Shorter HCV Tx Works in Advanced Disease

Provided by MedPage Today

Twelve weeks of treatment yielded high efficacy rates in hepatitis C (HCV) patients with advanced liver disease or recurrent HCV after transplant.

by Michael Smith
North American Correspondent, MedPage Today

VIENNA -- In hepatitis C virus (HCV) patients with advanced liver disease or recurrent HCV after transplant, 12 weeks of treatment yielded high efficacy rates, a researcher said here.

Efficacy did not differ greatly among patients randomly assigned to 12 or 24 weeks of treatment with the fixed-dose combination of ledipasvir/sofosbuvir (Harvoni) given with ribavirin, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

And the combination was generally well-tolerated -- an important consideration among the seriously ill patients in the so-called SOLAR-2 trial, Manns told reporters here at the annual meeting of the European Association for the Study of the Liver.

The study evaluated the safety and efficacy of the therapy in patients with Child-Pugh scores of B and C either pre- or post-transplant, or in those whose disease had recurred after transplant but who were Child-Pugh A or had fibrosis scores of F0 through F3.

The goal was to compare outcomes with 12 weeks of therapy with those after 24 weeks -- the recommended duration for such patients in Europe, Manns said.

For most patients with conditions similar to those in the trial, Manns said, "I would feel comfortable treating for 12 weeks."

But most of the 328 patients had genotype 1 disease, and the handful of patients in the study with genotype 4 HCV did not do as well, he noted. For those patients, he said, he would continue to aim for 24 weeks of therapy "depending on tolerability."

What to do with the difficult-to-treat patients in the study is a tough question, commented Markus Peck-Radosavljevic, MD, of the Medical University of Vienna and current Secretary General of EASL.

On one hand, Peck-Radosavljevic told MedPage Today, the study does show that the treatment "is not endangering" the patients and can lead to cures in most cases.

But on the other hand, he said, "there might be a point where you don't do them a favor by making them virus-free."

It could happen, he said, that treatment might cure a patient of HCV, leaving him or her ineligible for a transplant but still with a seriously damaged liver.

In many cases, he said, it might be better to go ahead with a transplant and count on being able to cure recurrent HCV afterward.

Patients in the trial, Manns said, had either genotype 1 or 4 and were stratified into six groups:

• Patients without transplant and either Child-Pugh B or Child-Pugh C cirrhosis -- groups 1 and 2
• Patients with recurrent HCV after liver transplantation and either without cirrhosis or with Child-Pugh A, B, or C cirrhosis -- groups 3 through 6

The endpoint of the study was sustained virologic response 12 weeks after the end of treatment (SVR₁₂).

Overall, Manns reported, post-transplant patients without fibrosis or with Child-Pugh A status did equally well with 12 or 24 weeks of therapy -- SVR₁₂ rates were 95% and 98%, respectively.

Patients with Child-Pugh B or C cirrhosis, regardless of transplant status, did less well but, again, treatment duration seemed to have little effect -- 85% with SVR₁₂ at 12 weeks and 88% at 24 weeks, Manns reported.

Differences appeared when the patients were broken down by genotype, however.

Among patients with genotype 1 disease, 12- and 24-week SVR₁₂ rates were 96% and 98% if they had low fibrosis scores or Child-Pugh A cirrhosis, and 88% and 89%, respectively, for those with Child-Pugh B or C cirrhosis.

The 18 patients with genotype 4 and less advanced liver damage had SVR₁₂ rates of 91% and 100% after 12 and 24 weeks of therapy, respectively.

But among the 14 patients with genotype 4 and Child-Pugh B and C cirrhosis, 12- and 24-week SVR₁₂ rates were 57% and 86%, respectively.

Most patients reported at least one adverse event, with rates of between 92% and 95%, Manns said, but serious adverse events were much less common -- reported by between 14% and 28% of patients, with more seen among those with more advanced disease.

There were no treatment-related adverse events in patients without cirrhosis and nine among those with cirrhosis, including five reports of anemia and one each of falling, vomiting, diarrhea, and hyperbilirubinemia.

