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FDA:
VI. GENERAL SUMMARY
The currently available data support a favorable benefit-risk assessment for the use of sofosbuvir as part of a combination regimen for the treatment of chronic hepatitis C. In the HCV GT 2 and 3 populations, the sofosbuvir and ribavirin combination regimen provides the first all-oral, interferon-free treatment, as well as a shorter treatment duration and improved safety profile compared to the current standard of care interferon-based regimen. In addition, SOF+RBV provides a therapeutic option for patients who are ineligible, intolerant or unwilling to take interferon-based regimens, thus addressing an unmet need in this patient population.
In the HCV GT 1 and 4 populations, sofosbuvir in combination with pegylated interferon and ribavirin provides increased efficacy and shorter treatment duration compared with currently approved regimens. The shorter 12 week duration translates into a better tolerated side effect profile with observed treatment discontinuations due to AEs of less than 2%. The available data are believed to be insufficient to make definite dosing recommendations for patients with GT 5 or 6.
No major safety issues associated with sofosbuvir use have been identified to date. The observed safety profile between the two durations (SOF+RBV 12 weeks versus SOF+RBV 16 weeks) evaluated in FUSION is similar.
Gilead Briefing Document Attached:
EXECUTIVE OVERVIEW
On 08 April 2013, Gilead Sciences (Gilead) submitted a New Drug Application (NDA) to the United States (US) Food and Drug Administration (FDA) for sofosbuvir (SOF). SOF is a uridine nucleotide analog with potent anti-viral activity against hepatitis C virus (HCV) genotypes 1 through 6. SOF has a favorable safety profile. When administered in combination with ribavirin (RBV) for genotypes 2 and 3 HCV infection, it is the first all-oral therapy for this patient population, many of whom previously failed treatment or could not be treated. For patients with genotypes 1, 4, 5, and 6 HCV infection, SOF in combination with RBV and pegylated interferon (Peg-IFN) provides a shorter, simpler, and more effective interferon-limiting regimen.
The proposed indication for SOF is for the treatment of chronic HCV infection, in combination with other agents in adult patients with genotype 1 to 6 and/or adult patients awaiting liver transplantation. The recommended dose of SOF is one 400-mg tablet once daily administered orally with or without food. Table 1 summarizes the proposed SOF regimens and treatment durations.
Conclusions
The availability of SOF in combination with other anti-HCV drugs will provide physicians with a new, safe, and effective treatment option for patients with chronic HCV infection. Benefits of treatment with SOF include high response rates with shorter treatment durations than the previous standard-of-care treatments, little risk of the development of resistance, and an improved or similar safety profile to the currently available therapies. For patients with genotype 2 or 3 HCV infection, including those who failed prior treatment or who are ineligible or intolerant to current therapies, it will be the first time that a treatment option is available. Overall, the results of the SOF development program support the positive benefit/risk profile for the proposed indication for SOF to be administered in combination with other agents for the treatment of chronic HCV infection in adults (Section 1, Table 1).
FUSION: Treatment-Experienced Patients with Chronic Genotype 2 or 3 HCV Infection see p 78 Gilead document
FDA ANTIVIRAL DRUGS ADVISORY COMMITTEE MEETING
OCTOBER 25, 2013
BACKGROUND PACKAGE
FOR
NDA 204671
SOFOSBUVIR (GS-7977)
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION RESEARCH
OFFICE OF ANTIMICROBIAL PRODUCTS
DIVISION OF ANTIVIRAL PRODUCTS
During the Advisory Committee meeting, analyses will be presented addressing use of SOF+PEG+RBV in this population, including limitations of this approach such as the NEUTRINO single arm trial design and potential subpopulations in which this 12 week regimen may not be optimal (e.g., prior null responders). Acknowledging the lack of data directly obtained in this patient population, we believe that the SOF+PEG+RBV shorter treatment duration and improved tolerability profile warrants consideration by the Committee for use in HCV GT1 patients who have failed a prior PEG+RBV regimen.
