from the review.
`
`The NDA is recommended for approval from the CMC perspective (9/26/2014 addendum).
`The biopharmaceutics review finds the amended procedure for monitoring for
`
`ledipasvir satisfactory (9/26/2014 addendum). The Product Quality Microbiology Review
`identifies no product quality microbiology deficiencies. The manufacturing facilities
`inspection summary of September 3, 2014 finds the facilities to be acceptable.
`
`The recommendation from the pharmacology/toxicology reviewers is for approval. The
`general toxicology of sofosbuvir was previously reviewed under Gilead’s NDA 204671 and is
`described in detail in the reviews for Gilead’s NDA 204671. The review of the toxicology
`studies for ledipasvir finds no clear organ of toxicity in studies in mice rats and dogs. There
`was note of a potential hepatobiliary toxicity signal that was not considered adverse and not
`dose dependent; the potential toxicity was a slight increase in alkaline phosphatase and/or
`alanine aminotransferase and increased liver/gall bladder weights (high-dose males only) in
`the absence of correlating histopathologic changes. Also noted was slight to minimal, random
`hepatocyte necrosis and bile duct hyperplasia. These findings, classified as non-adverse, were
`observed at exposures 8 to 30 times higher in mice and rats than the human exposure for
`ledipasvir. An ophthalmology consultation was requested to evaluate the potential for
`phototoxicity from ledipasvir. Gilead provided a 3-day multiple oral dose ocular phototoxicity
`study in pigmented male rats; no eye reactions indicative of phototoxicity were noted in this
`study. In addition, Gilead provided a single dose oral phototoxicity study in albino female
`hairless mice; no skin reactions indicative of phototoxicity were noted to have occurred in this
`study. Harvoni (ledipasvir/sofosbuvir) is categorized as pregnancy category B.
`Carcinogenicity studies of ledipasvir in mice and rats are ongoing. Two-year carcinogenicity
`studies of sofosbuvir in mice and rats showed no increase in drug-related neoplasms at the
`exposures achieved in animals (4- and 18-fold in male and female mice respectively and 8-
`and 10-fold in male and female rats respectively).
`
`The Clinical Virology Reviewers recommend that the data in NDA 205834 support approval.
`Ledipasvir is an inhibitor of the HCV NS5A protein. Sofosbuvir acts via inhibition of the
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`Reference ID: 3642277
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`(b) (4)
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`NDA 205834
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`Page 3 of 4
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`NS5B RNA-dependent RNA polymerase. The product labeling describes resistance mutations
`associated with decreased susceptibility in HCV replicons in cell culture and treatment
`emergent mutations from patients experiencing virologic failure.
`
`The Clinical Pharmacology reviewers find there is sufficient clinical pharmacology
`information to support approval of the application. Following oral administration of Harvoni,
`ledipasvir median peak concentrations were observed 4 to 4.5 hours after dosing and
`sofosbuvir was absorbed with a peak plasma concentration approximately 0.8 to 1 hours after
`dosing. Ledipasvir is >99.8% bound to plasma proteins; sofosbuvir is 61-65% bound to
`human plasma proteins. Ledipasvir is predominantly eliminated in the feces as the parent
`drug. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active
`nucleoside analog triphosphate GS-461203. The major elimination pathway is renal excretion
`with the metabolite GS-331007 representing the predominant metabolite in urine. No dosage
`adjustment for Harvoni is required in patients with mild and moderate renal impairment. The
`safety of Harvoni has not been established in patients with severe renal impairment or end
`stage renal disease; a statement is included in the Dosage and Administration section noting
`that no dose recommendation can be given for patients with severe renal impairment or with
`end stage renal disease. No dose adjustment for Harvoni is recommended for patients with
`mild, moderate, or severe hepatic impairment. The product labeling includes a Warnings and
`Precautions statement that Harvoni should not be used with rifampin or St. John’s wort
`because they are potent P-gp inducers and may lead to reduced concentrations and therapeutic
`effect of ledipasvir and sofosbuvir. The labeling also includes information on drug
`interactions.