Although there were 10 deaths, none was considered related to treatment, Manns said.

The study was supported by Gilead Sciences. Manns disclosed relevant relationships with AbbVie, BI, BMS, Gilead, Janssen, Merck, Novartis, Roche, Idenix, and GSK. Some authors are employees of Gilead.

Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

Primary Source: European Association for the Study of the Liver

Source Reference: Manns M, et al "Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post liver transplantation patients with HCV infection: Preliminary results of the prospective SOLAR 2 trial" EASL 2015; Abstract G02.

Source

Also See: Gilead’s Harvoni and Sovaldi Demonstrate Efficacy and Safety among Chronic Hepatitis C Patients with Advanced Liver Disease

Gilead’s Harvoni and Sovaldi Demonstrate Efficacy and Safety among Chronic Hepatitis C Patients with Advanced Liver Disease

-- High Cure Rates in More Than 600 Genotype 1 and 4 Patients With Limited or No Approved Treatment Options --

VIENNA, Austria--(BUSINESS WIRE)--Apr. 23, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from several Phase 2 clinical studies evaluating investigational uses of Harvoni^® (ledipasvir 90 mg/sofosbuvir 400 mg) and other Sovaldi^® (sofosbuvir 400 mg)-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in patients with advanced liver disease, including patients with decompensated cirrhosis, patients with fibrosing cholestatic hepatitis C (a rare and severe form of the disease following liver transplantation) and patients with portal hypertension. These data will be presented this week at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.

“The patients included in these analyses are among the most difficult to both treat and cure and, until now, have had limited or no treatment options,” said Michael P. Manns, MD, Professor and Chairman, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. “These data demonstrate that, even among these difficult-to-treat patient groups, sofosbuvir-based oral therapy offers the potential of high cure rates, improves outcomes and is generally well tolerated with a favorable safety profile.”

Harvoni and Sovaldi are each approved in the United States for the treatment of chronic HCV infection. Harvoni is indicated for patients with genotype 1; Sovaldi is used in combination with other agents and its efficacy has been established in patients with genotypes 1-4.

Decompensated and Post-Liver Transplantation

In SOLAR-2 (Study GS-US-337-0124, Oral #G02), 328 genotype 1 or 4 HCV patients with decompensated liver disease before liver transplantation or recurrent HCV infection following liver transplantation were randomized to receive either 12 or 24 weeks of Harvoni plus ribavirin (RBV). Ten patients were excluded from the analysis because of transplantation (n=7) or because they were pre-transplantation, but not decompensated (n=3); an additional 27 of these patients have not yet reached post-treatment week 12. The number and proportion of genotype 1 patients with available data achieving sustained virologic response 12 weeks after treatment (SVR12) are summarized in the table below.

Of the 32 genotype 4 patients, 27 (84 percent) achieved SVR12. Additionally, among patients with compensated and decompensated cirrhosis before and after liver transplantation, virologic response was associated with improvements in Model for End-Stage Liver Disease (MELD) and CPT scores used to stage end-stage liver disease.

The most common adverse events were fatigue, anemia, nausea and headache. Overall, six patients discontinued treatment due to adverse events, five of whom had decompensated cirrhosis.

Further supporting the safety profile of Harvoni plus RBV among this patient population was data from a pooled safety analysis of 659 patients treated in the SOLAR-1 and SOLAR-2 studies (ePoster #P0774). Both studies evaluated Harvoni plus RBV for 12 or 24 weeks in genotype 1 or 4 HCV patients with decompensated liver disease or recurrent HCV infection following liver transplantation. SOLAR-1 was conducted in the United States, with data presented in November at The Liver Meeting 2014 and SOLAR-2 was conducted in Australia, Canada, Europe and New Zealand. Overall, adverse events were similar to those seen in previous studies, including the Phase 3 ION studies. Fewer than three percent (n=19/659) of patients discontinued due to an adverse event, none of which were attributed to Harvoni treatment. There were a total of 20 deaths in these two studies, none of which was assessed by the investigator as related to study treatment.