As more DAA-based therapies emerge, the patient population who failed a prior PEG+RBV regimen is anticipated to diminish over time, and the traditional PEG+RBV-based treatment-naïve and treatment-experienced definitions may not be optimal. In addition, we recognize the baseline predictors identified from the long experience with PEG+RBV treatment may be different from those identified with DAA-based regimens.
C. Drug Interactions
Sofosbuvir is a substrate of drug transporters P-gp and BCRP, while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of sofosbuvir and thus should not be used with sofosbuvir. Coadministration of sofosbuvir with drugs that inhibit P-gp and/or BCRP would likely increase sofosbuvir plasma concentration (e.g., cyclosporine). The effects of coadministered drugs on the exposure of SOF and GS-331007 have been studied for cyclosporine, darunavir/ritonavir, emtricitabine, efavirenz, raltegravir, rilpivirine, tacrolimus, and tenofovir disoproxil fumarate. No clinically significant effect of sofosbuvir on these drug exposures has been observed. No significant changes in the exposures of sofosbuvir and GS-331007 caused by these coadministered drugs have been observed, with the exception of cyclosporine (CsA).
Coadministration of sofosbuvir with the P-gp and BCRP inhibitor CsA (administered as a single high dose of 600 mg), resulted in an increase (approximately 4.5-fold) in sofosbuvir exposure, but the exposure of GS-331007 was unchanged in the presence of CsA. The safety margins for sofosbuvir and metabolites after coadministration with CsA are adequate (AUC safety margins range from 2.9 to 10.3), when compared with exposures obtained in rat and dog in 3 to 9-month toxicology studies. Furthermore, limited safety data from ongoing post-transplant study (GS-US-334-0126) indicated that the safety of SOF+RBV is similar between subjects not taking CsA (N=30) and subjects taking CsA (N=10). Therefore, no dose modification of sofosbuvir is recommended when coadministered with CsA.
FROM GILEAD Briefing Document:
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VI. GENERAL SUMMARY
\The currently available data support a favorable benefit-risk assessment for the use of sofosbuvir as part of a combination regimen for the treatment of chronic hepatitis C. In the HCV GT 2 and 3 populations, the sofosbuvir and ribavirin combination regimen provides the first all-oral, interferon-free treatment, as well as a shorter treatment duration and improved safety profile compared to the current standard of care interferon-based regimen. In addition, SOF+RBV provides a therapeutic option for patients who are ineligible, intolerant or unwilling to take interferon-based regimens, thus addressing an unmet need in this patient population.
In the HCV GT 1 and 4 populations, sofosbuvir in combination with pegylated interferon and ribavirin provides increased efficacy and shorter treatment duration compared with currently approved regimens. The shorter 12 week duration translates into a better tolerated side effect profile with observed treatment discontinuations due to AEs of less than 2%. The available data are believed to be insufficient to make definite dosing recommendations for patients with GT 5 or 6.
No major safety issues associated with sofosbuvir use have been identified to date. The observed safety profile between the two durations (SOF+RBV 12 weeks versus SOF+RBV 16 weeks) evaluated in FUSION is similar.
VII. PRELIMINARY TOPICS FOR THE ADVISORY COMMITTEE
The Division is convening this meeting to solicit the Committee's comments on the following topics. Please note, however, that these are preliminary topics and are still subject to change.
1. Considering potential risks and benefits do the available data support approval of sofosbuvir in combination with pegylated interferon and ribavirin for treatment of chronic hepatitis C in treatment-naïve adult patients with genotype 1 and 4 infection?
Background Information for Consideration (Issue 1): As the question states, we are asking the Committee to weigh all the risks and benefits in the vote for approval. Please note that a vote for approval, in general terms, doesn't mean that one must agree with all of the proposed dosing recommendations or that one must define all labeling recommendations. Questions 3 through 7 that follow the general approval question/vote will give the Committee a chance to provide opinions on more granular issues and labeling recommendations, if there is consensus that the overall risk-benefit is positive and supportive of approval for use in treatment of hepatitis C. If not, please consider what additional studies should be recommended.
2. Considering potential risks and benefits do the available data support approval of sofosbuvir in combination with ribavirin for treatment of chronic hepatitis C in adult patients with genotype 2 and 3 infection?
