November 25, 2013

Press Release

22/11/2013

Opinion concerns use in combination with sofosbuvir in patients with chronic hepatitis C in urgent need of therapy to prevent progression of liver disease

The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme.

Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation. In this specific case, Sweden has requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to daclatasvir, for the use in combination with sofosbuvir, with or without ribavirin, for a specific patient population.

The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognised that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes.

Daclatasvir and sofosbuvir are both first-in-class anti-viral medicines against HCV. These medicines have been studied in combination, with or without ribavirin, in aclinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury.

This is the second opinion provided by the CHMP on compassionate use of medicines in development for the treatment of hepatitis C. Overall, it is the fourth time compassionate use has been assessed by the CHMP.

The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States' legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.

The assessment report and conditions of use of daclatasvir in combination with sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency's website.

Notes

  • The first compassionate-use opinion for a hepatitis C treatment was adopted by the CHMP in October 2013.
  • Sofosbuvir, which is part of this compassionate-use opinion, received a positive opinion from the CHMP recommending granting of a marketing authorisation at its November 2013 meeting.
  • Daclatasvir is developed by Bristol-Myers Squibb and sofosbuvir is developed by Gilead.

European Medicines Agency advises oncompassionate use of daclatasvir (English only) 22/11/2013

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J&J HCV drug OK'd; educational push planned

Provided by MM&M

NOVEMBER 25, 2013

olysio_500835

Janssen's hepatitis C drug Olysio (simeprevir) scored FDA approval Friday evening, kicking off a new wave of hepatitis C drugs. It offers modest benefit over standard of care, but a subgroup of patients has encountered resistance, and the med could have trouble catching on as newer antivirals become more broadly available for treating the liver-destroying disease.

An NS3/4A protease inhibitor, Olysio was approved as part of a treatment regimen that also includes pegylated interferon (INF) and ribavirin (RBV) in patients with genotype-1 infection, which accounts for most cases of the virus. It followed a unanimous vote from an FDA ad-com panel in October for that same genotype.

Janssen has priced Olysio at a wholesale acquisition price of $22,120 per bottle of 28 capsules (150 mg capsules), which is an approximately one-month supply. "We believe that the price of Olysio reflects its value and demonstrated efficacy and safety profile," said Janssen spokesman Craig Stoltz via e-mail, adding that Janssen is offering a support program including help with access.

That's roughly $66,360 for a three-month course. Pooled analysis of two Phase III trials demonstrated that 80% of treatment-naïve patients taking Olysio were able to clear the virus at 12 weeks (SVR12), vs. 50% of patients in placebo groups.

Efficacy wise, the drug offers a slight benefit over the two currently used direct-acting antivirals, Vertex's Incivek and Merck's Victrelis (both of which were approved in 2011), with similar to better safety/tolerability, according to an October analyst note from inThought Research.

But the efficacy of Olysio, in combination with INF and RBV, is greatly decreased in patients who have genotype 1a Q80K, a naturally occurring variation in the HCV NS3/4A protease enzyme that was identified in 48% of patients with GT-1a infection. In the two Phase-III studies involving treatment-naïve patients, among those with GT-1a receiving Olysio who had the Q80K polymorphism, 58% achieved SVR12 vs. 84% of patients without the Q80K polymorphism. In the placebo arm, 52% of patients with the Q80K polymorphism achieved SVR12. Prior-relapser patients also showed a reduced effect.

"Regarding Q80K, Janssen has long been committed to patient education and plans to make information about resistance testing available to providers," added Stoltz. "This includes details regarding the availability of NS3 sequencing testing and referring them to the diagnostic companies for specific questions about the tests that are offered."

The issue could, nevertheless, impact the new drug's market share. Gilead's much-anticipated NS5B inhibitor sofosbuvir, now awaiting approval with a PDUFA date of December 8, 2013, is also expected to launch with a regimen that contains INF and RBV for GT-2 and GT-3 patients.

Gilead is expected to rack up more than 50% of the HCV market and at least $2.3 billion in global annual sales by 2016, according to an inThought forecast, possibly more depending on the extent of the treatable population. Olysio could still pick up $637 million in global annual sales in that timeframe, the analysts predict.

Of note, Gilead has studied an INF- and RBV-free combo of sofosbuvir + simeprevir in the COSMOS study, which included treatment naïve or previous null responder patients. The oral cocktail demonstrated SVR4 rates of 96% and 100% with or without RBV, respectively, as reported by inThought. Gilead, however, is likely to promote sofosbuvir with its own ledipasvir (GS-5885), an NS5A protein inhibitor, rather than with Olysio.

For J&J's part, in October it acquired an NS5A oral compound from GlaxoSmithKline called GSK805, which it will look to commercialize in its own all-oral regimen. “This combination would include a protease inhibitor, a non-nucleoside polymerase inhibitor, and an NS5a inhibitor, which is the same combination AbbVie is using in its ‘Aviator' combination of ABT-450/r + ABT-267 + ABT-333 with or without ribavirin,” wrote inThought. “These oral combinations, however, are missing a nucleoside NS5b inhibitor like Gilead's sofosbuvir.”

J&J will probably be late to the all-oral game behind Gilead and AbbVie, whose INF-free regimen is in Phase III.  Second-wave companies also include Bristol-Myers Squibb and Merck.

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HCV Viral Load at Baseline Sets Need for Protease Inhibitors

Published: Nov 25, 2013

By Cole Petrochko, Staff Writer, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that this randomized trial suggests that, among a carefully selected group of patients with mild hepatitis C who respond well to interferon and ribavirin, the addition of a protease inhibitor may be unnecessary.
  • Be aware that, while this regimen may be cost-saving, it is not necessarily symptom-sparing, as interferon is the major cause of adverse symptomatology during treatment.

Hepatitis C genotype I patients with low viral load and sustained virologic response may be able to cut protease inhibitors from therapy, researchers found.

Among a cohort of treatment-naive, noncirrhosis hepatitis C patients with low viral load at baseline, those who achieved an undetectable viral load after 4 weeks of peginterferon alfa-2b and ribavirin had no significant differences in sustained viral load when continued on double-drug therapy versus triple-drug therapy that included a protease inhibitor, according to Brian Pearlman, MD, of the Center for Hepatitis C at the Atlanta Medical Center in Georgia, and Carole Ehleben, EdD, also of Atlanta Medical Center.