`
`Sofosbuvir’s efficacy was evaluated in three phase 3 clinical trials and shown to be efficacious
`in the treatment of CHC infections in patients with genotype 1 as ledipasvir / sofosbuvir
`90/400 mg once daily in treatment naive and treatment experienced patients with or without
`cirrhosis. The trials were historically controlled trials comparing sustained virologic response
`(SVR) rates from the trials in patients treated with Harvoni to pre-specified SVR rates derived
`from historical data. Based upon the results of these trials, the duration of treatment for
`treatment-naïve with and without cirrhosis and treatment experienced patients without
`cirrhosis is 12 weeks. The labeling also notes that for treatment-naïve, non-cirrhotic patients
`with a pre-treatment HCV viral load less than 6 million IU/mL, 8 weeks can be considered.
`The duration of treatment for treatment-experienced patients with cirrhosis is 24 weeks. Using
`these treatment regimens, the studies did not reveal an increase in response with the addition of
`ribavirin. With regard to the fixed dose combination of sofosbuvir and ledipasvir, (1) these
`active moieties have different mechanisms of action; (2) the sofosbuvir component has
`previously been shown to be effective in the treatment of CHC (3) there is both cell culture
`and short term in vivo data from patients with CHC showing activity of ledipasvir
`monotherapy; these data, along with the overall results on SVR in the phase 3 trials for
`Harvoni, support the role for each component of Harvoni. In addition, as noted in the draft
`guidance on developing drugs for treatment of patients with CHC, it is important to limit the
`duration of direct acting antiviral agents as monotherapy because of the concern of developing
`resistance.1
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`1 Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment (10/16/13)
`http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf
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`Reference ID: 3642277
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`NDA 205834
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`Page 4 of 4
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`In clinical trials the most common adverse effects reported in clinical study participants treated
`with Harvoni were fatigue, headache, nausea, diarrhea, and insomnia. The product labeling
`also describes infrequent elevations of bilirubin, asymptomatic transient lipase elevations, and
`creatinine kinase elevations that were reported in subjects treated with sofosbuvir (creatinine
`kinase was not evaluated in phase 3 trials of Harvoni). The labeling also includes Warnings
`and Precautions statements that sofosbuvir should not be taken with P-gp inducers and should
`not be taken with other products that contain sofosbuvir (Sovaldi).
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`NDA 205834 was not presented before the Antiviral Drugs Advisory Committee. There were
`no particular issues with safety, efficacy, or trial design that warranted presenting the
`application to an Advisory Committee.
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`With regard to the required pediatric studies, we are waiving the pediatric study requirement
`for ages less than 3 years because necessary studies are impossible or highly impractical.
`Moreover, spontaneous clearance is possible and the risk-benefit balance would not favor
`treatment in this age group. We are deferring submission of a pediatric study for ages 3 to less
`than 18 years for this application because this product is ready for approval for use in adults
`and the pediatric studies have not been completed. The required pediatric assessments are
`enumerated in the approval letter.
`
`In summary, I agree with the review team, CDTL, and the Division Director, that the overall
`benefits and risks support the approval of NDA 205834 for Harvoni (ledipasvir/sofosbuvir)
`90/400 mg for the treatment of patients with CHC genotype 1 as described in the product
`labeling. The benefits of Harvoni for the treatment of CHC outweigh the risk of treatment
`with Harvoni. The approval of the combination of ledipasvir/sofosbuvir provides for a
`treatment regimen, one pill, taken once daily for treatment naive and experienced patients with
`or without cirrhosis that does not need to be taken in combination with interferon or ribavirin.
`The product labeling adequately describes the safety and efficacy findings. Postmarketing
`requirements include studies that will provide additional information on resistance mutations
`and pediatric safety and efficacy data in children ages 3 to less than 18 years of age.
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`____________________
`Edward Cox, MD, MPH
`Director, Office of Antimicrobial Products
`OND/CDER/FDA
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`Reference ID: 3642277
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`

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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/
`----------------------------------------------------
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`LINDA C ONAGA
`10/10/2014
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`JOHN J FARLEY on behalf of EDWARD M COX
`10/10/2014
`Signing on behalf of Dr. Edward Cox
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`Reference ID: 3642277
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`