Background Information for Consideration (Issue 2): As the question states, we are asking the committee to weigh all the risks and benefits in the vote for approval. The general background information included in Question 1 applies to this question as well.
3. Please comment on the strength of evidence for use of sofosbuvir in combination with pegylated interferon and ribavirin for treatment of chronic hepatitis C in patients with genotype 1 infection who are nonresponders to a prior course of pegylated interferon and ribavirin. Please comment if additional data are needed in this population.
4. Please comment on the strength of evidence (bridging analyses) for use of sofosbuvir and ribavirin for 16 weeks duration in treatment-naïve genotype 3 patients.
5. Please comment on the strength of evidence for use of sofosbuvir and ribavirin for 16 weeks duration in subgroups of genotype 2 patients who may benefit from an extended duration of therapy.
6. Please comment on the strength of evidence for use of sofosbuvir in combination with ribavirin in HCC patients meeting Milan criteria awaiting liver
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B. HCV Genotype 1, 4, 5 and 6 Population
1. Efficacy in HCV Genotype 1, 4, 5 and 6 treatment-naïve population (NEUTRINO)
This Phase 3, multicenter, open-label trial enrolled treatment-naive subjects with chronic genotype 1, 4, 5, or 6 HCV infection. Subjects received SOF (400 mg once daily) + PEG (180 μg/week) + RBV (1000 or 1200 mg/day) for 12 weeks. A total of 327 subjects received study drugs, including 17% with compensated cirrhosis.
Overall, a statistically significant proportion of subjects achieved SVR12 (90%, p < 0.0001) compared with a historical SVR12 rate of 60% (Table 6). Relapse accounted for most treatment failures, with an overall rate of 9%. No subject had on-treatment virologic failure. Subjects with GT1 (N=292) had an SVR12 rate of 89%, with a GT1a and GT1b subtype difference noted (SVR12 92% and 82%, respectively). Subjects with GT4 (N=28) had an SVR12 rate of 96%. It should be noted that few subjects with GT5 (N=1) and GT6 (N=6) were included in the clinical trial and the available data are believed to be insufficient to make definitive dosing recommendations for patients with HCV GT5 or 6 infection.
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3. HCV Genotype 1 Infection, Prior Pegylated Interferon Nonresponders: Exploratory Analyses
HCV GT1 patients who failed prior treatment with PEG+RBV were not specifically studied in the SOF development program. Clinical HCV trials have generally categorized patients as treatment-naïve or treatment-experienced based upon their prior virologic response to a PEG+RBV regimen. Previous FDA analyses have demonstrated that PEG+RBV nonresponders are represented within the treatment-naïve population (Liu et al. Hepatology 2013, Liu et al. CID 2012, Florian et al. Hepatology 2013). Other baseline factors or patient characteristics such as cirrhosis status and viral load have been shown to predict response to a PEG+RBV regimen. The observed high overall SVR rate in HCV GT1 treatment-naïve subjects from NEUTRINO led the Division to use a similar approach to explore if the data may support use of SOF+PEG+RBV for 12 weeks in patients who have failed a prior PEG+RBV regimen. During the Advisory Committee meeting, analyses will be presented addressing use of SOF+PEG+RBV in this population, including limitations of this approach such as the NEUTRINO single arm trial design and potential subpopulations in which this 12 week regimen may not be optimal (e.g., prior null responders). Acknowledging the lack of data directly obtained in this patient population, we believe that the SOF+PEG+RBV shorter treatment duration and improved tolerability profile warrants consideration by the Committee for use in HCV GT1 patients who have failed a prior PEG+RBV regimen.
As more DAA-based therapies emerge, the patient population who failed a prior PEG+RBV regimen is anticipated to diminish over time, and the traditional PEG+RBV-based treatment-naïve and treatment-experienced definitions may not be optimal. In addition, we recognize the baseline predictors identified from the long experience with PEG+RBV treatment may be different from those identified with DAA-based regimens.