These similarities remained regardless of viral subtype -- genotypes 1a or 1b -- or interleukin 28b genotypes, as well as ethnicity (black versus white), they wrote online in the journal Hepatology.

Recent clinical trial data demonstrated the "near perfect cure rates" of a four-drug hepatitis C virus (HCV) treatment as part of the SAPPHIRE-1 study. Other all-oral treatments containing two- and three-drug combinations have also shown to be well tolerated and safe, with cure rates of 89% or greater.

The authors noted that the current standard of therapy for treatment-naive HCV genotype I patients is a triple therapy of peginterferon, ribavirin, and a protease inhibitor. They studied whether the inclusion of a protease inhibitor in such patients who achieve rapid virologic response after 4 weeks of peginterferon and ribavirin therapy was necessary. The study population included 233 patients with low HCV viral load at baseline who did not have cirrhosis.

Baseline characteristics the researchers recorded included age, sex, body mass index, fasting glucose, 25-hydroxyvitamin D levels, ethnicity, histological results of pretreatment liver biopsy, and quantitative HCV viral load. Patients were stratified by HCV genotype and interleukin-28b genotype.

Roughly half of the sample (48%) achieved rapid virologic response to the 4-week regimen, and these participants were randomized to either two- or three-drug therapy, with the three-drug group receiving 24 weeks of treatment and the two-drug group receiving 20 weeks of treatment.

At baseline and at monthly follow-up, researchers recorded participant's physical characteristics, weight, Beck's Depression Inventory, blood count and differential, hepatic profile, thyroid stimulating hormone, electrolytes, serum creatinine, serum uric acid, and serum beta-human chorionic gonadotropin testing.

In addition to virologic response, adverse event profiles were not significantly different between two- and three-drug groups, nor were dose reductions and discontinuation.

"Baseline patient ethnicity, viral subtype, and interleukin-28b genotype did not seem to impact sustained virologic response rates ultimately, regardless of therapy used," they concluded, adding that these findings amplify "the point that on-treatment predictors of therapy success trump pretreatment expectations."

They also noted that protease inhibitors "are costly, and are not yet available in many countries that lack the monetary resources to cover them," and that these findings may present a significant cost savings in at least those HCV patients with a low viral load.

They cautioned that their research was limited to patients who had a low viral load at baseline, and these results may not generalize to patients with a high viral load at baseline. In addition, the study was performed in a single center and had no formal statistical hypothesis testing.

Pearlman declared support from Merck.

Primary source: Hepatology
Source reference: Pearlman BI, Ehleben C "Hepatitis C genotype 1 virus with low viral load and rapid virologic response to peginterferon/ribavirin obviates a protease inhibitor"Hepatology 2013; DOI: 10.1002/hep.26777.

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Provided by NATAP

Download the PDF here
Am J of Transplantation 2013
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AASLD: HCV Treatment Reduces Liver Disease/Death/Transplant - (11/18/13)

AASLD: (telaprevir/boceprevir) Sustained Virological Response After Protease Inhibitor-based Therapy For Hepatitis C Recurrence After Liver Transplantation: A Multicentric European Experience - (11/18/13)

AASLD: Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection After Liver Transplantation - (11/06/13)

AASLD: Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation: Preliminary Results of a Prospective, Multicenter Study- (11/05/13)

AASLD: Initial Evaluation of the Sofosbuvir Compassionate Use Program for Patients With Severe Recurrent HCV Following Liver Transplantation - (11/06/13)

64rd Annual Meeting of the American Association for the Study of Liver Diseases Washington, DC Nov 1-5 2013
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A case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis c following liver retransplantation http://www.natap.org/2012/HCV/082012_02.htm


Sofosbuvir and Daclatasvir Combination Therapy in a Liver Transplant Recipient With Severe Recurrent Cholestatic Hepatitis C

American Journal of Transplantation
June 13 2013
R. J. Fontana1,*, E. A. Hughes2, M. Bifano2, H. Appelman3, D. Dimitrova2, R. Hindes4 and W. T. Symonds4

"The lack of clinically apparent drug-drug interactions with the calcineurin inhibitors make both daclatasvir and sofosbuvir very attractive for future use in LT recipients with recurrent HCV infection [14, 15]. Of note, another LT recipient with severe recurrent HCV infection was recently treated with DCV, peginterferon and ribavirin for 24 weeks and did not experience any apparent drug-drug interactions with cyclosporine [24]"

Abstract

Recurrent HCV infection following liver transplantation can lead to accelerated allograft injury that is difficult to treat with interferon. The aim of this study is to describe the first ever use of an interferon-free, all oral regimen in a liver transplant recipient with severe recurrent HCV. A 54-year-old male with HCV genotype 1b developed severe cholestatic HCV at 6 months posttransplant with ascites, AST 503 IU/mL, alkaline phosphatase of 298 IU/mL, HCV RNA of 12 000 000 IU/mL, and histological cholestasis with pericellular fibrosis. Sofosbuvir, an HCV polymerase inhibitor (400 mg/day), and daclatasvir, an HCV NS5A replication complex inhibitor (60 mg/day), were co-administered for 24 weeks. Within 4 weeks of initiating treatment, serum HCV RNA levels became undetectable and liver biochemistries normalized with concomitant resolution of ascites. The patient achieved a sustained virological response with undetectable HCV RNA at 9 months posttreatment. During and following treatment, the daily dose and blood level of tacrolimus remained stable and unchanged. The rapid and sustained suppression of HCV replication in this liver transplant recipient provides great promise for the use of combination oral antiviral regimens in other immunosuppressed and interferon refractory HCV patients.

Introduction

Hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) in the United States and many parts of the world [1]. However, patient survival is significantly lower in HCV patients compared to other recipients due, in part, to the inevitable recurrence of HCV infection in the allograft that is characterized by high levels of HCV replication that can lead to accelerated necroinflammation and fibrosis [2, 3]. Peginterferon and ribavirin combination therapy has been used in selected LT recipients with moderate to severe recurrent HCV but is limited by frequent side effects and low antiviral efficacy [4, 5]. Although the protease inhibitors, boceprevir and telaprevir, markedly improve response rates when combined with peginterferon and ribavirin in HCV genotype 1 patients, both of these drugs are substrates and inhibitors of CYP3A4 which can lead to potentially severe drug-drug interactions when co-administered with calcineurin inhibitors [6, 7]. Preliminary data indicate that these drugs are associated with a high rate of anemia, infection and poor tolerability in LT recipients [8, 9]. As a result, use of these agents with peginterferon and ribavirin is currently not recommended in LT recipients until further studies have been completed. Daclatasvir (DCV) is a potent NS5A replication complex inhibitor with demonstrated antiviral activity in HCV genotype 1 patients when co-administered with peginterferon and ribavirin [10, 11]. Similarly, sofosbuvir (GS-7977), a potent oral nucleotide analogue inhibitor of HCV polymerase activity, has shown great promise when combined with ribavirin with or without peginterferon in both naïve and previously treated patients with multiple HCV genotypes [12, 13]. Both of these investigational agents are orally dosed once a day and have had a generally favorable side effect profile. In addition, neither drug is anticipated to cause significant drug-drug interactions when co-administered with other CYP3A4 substrates [14, 15]. The aim of this study is to report the first ever use of sofosbuvir combined with daclatasvir in a LT recipient with severe recurrent cholestatic HCV infection.

Results

A 54-year-old African American male with diabetes and coronary artery disease developed liver failure due to severe HCV genotype 1b infection that was resistant to prior interferon monotherapy and peginterferon and ribavirin combination therapy given pretransplant. At the time of LT, he had refractory ascites with a laboratory MELD score of 24. Within 6 months of LT, he developed severe recurrent cholestatic HCV infection with an HCV RNA level of 12 000 000 IU/mL, a serum aspartate aminotransferase (AST) of 503 IU/L, alanine aminotransferase (ALT) of 584 IU/L, alkaline phosphatase of 298 IU/L, total bilirubin of 1.9 mg/dL (direct 1.5 mg/dL) and INR of 1.3. He was fatigued with moderate ascites on exam and his body mass index was 22.2 kg/m2. An ERCP at month 4 postLT showed no evidence of a biliary stricture, a liver ultrasound with Doppler excluded portal vein thrombosis, and an inferior venacavagram with pressure measurements at month 6 postLT showed no evidence of venous outflow obstruction. A liver biopsy demonstrated mildly active chronic hepatitis C with focal bridging fibrosis and diffuse swelling of hepatocytes with perisinusoidal collagen deposition, both common features of fibrosing cholestatic hepatitis [16] (Figure 1).

Despite early discontinuation of mycophenolate mofetil and minimizing his tacrolimus and prednisone, his clinical status continued to deteriorate. Following the approval of an emergency IND by the FDA (#113 500), the patient signed a written informed consent approved by the local IRB to receive DCV, 60 mg/day (Bristol-Meyers Squibb, Princeton, NJ) and sofosbuvir 400 mg/day (Gilead Sciences, Foster City, CA) for 24 weeks at the University of Michigan Institute for Clinical and Health research Unit (Ann Arbor, MI). The research protocol included a pretreatment baseline visit as well as planned study visits at weeks 1, 2, 3, 4 and every 2 weeks through week 24 as well as at posttreatment weeks 4 and 24 wherein routine labs and tacrolimus levels were obtained as well as monitoring for adverse events. Study medications were dispensed on a monthly basis and the patient kept a log of daily medication administration as well as all concomitant medications. Serum HCV RNA was measured using the Roche Cobas Taqman assay (lower limit of quantification = 43 IU/mL) at weeks 0, 1, 2, 4, 12 and 24 and months 1, 2 and 6 posttreatment.

On the first day of drug dosing, his serum creatinine was 1.0 mg/dL, hemoglobin 13.9 g/dL, white blood cell count (WBC) 4.4 x 103/mL and platelets were 166 x 103/mL. Concomitant medications included furosemide, pantoprazole, vitamin D, tacrolimus 1.5 mg twice a day, insulin NPH 32 units each AM and prednisone 3 mg/day. The patient was IL28-B genotype CT. Within 4 weeks of starting treatment, HCV RNA was below the lower limit of detection (i.e. <43 IU/mL) and his liver biochemistries normalized (AST 24, ALT 17, alkaline phosphatase 96, total bilirubin 0.8) along with improvement of his albumin to 4.3 g/dL and INR of 1.0 (Figure 2). In addition, his symptoms of fatigue and ascites resolved. The patient completed 24 weeks of sofosbuvir and daclatasvir combination therapy with persistently undetectable HCV RNA and normal liver biochemistries. The patient did not experience any adverse laboratory or clinical adverse events attributed to either study drug. In fact with improvement in his fatigue, he was able to return to work by month 3 of antiviral treatment. At the end of treatment, his hemoglobin was 15.0 g/dL, WBC 7.7 x 103/mL, platelets 202 x 103/mL, INR 1.0 and creatinine was 1.3 mg/dL. The tacrolimus dose remained unchanged throughout antiviral treatment with a stable serum trough level of 4-6 ng/mL. During posttreatment follow-up, the patient did not receive any additional antiviral agent and was maintained on tacrolimus. He has remained well with undetectable HCV RNA at 9 months follow-up consistent with a sustained virological response. In addition, his serum AST 13 IU/mL, ALT 18 IU/mL, alk phos 101 IU/mL and total bilirubin of 0.5 mg/dL remain normal. Finally, his serum creatinine is stable at 1.3 mg/dL, hemoglobin 15.4 g/dL, WBC 7.8 x 103/mL and platelets of 195 x 103/mL.

Daclatasvir Pharmacokinetics

Daclatasvir pharmacokinetic parameters were stable throughout dosing (Table 1). The daclatasvir trough concentrations ranged from 57 to 196 ng/mL which is within the range of exposure where DCV has demonstrated antiviral activity when co-administered alone or in combination with peginterferon and ribavirin or other direct acting antiviral agents. The DCV Tmax for this subject was 4 h with a Cmax of 597 ng/mL which are also within the anticipated range of exposure.