Extending the treatment duration by 4 weeks increased SVR12 rates in HCV GT2 subjects from 82% to 89%, and in HCV GT3 subjects from 30% to 62%.
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Across the Phase 3 trials, higher SVR12 rates occurred in HCV GT2 subjects compared with HCV GT3 subjects.
· FISSION (treatment-naïve): HCV GT2 subjects had a significantly higher SVR12 rate than HCV GT3 subjects in the SOF+RBV 12 Week group (95% and 56% of HCV GT2 and 3 subjects, respectively) (p-value <0.0001).
· POSITRON (IFN-intolerant, ineligible, unwilling): HCV GT2 subjects had significantly higher SVR12 rates than HCV GT3 subjects in the SOF+RBV 12 Week group (93% and 61%, respectively) (p-value < 0.0001).
· FUSION (treatment-experienced): the SVR12 rate difference between HCV GT2 and 3 subjects was significant within each treatment duration group.
->SOF+RBV for 12 weeks: SVR12 rates were 82% and 30% for HCV GT2 and 3 subjects, respectively (p-value < 0.0001).
->SOF+RBV for 16 weeks: SVR12 rates were 89% and 62% for HCV GT2 and 3 subjects, respectively (p-value = 0.0052).
The HCV GT3 relapse rate in the 16 Week arm was still as high as 38% even though much lower than 66% in the 12 Week arm. This observation suggests the efficacy could potentially be further improved with longer treatment duration or an additional antiviral agent (e.g., PEG or another direct acting antiviral).
b. Bridging Analyses to Explore Treatment Duration in Treatment-Naïve Genotype 3 Subjects
The collective evidence from the Phase 3 trials indicates 12 weeks of SOF+RBV is not the optimal regimen for HCV GT3 patients. Reduced response rates in HCV GT3 subjects were driven by relapse, indicating extending the duration of therapy may improve SVR. FUSION demonstrated HCV GT3 treatment-experienced subjects receiving SOF+RBV for 16 weeks had significantly increased SVR12 rates compared with the same regimen for 12 weeks, 62% versus 30%, respectively, as well as lower relapse rates (38% versus 66%, respectively). Additionally, response rates for HCV GT3 subjects were consistently lower than HCV GT2 subjects across all three trials. These observations suggest that a longer treatment duration may also be beneficial in the HCV GT3 treatment-naïve population; however, the available Phase 3 trials only evaluated SOF+RBV for 12 weeks. Due to the overall lower SVR12 rate observed in HCV GT3 patients, the FDA requested the Applicant to provide analyses justifying a treatment duration for HCV GT3 treatment-naïve patients based on the available Phase 3 data. These analyses, which are included in the Applicant's background package, show their bridging analysis to estimate the SVR12 rate for 16 weeks of SOF+RBV in HCV GT3 treatment-naïve patients using the GT3 data from FISSION and FUSION.
FDA analyses were also conducted to estimate the treatment response of 16 weeks of SOF+RBV treatment in HCV GT3 treatment-naïve subjects. Instead of applying the Applicant's model to estimate the SVR12 rate, the FDA analyses extrapolated the SVR12 rate from the observed SVR12 rates in FISSION and FUSION based on an assumption of equivalent odds ratios of SOF+RBV 16 Weeks over SOF+RBV 12 Weeks compared to SOF+RBV 12 Weeks in both treatment-naïve and treatment-experienced HCV GT3 subjects. This odds ratio analysis predicted an SVR12 rate of 83% for 16 weeks of SOF+RBV in HCV GT3 treatment-naive subjects (Table 4). Alternative calculations based on using either relative risk (RR) or proportion difference (PD) were also evaluated and resulted in estimated SVR12 rates of 76% and 88%, respectively. Thus, these exploratory post-hoc analyses determined the estimated SVR12 rate for 16 weeks in HCV GT3 treatment-naive subjects ranges from 76% to 88% depending on the extrapolation approach used, and suggest 16 weeks of SOF+RBV treatment in HCV GT3 treatment-naïve subjects would lead to a higher SVR12 rate than the 56% SVR12 rate observed for 12 weeks of SOF+RBV treatment in the FISSION trial.
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