Discussion

Severe recurrent HCV infection following LT is very challenging to manage. Interferon and ribavirin are difficult to initiate in many LT recipients due to their persistent pancytopenia from residual portal hypertension/splenomegaly and chronic renal insufficiency that precludes use of full dose peginterferon and ribavirin, respectively [4]. In addition, as many as 30-70% of treated patients require a medication dose reduction and 20-40% terminate therapy prematurely due to intolerable side effects. Furthermore, there is increasing recognition of immune-mediated allograft dysfunction due to Interferon that may not only require early discontinuation of treatment but also lead to premature graft failure and/or even death [5, 17]. However, since recent studies have demonstrated that LT recipients who achieve SVR have a significantly improved survival compared to nonresponders and untreated patients, there is an urgent need to develop safer and more effective therapies for LT recipients [18, 19]. The current study demonstrates that sofosbuvir in combination with daclatasvir is an efficacious and well-tolerated interferon free regimen in a LT recipient with severe recurrent cholestatic HCV infection. Ongoing studies have demonstrated that each of these agents when combined with peginterferon and ribavirin markedly improves SVR rates compared to peginterferon and ribavirin alone in HCV genotype 1 patients [11, 13]. In addition, potent antiviral efficacy of sofosbuvir combined with DCV with or without ribavirin for 24 weeks has been demonstrated in HCV genotype 1 patients [20]. In those phase 2 studies, 100% of patients became HCV RNA negative at week 4 and there was no evidence of resistance to either agent during or after therapy. Consistent with these findings, our interferon refractory patient who had a very high baseline HCV RNA level in the setting of tacrolimus and prednisone immunosuppression, achieved a serum HCV RNA below the lower limit of detection at week 4 and remained undetectable during and after treatment. These data demonstrate the potent antiviral activity of these individual agents when co-administered even to an immunosuppressed LT recipient. Furthermore, the excellent safety and side effect profile of this drug combination makes this interferon free regimen an attractive treatment option for other LT recipients with recurrent HCV infection. Daclatasvir in combination with peginterferon and ribavirin has generally been well-tolerated in over 1100 patients treated worldwide. No significant increase in the rate of laboratory or clinical adverse events was observed when compared to peginterferon and ribavirin alone and no unique daclatasvir related adverse events were identified [21]. Sofosbuvir has also been generally well tolerated with use in over 500 patients worldwide and an adverse event profile similar to placebo when given with ribavirin alone or in combination with peginterferon and ribavirin [22]. However, the dose and/or dosing interval of sofosbuvir may need to be altered in patients with severe renal impairment (i.e. GFR < 30 mL/min) as renal elimination is the main route of clearance for sofosbuvir and its metabolites [23]. In ongoing studies, some patients receiving sofosbuvir have reported headache and insomnia which are difficult to attribute to the sofosbuvir versus the peginterferon and ribavirin. Although preliminary data demonstrate that boceprevir or telaprevir with peginterferon and ribavirin can lead to rapid suppression of HCV replication in LT recipients with genotype 1, significant side-effects including transfusion dependent anemia, renal insufficiency, infection and even death have been reported highlighting the need for simpler and better tolerated therapies [8, 9].

The lack of clinically apparent drug-drug interactions with the calcineurin inhibitors make both daclatasvir and sofosbuvir very attractive for future use in LT recipients with recurrent HCV infection [14, 15]. Of note, another LT recipient with severe recurrent HCV infection was recently treated with DCV, peginterferon and ribavirin for 24 weeks and did not experience any apparent drug-drug interactions with cyclosporine [24]. In conclusion, the current study demonstrates the feasibility of combining potent oral antiviral agents with differing mechanisms of action in an LT recipient with severe recurrent cholestatic HCV infection. Although this African American patient had an unfavorable IL28-B genotype and a lack of response to prior peginterferon and ribavirin therapy, he rapidly responded to this interferon-free regimen. This case illustrates that the use of potent oral antiviral agents such as daclatasvir and sofosbuvir even early after transplantation offers great promise to the many HCV patients worldwide who are experiencing reduced quality of life and survival due to recurrent infection [2, 18]. Based upon this case, prospective studies involving these and other investigational oral antiviral agents in development should be undertaken for the growing number of LT recipients with clinically significant recurrent HCV infection. In addition, use of interferon-free regimens is of great interest in LT candidates with decompensated cirrhosis to reduce the frequency and severity of HCV recurrence but further studies in this difficult to treat population are needed.

Provided by NATAP

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Article in Press

Journal of Hepatology
Sarah Tischer 1, Robert J. Fontana 2
1 Department of Pharmacy Services, 2 Department of Internal Medicine.
University of Michigan Medical Center, Ann Arbor, MI 48109

Abstract

Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldeprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.

"Available data also suggest a lower likelihood of clinically significant DDI's with some of the new DAA's compared to BOC and TPV (Table 3) (32, 82,83, 88-89). However, several are CYP3A and drug transporter substrates and inhibitors. For example, the AUC of tacrolimus decreased by 17% and that of cyclosporine increased by 19% with simeprevir co-administration (78). ABT-450 is an inhibitor of OATP1B1 that leads to unconjugated hyperbilirubinemia and the boosting of its bioavailability with ritonavir, a potent CYP3A4 substrate, may create difficulties in the LT population (79). Although, sofosbuvir does not undergo metabolism via CYP3A, dose adjustments are anticipated for patients with moderate or severe renal impairment. Faldaprevir can lead to unconjugated hyperbilirubinemia via inhibition of UGT1A1 (80). Lastly, simeprevir is a substrate of OATP1B1 and results in an increase in total bilirubin levels in subjects treated with ribavirin (81)."

"Administration of daclatasvir with PEG-IFN and RBV for 24 In addition, the first ever successful use of an IFN-free regimen consisting of sofosbuvir and daclatasvir in a LT recipient with FCH was recently reported (83). Sofosbuvir combined with ascending doses of ribavirin for 24 weeks was also associated with a 77% week 4 post-treatment response rate and excellent tolerability in a recent pilot study (84). However, large, prospective, multicenter studies are needed to determine the optimal agent(s), duration of therapy, and safety profile of the new DAA's in LT recipients (86)."

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PRESS RELEASE

Nov. 25, 2013, 8:01 a.m. EST

Every Pledge on ProjectIDesign.com Will Reveal a Piece of a New, Community-Created Design

PR-Logo-Newswire

WHITEHOUSE STATION, N.J., Nov. 25, 2013 /PRNewswire via COMTEX/ -- To commemorate World AIDS Day 2013, Merck MRK +1.55% , known as MSD outside the United States and Canada, is encouraging people impacted by HIV to take action with the educational HIV campaign, I Design. Starting today, visitors to www.ProjectIDesign.com can mark the day by making a pledge to learn more about HIV, educate someone else about the condition, or help themselves or a loved one manage their HIV care.

Each pledge will virtually reveal a portion of a specially-designed fashion item from I Design campaign spokesperson, fashion designer and Project Runway All Stars Season 1 winner Mondo Guerra. The community pledges will culminate in the unveiling of an exclusive fashion item on World AIDS Day, Sunday, December 1, 2013. This endeavor is in line with the goal of World AIDS Day: bring together people from around the world, raise awareness about HIV/AIDS and demonstrate international solidarity.

The one-of-a-kind fashion item is crafted from printed canvases created by the HIV Community during this year's United States Conference on AIDS (USCA 2013). It symbolizes the uniqueness of each person living with HIV. Individuality is a focus of the I Design campaign, which encourages people to talk with their doctors to "tailor" their HIV treatment plan.

"This year's World AIDS Day creation, as part of the I Design campaign, is particularly special because the community has physically contributed to this piece and is going to unveil it one pledge at a time," said Mondo Guerra. "I was inspired by the many touching stories that people living with HIV shared with me through the campaign over the course of this year. This piece reflects how we came together in support of this important cause."

As a fashion designer, Mondo has a history of using his artistic skills as an advocate to raise HIV awareness. This includes his "positivity print" from Project Runway Season 8 and the I Design "individuality scarf"--a scarf that can be uniquely styled and worn in different ways by all people--that debuted at this year's USCA.

Join the I Design campaign and make a pledge on this World AIDS Day at www.ProjectIDesign.com.

About I Design I Design is a national HIV education campaign led by Merck, notable fashion designer Mondo Guerra and award-winning photographer Duane Cramer, aimed at helping to empower people living with HIV to have open and meaningful discussions with their doctors about their treatment plan based on their medical and lifestyle needs.

To learn more about the campaign, visit www.ProjectIDesign.com where you can download a conversation checklist, which offers tips on how to engage in an open and honest dialogue with your doctor; design a digital textile illustrating your approach to managing HIV; and view videos and photos. To help you track and manage your health, there are the "My Health Matters" and "My Positive Agenda" mobile and desktop apps. These easy-to-use tools help you track the symptoms of your HIV, set up reminders to take your medications on time and keep a record of when you have taken them, which can serve to prompt you on important discussion points when you are with your doctor. For additional tips and to follow Merck, Mondo and Duane's collaboration on I Design, join them on Twitter @Merck, @LoveMondoTrasho and @DuaneCramer.

About MerckToday's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

SOURCE Merck

Source

Gut. 2013 Nov 13. doi: 10.1136/gutjnl-2013-305785. [Epub ahead of print]

Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Batrla-Utermann R, Wang LY, You SL, Hsiao CK, Chen PJ, Chen CJ; for the R.E.V.E.A.L.-HBV Study Group.

Collaborators (25)

The Genomics Research Center, Academia Sinica, , Taipei, Taiwan.

Abstract

BACKGROUND AND AIMS: The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk.

METHODS: This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers.

RESULTS: The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30-75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither.

CONCLUSIONS: Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk.

KEYWORDS: HEPATITIS B, HEPATOCELLULAR CARCINOMA

PMID: 24225939 [PubMed - as supplied by publisher]

Source

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On November 22, 2013 FDA approved Olysio (simeprevir) 150 mg capsules for the treatment of chronic hepatitis C (CHC) infection, as a component of a combination antiviral treatment regimen. Below is a summary of the basis of approval and highlights from the prescribing information. Please refer to the full prescribing information for all the information needed to use OLYSIO safely and effectively.

INDICATIONS AND USAGE

OLYSIO is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

OLYSIO efficacy has been established in combination with peginterferon alfa and ribavirin, in HCV genotype 1 infected subjects with compensated liver disease (including cirrhosis)

The following points should be considered when initiating OLYSIO for treatment of chronic hepatitis C infection:

OLYSIO must not be used as monotherapy

OLYSIO efficacy in combination with peginterferon alfa and ribavirin is influenced by baseline host and viral factors.

OLYSIO efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.

OLYSIO efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes OLYSIO or other HCV protease inhibitors.

Dosage and Administration

The recommended dose of OLYSIO is one capsule of 150 mg taken orally once daily with food. The type of food does not affect exposure to simeprevir. The capsule should be swallowed as a whole.

OLYSIO should be used in combination with peginterferon alfa and ribavirin. For peginterferon alfa and ribavirin specific dosage instructions, refer to their respective prescribing information.

Duration of Treatment with OLYSIO, Peginterferon Alfa and Ribavirin

 

Treatment with OLYSIO, Peginterferon alfa and Ribavirin*

Treatment with Peginterferon alfa and Ribavirin*

Total Treatment Duration*

Treatment-naïve and prior relapser patients including those with cirrhosis

First 12 weeks

Additional 12 weeks

24 weeks

Prior non-responder patients (including partial and null responders) including those with cirrhosis

First 12 weeks

Additional 36 weeks

48 weeks

* Recommended duration of treatment if patient does not meet stopping rule (see Table 2).

 Prior relapser: undetectable HCV RNA at the end of prior interferon‑based therapy and detectable HCV RNA during follow‑up 

 Prior partial responder: prior on-treatment ≥ 2 log10 IU/ml reduction in HCV RNA from baseline at Week 12 and detectable HCV RNA at end of prior interferon‑based therapy. Prior null responder: prior on‑treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior interferon‑based therapy.

Hepatic Impairment

No dose recommendation can be given for patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C) due to higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity

The safety and efficacy of OLYSIO have not been studied in HCV‑infected patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). The combination of peginterferon alfa and ribavirin is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate or severe hepatic impairment.

WARNINGS AND PRECAUTIONS

Photosensitivity

Photosensitivity reactions have been observed with OLYSIO in combination with peginterferon alfa and ribavirin, including serious reactions which resulted in hospitalization. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment with OLYSIO in combination with peginterferon alfa and ribavirin, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.

Use sun protective measures and limit sun exposure during treatment with OLYSIO in combination with peginterferon alfa and ribavirin. Avoid use of tanning devices during treatment with OLYSIO in combination with peginterferon alfa and ribavirin. Discontinuation of OLYSIO should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO in the setting of a photosensitivity reaction, expert consultation is advised.

Rash

Rash has been observed in subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin. Rash occurred most frequently in the first 4 weeks of treatment with OLYSIO in combination with peginterferon alfa and ribavirin, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO have been reported. Most of the rash events in OLYSIO‑treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO should be discontinued. Patients should be monitored until the rash has resolved.

Sulfa Allergy

OLYSIO contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO.

ADVERSE REACTIONS

The most common reported adverse reactions (greater than 20% of subjects) in subjects receiving the combination of OLYSIO with peginterferon and ribavirin and occurring with at least 3% higher frequency compared to subjects receiving placebo in combination with peginterferon alfa and ribavirin during the first 12 weeks of treatment were: rash (including photosensitivity), pruritus and nausea.

DRUG INTERACTIONS

Potential for OLYSIO to Affect Other Drugs

Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.

Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co‑administration of OLYSIO with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.

Simeprevir inhibits OATP1B1/3 and P‑glycoprotein (P‑gp) transporters. Co‑administration of OLYSIO with drugs that are substrates for OATP1B1/3 and P‑gp transport may result in increased plasma concentrations of such drugs.

Potential for Other Drugs to Affect OLYSIO

The primary enzyme involved in the biotransformation of simeprevir is CYP3A. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co‑administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co‑administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy. Therefore, co‑administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended.

Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen may be Recommended Based on Drug Interaction Studies or Predicted Interaction 

Concomitant Drug

Class

Drug Name

Effect on Concentration of Simeprevir or Concomitant Drug

Clinical Comment

Antiarrhythmics

Digoxin*

 digoxin

Concomitant use of OLYSIO with digoxin resulted in increased concentrations of digoxin due to inhibition of P‑gp by simeprevir. Routine therapeutic drug monitoring of digoxin concentrations is acceptable.

Amiodarone

Disopyramide

Flecainide

Mexiletine

Propafenone

Quinidine

 antiarrhythmics

Concomitant use of OLYSIO with these antiarrhythmics may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted and therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co‑administered with OLYSIO.

Anticoagulants

Warfarin*

 warfarin

No dose adjustment is required when OLYSIO is co‑administered with warfarin. Routine monitoring of the international normalized ratio (INR) is acceptable.

Anticonvulsants

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

 simeprevir

Concomitant use of OLYSIO with carbamazepine, oxcarbazepine, phenobarbital or phenytoin may result in significantly decreased plasma concentrations of simeprevir due to strong CYP3A induction by these anticonvulsants. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with these anticonvulsants.

Anti‑infectives

Antibiotics:

Erythromycin*

 simeprevir

 erythromycin

Concomitant use of OLYSIO with erythromycin resulted in significantly increased plasma concentrations of both erythromycin and simeprevir due to inhibition of CYP3A and P‑gp by both erythromycin and simeprevir. It is not recommended to co‑administer OLYSIO with erythromycin.

Antibiotics:

Clarithromycin

Telithromycin

 simeprevir

Concomitant use of OLYSIO with clarithromycin or telithromycin may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by these antibiotics. It is not recommended to co‑administer OLYSIO with clarithromycin or telithromycin.

Antifungals (systemic administration):

Itraconazole

Ketoconazole

Posaconazole

 simeprevir

Concomitant use of OLYSIO with systemic itraconazole, ketoconazole or posaconazole may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by these antifungals. It is not recommended to co‑administer OLYSIO with systemic itraconazole, ketoconazole or posaconazole.

Antifungals (systemic administration):

Fluconazole

Voriconazole

 simeprevir

Concomitant use of OLYSIO with systemic fluconazole or voriconazole may result in increased plasma concentrations of simeprevir due to mild to moderate CYP3A inhibition by these antifungals. It is not recommended to co‑administer OLYSIO with systemic fluconazole or voriconazole.

Antimycobacterials:

Rifampin*†

Rifabutin

Rifapentine

 simeprevir

↔ rifampin, rifabutin, rifapentine

Concomitant use of OLYSIO with rifampin, rifabutin or rifapentine may result in significantly decreased plasma concentrations of simeprevir due to CYP3A4 induction by these antimycobacterials. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with rifampin, rifabutin or rifapentine.

Calcium Channel Blockers

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Nisoldipine

Verapamil

 calcium channel blockers

Concomitant use of OLYSIO with calcium channel blockers may result in increased plasma concentrations of calcium channel blockers due to intestinal CYP3A4 and/or P‑gp inhibition by simeprevir. Caution is warranted and clinical monitoring of patients is recommended when OLYSIO is co‑administered with calcium channel blockers.

Corticosteroids

Systemic

Dexamethasone

 simeprevir

Concomitant use of OLYSIO with systemic dexamethasone may result in decreased plasma concentrations of simeprevir due to moderate induction of CYP3A4 by dexamethasone. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with systemic dexamethasone.

Gastrointestinal Products

Propulsive:

Cisapride

 cisapride

Cisapride has the potential to cause cardiac arrhythmias. Concomitant use of OLYSIO with cisapride may result in increased plasma concentrations of cisapride due to intestinal CYP3A4 inhibition by simeprevir. It is not recommended to co‑administer OLYSIO with cisapride.

Herbal Products

Milk thistle

(Silybum marianum)

 simeprevir

Concomitant use of OLYSIO with milk thistle may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by milk thistle. It is not recommended to co‑administer OLYSIO with milk thistle.

St. John's wort (Hypericum perforatum)

 simeprevir

Concomitant use of OLYSIO with products containing St. John’s wort may result in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by St. John’s wort. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with products containing St. John’s wort.

HIV Products

Cobicistat‑containing product (elvitegravir/cobicistat/

emtricitabine/tenofovir disoproxil fumarate)

 simeprevir

Concomitant use of OLYSIO and a cobicistat‑containing product (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by cobicistat. It is not recommended to co‑administer OLYSIO with a cobicistat‑containing product.

Non‑Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):

Efavirenz*

 simeprevir

↔ efavirenz

Concomitant use of OLYSIO with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with efavirenz.

Other NNRTIs

(Delavirdine, Etravirine, Nevirapine)

 or  simeprevir

Concomitant use of OLYSIO with delavirdine, etravirine or nevirapine may result in altered plasma concentrations of simeprevir due to CYP3A inhibition (delavirdine) or induction (etravirine and nevirapine) by these drugs. It is not recommended to co‑administer OLYSIO with delavirdine, etravirine or nevirapine.

Protease Inhibitors (PIs):

Darunavir/ritonavir*‡

 simeprevir

 darunavir

Concomitant use of OLYSIO with darunavir/ritonavir resulted in increased plasma concentrations of simeprevir due to CYP3A inhibition by darunavir/ritonavir. It is not recommended to co‑administer darunavir/ritonavir and OLYSIO.

Protease Inhibitors (PIs):

Ritonavir*#

 simeprevir

Concomitant use of OLYSIO with ritonavir resulted in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by ritonavir. It is not recommended to co‑administer OLYSIO with ritonavir.

Other ritonavir‑boosted or unboosted HIV PIs, e.g., Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir

 or  simeprevir

Concomitant use of OLYSIO with ritonavir‑boosted or unboosted HIV PIs may result in altered plasma concentrations of simeprevir due to CYP3A inhibition or induction by these HIV PIs. It is not recommended to co‑administer OLYSIO with any HIV PI, with or without ritonavir.

HMG CO‑A Reductase Inhibitors

Rosuvastatin*

 rosuvastatin

Concomitant use of OLYSIO with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir. Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co‑administered with OLYSIO.

Atorvastatin* 

 atorvastatin

Concomitant use of OLYSIO with atorvastatin resulted in increased plasma concentrations of atorvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Use the lowest necessary dose of atorvastatin, but do not exceed a daily dose of 40 mg when co-administering with OLYSIO.

Simvastatin*

 

 simvastatin

Concomitant use of OLYSIO with simvastatin resulted in increased plasma concentrations of simvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co‑administered with OLYSIO.

Pitavastatin

Pravastatin

Lovastatin

 pitavastatin, pravastatin, lovastatin

Concomitant use of OLYSIO with pitavastatin, pravastatin or lovastatin has not been studied. The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co‑administered with OLYSIO.

Immunosuppressants

Cyclosporine*

 cyclosporine

No dose adjustment is required when OLYSIO is co‑administered with cyclosporine. Routine monitoring of blood concentrations of cyclosporine is acceptable.

Tacrolimus*

 tacrolimus

No dose adjustment is required when OLYSIO is co‑administered with tacrolimus. Routine monitoring of blood concentrations of tacrolimus is acceptable.

Sirolimus

 or  sirolimus

Concomitant use of OLYSIO and sirolimus may result in mildly increased or decreased plasma concentrations of sirolimus. Routine monitoring of blood concentrations of sirolimus is acceptable.

Phosphodiesterase Type 5 (PDE‑5) Inhibitors

Sildenafil

Tadalafil

Vardenafil

 PDE‑5 inhibitors

Concomitant use of OLYSIO with PDE‑5 inhibitors may result in mild increases in concentrations of PDE‑5 inhibitors due to intestinal CYP3A4 inhibition by simeprevir.

No dose adjustment is required when OLYSIO is co‑administered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction.

Dose adjustment of the PDE‑5 inhibitor may be required when OLYSIO is co‑administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE‑5 inhibitor and increase as needed, with clinical monitoring as appropriate.

Sedatives/Anxiolytics

Midazolam* (oral administration)

 midazolam

Concomitant use of OLYSIO with orally administered midazolam resulted in increased plasma concentrations of midazolam due to mild inhibition of intestinal CYP3A4 by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co‑administered with OLYSIO via the oral route.

Triazolam (oral administration)

 triazolam

Concomitant use of OLYSIO with orally administered triazolam may result in mild increases in concentrations of triazolam due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co‑administered with OLYSIO via the oral route.

The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK.

* These interactions have been studied in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted [see Clinical Pharmacology (12.3), Tables 6 and 7].

 The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co‑administered with rifampin 600 mg once daily.

 The dose of OLYSIO in this interaction study was 50 mg when co‑administered in combination with darunavir/ritonavir, compared to 150 mg in the OLYSIO alone treatment group.

# The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co‑administered in combination with ritonavir 100 mg given twice daily.

CLINICAL STUDIES

The efficacy of OLYSIO in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment‑naïve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon‑based therapy (PROMISE) and one Phase 2b trial in subjects who failed prior therapy with peginterferon (Peg‑IFN) and ribavirin (RBV) (including prior relapsers, partial and null responders) (ASPIRE). Prior relapsers were subjects who had undetectable HCV RNA at the end of prior IFN‑based therapy and detectable HCV RNA during follow‑up; prior partial responders were subjects with prior on‑treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and detectable HCV RNA at the end of prior therapy with Peg‑IFN and RBV; and null responders were subjects with prior on‑treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg‑IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC.

In subjects who were treatment‑naïve and prior relapsers, the overall duration of treatment with Peg‑IFN‑alfa and RBV in the Phase 3 trials was response‑guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on‑treatment protocol‑defined response‑guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detectable or undetectable) at Week 4 AND undetectable HCV RNA at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL LLOQ and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on‑treatment virologic response discontinued treatment in a timely manner.

SVR (virologic cure) was defined as undetectable HCV RNA 24 weeks after planned end of treatment (SVR24) in the Phase 2b trial and was defined as HCV RNA lower than 25 IU/mL detectable or undetectable 12 weeks after the planned end of treatment (SVR12) in the Phase 3 trials.

Treatment‑Naïve Adult Subjects with HCV Genotype 1 Infection

The efficacy of OLYSIO in treatment‑naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double‑blind, placebo‑controlled, 2‑arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The design of both trials was similar. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg‑IFN‑alfa‑2a (QUEST 1 and QUEST 2) or Peg‑IFN‑alfa‑2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg‑IFN‑alfa and RBV in accordance with the on‑treatment protocol‑defined RGT criteria. Subjects in the control groups received 48 weeks of Peg‑IFN‑alfa‑2a or ‑2b and RBV.

In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the OLYSIO and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg‑IFN‑alfa‑2a; in QUEST 2, 69% of the subjects received Peg‑IFN‑alfa‑2a and 31% received Peg‑IFN‑alfa‑2b.

Table 10 shows the response rates in treatment‑naïve adult subjects with HCV genotype 1 infection. In the OLYSIO treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 10: Treatment Outcome in Treatment‑Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2; Intent‑to‑Treat Analysis)

Treatment Outcome

OLYSIO + PR

N=521

% (n/N)

Placebo + PR

N=264

% (n/N)

Overall SVR12 (genotype 1a and 1b)

Genotype 1a

Without Q80K

With Q80K

Genotype 1b

80 (419/521)

75 (191/254)

84 (138/165)

58 (49/84)

85 (228/267)

50 (132/264)

47 (62/131)

43 (36/83)

52 (23/44)

53 (70/133)

Outcome for all subjects without SVR12

On‑treatment failure*

8 (42/521)

33 (87/264)

Viral relapse

11 (51/470) 

23 (39/172)

OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

* On‑treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol‑specified treatment stopping rules and/or experienced viral breakthrough).

 Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT. Includes 4 OLYSIO‑treated subjects who experienced relapse after SVR12.

In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of OLYSIO‑treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459).

Seventy‑eight percent (78%; 404/521) of OLYSIO‑treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404), while 8% (32/392) with undetectable HCV RNA at end of treatment had viral relapse.

SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 11 shows the SVR rates by METAVIR fibrosis score.

Table 11: SVR12 Rates by METAVIR Fibrosis Score in Treatment‑Naïve Adult Patients with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2)

Subgroup

OLYSIO + PR

% (n/N)

Placebo + PR

% (n/N)

F0‑2

84 (317/378)

55 (106/192)

F3‑4

68 (89/130)

36 (26/72)

OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

SVR12 rates were higher for subjects receiving OLYSIO with Peg‑IFN‑alfa‑2a or Peg‑IFN‑alfa‑2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg‑IFN‑alfa‑2a or Peg‑IFN‑alfa‑2b and RBV (62% and 42%, respectively) (QUEST 2).

Adult Subjects with HCV Genotype 1 Infection who Failed Prior Therapy

The PROMISE trial was a randomized, double‑blind, placebo‑controlled, 2‑arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN‑based therapy. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg‑IFN‑alfa‑2a and RBV, followed by 12 or 36 weeks of therapy with Peg‑IFN‑alfa‑2a and RBV in accordance with the protocol‑defined RGT criteria. Subjects in the control group received 48 weeks of Peg‑IFN‑alfa‑2a and RBV.

Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN‑based HCV therapy was Peg‑IFN‑alfa‑2a /RBV (68%) or Peg‑IFN‑alfa‑2b/RBV (27%).

Table 12 shows the response rates for the OLYSIO and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon‑based therapy. In the OLYSIO treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.

Table 12: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN‑Based Therapy (PROMISE; Intent‑to‑Treat Analysis)

Treatment Outcome

OLYSIO + PR

N=260

% (n/N)

Placebo + PR

N=133

% (n/N)

Overall SVR12 (genotype 1a and 1b)

Genotype 1a

Without Q80K

With Q80K

Genotype 1b

79 (206/260)

70 (78/111)

78 (62/79)

47 (14/30)

86 (128/149)

37 (49/133)

28 (15/54)

26 (9/34)

30 (6/20)

43 (34/79)

Outcome for all subjects without SVR12

On‑treatment failure*

3 (8/260)

27 (36/133)

Viral relapse

18 (46/249)

48 (45/93)

OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

* On‑treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol‑specified treatment stopping rules and/or experienced viral breakthrough).

 Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow‑up HCV RNA assessment. Includes 5 OLYSIO‑treated subjects who experienced relapse after SVR12.

In PROMISE, 93% (241/260) of OLYSIO‑treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241).

Seventy‑seven percent (77%; 200/260) of OLYSIO‑treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200), while 13% (25/196) with undetectable HCV RNA at end of treatment had viral relapse.

SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, andIL28B genotype. Table 13 shows the SVR rates by METAVIR fibrosis score.

Table 13: SVR12 Rates by METAVIR Fibrosis Score in Adult Patients with HCV Genotype 1 Infection who Relapsed after Prior Interferon‑Based Therapy (PROMISE)

Subgroup

OLYSIO + PR

% (n/N)

Placebo + PR

% (n/N)

F0‑2

82 (137/167)

41 (40/98)

F3‑4

73 (61/83)

24 (8/34)

OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT.

The ASPIRE trial was a randomized, double‑blind, placebo‑controlled, 7‑arm, Phase 2b trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg‑IFN‑alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg OLYSIO in combination with 48 weeks of Peg‑IFN‑alfa‑2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg‑IFN‑alfa‑2a and RBV.

Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800000 IU/mL; 63% had METAVIR fibrosis score F0, F1, or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg‑INF‑alfa and RBV. One hundred ninety‑nine subjects received OLYSIO 150 mg once daily (pooled analysis) of which 66 subjects received OLYSIO for 12 weeks and 66 subjects received placebo in combination with Peg‑IFN‑alfa and RBV.

Table 14 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.

Table 14: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg‑IFN‑alfa and RBV Therapy (ASPIRE Trial, Prior Partial and Null Responders)

Treatment Outcome

150 mg OLYSIO 12 Weeks + PR 

N=66

% (n/N)

Pooled 100 mg and 150 mg OLYSIO 12 Weeks + PR 

N=132

% (n/N)

Placebo + PR

N=66

% (n/N)

SVR24

Prior relapser

77 (20/26)

83 (44/53)

37 (10/27)

Prior partial responders

65 (15/23)

67 (31/46)

9 (2/23)

Prior null responders

53 (9/17)

45 (15/33)

19 (3/16)

Outcome for all subjects without SVR24

On‑treatment virologic failure*

Prior relapser

8 (2/26)

6 (3/53)

22 (6/27)

Prior partial responders

22 (5/23)

20 (9/46)

78 (18/23)

Prior null responders

35 (6/17)

36 (12/33)

75 (12/16)

Viral Relapse

Prior relapser

13 (3/23)

8 (4/49)

47 (9/19)

Prior partial responders

6 (1/17)

8 (3/36)

50 (2/4)

Prior null responders

18 (2/11)

20 (4/20)

25 (1/4)

150 mg OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks; Placebo: placebo with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT.

* On‑treatment virologic failure was defined as the proportion of subjects who met the protocol‑specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had detectable HCV RNA at EOT (for subjects who completed therapy).

 Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at EOT and with at least one follow‑up HCV RNA assessment.

In prior partial responders, SVR24 rates in subjects receiving OLYSIO with Peg‑IFN‑alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg‑IFN‑alfa and RBV. In prior null responders, SVR24 rates in subjects receiving OLYSIO with Peg‑IFN‑alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg‑IFN‑alfa and RBV.

SVR24 rates were higher in the OLYSIO‑treated subjects compared to subjects receiving placebo in combination with Peg‑IFN‑alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype.

The complete label will be available soon at Drugs@FDA

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration


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