Fibrosing Cholestatic Hepatitis C

A further subset of the SOLAR-1 and SOLAR-2 studies (ePoster #P0779) demonstrated 100 percent SVR12 rates among 11 patients who were confirmed to have fibrosing cholestatic hepatitis (FCH), following 12 or 24 weeks of Harvoni plus RBV. FCH is a rare and severe form of recurrent hepatitis that occurs after liver transplantation. It is associated with high morbidity and mortality rates and there are no currently approved treatment options.

Cirrhosis and Portal Hypertension

Study GS-US-334-0125 (ePoster LB #4283) evaluated 50 genotype 1-4 HCV-infected patients with cirrhosis and portal hypertension. Patients were randomized to receive either 48 weeks of Sovaldi plus RBV initially (n=25) or at the conclusion of a 24-week observation period (n=21). Four patients in the observation arm discontinued the study prior to receiving treatment. Of the patients who received treatment with Sovaldi plus RBV, 72 percent (n=33/46) achieved SVR12. A subset of 37 patients had paired hepatic venous pressure gradient (HVPG) measurements at baseline and end of treatment. Of these, 38 percent (14/37) of patients experienced a ≥10 percent reduction and 24 percent (9/37) of patients experienced a ≥20 percent decrease in HVPG from baseline to end of treatment. A baseline total bilirubin of <1.5 mg/dL was associated with a ≥20 percent decrease in HVPG (p=0.03). This study is the first to demonstrate the effect of direct acting antivirals like Sovaldi on HVPG, and additional assessments will be undertaken in these patients one-year post treatment.

The safety and efficacy of these investigational uses of Harvoni and Sovaldi have not been established.

Important Safety Information About Harvoni

Warnings and Precautions

Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (≥10 percent, all grades) adverse reactions were fatigue and headache.

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

Important Safety Information About Sovaldi

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral (DAA): Amiodarone is not recommended for use with Sovaldi in combination with another DAA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Pregnancy: Use with ribavirin or peginterferon alfa/ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20 percent, all grades) adverse reactions for:

Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia

Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

About Gilead

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including that Gilead may observe unfavorable results from additional clinical trials involving Sovaldi and Harvoni for various difficult-to-treat patient groups, including patients with decompensated cirrhosis, fibrosing cholestatic hepatitis C and portal hypertension. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full Prescribing Information for Sovaldi and Harvoni is available at www.gilead.com.

Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc., or its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Sung Lee, +1 650-524-7792 (Investors)
Nathan Kaiser, +1 650-522-1853 (Media)
Michele Rest, +1 650-577-6935 (Media)

Source

B.C covers two curative hepatitis C drugs

Monday, March 23, 2015 3:00 PM

VICTORIA - British Columbia is providing public drug plan coverage of two new, often curative, hepatitis C drugs effective March 24, 2015, announced Minister of Health Terry Lake today.

People with hepatitis C will be able to apply tomorrow for coverage under B.C.’s PharmaCare program of Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir). These new medications cure about 90% or more of people treated; are easier to take; involve a much shorter course of treatment; and have fewer side effects than older drugs.

“These two new drugs can utterly change the lives of people with hepatitis C for the better,” said B.C. Health Minister Terry Lake. “These drugs represent a significant advance in the treatment of chronic hepatitis C, and more British Columbians affected by this virus now have significantly better odds of becoming free of the disease.”

British Columbia and Ontario jointly led negotiations with the drugs’ manufacturer through the pan-Canadian Pharmaceutical Alliance (pCPA). The alliance’s process allows participating provinces and territories to leverage their collective buying power and negotiate better prices for new drugs.

“This is another example of the power of our collective action, when we choose to work as one,” said Ontario Minister of Health and Long-Term Care Dr. Eric Hoskins. “By working collectively to leverage our joint buying-power, we have been able to expand access for patients in a responsible way that makes our health-care system more sustainable.”

Each participating jurisdiction can choose whether to accept the deal and cover the drugs on their public drug plans. Prices and terms for this negotiation are confidential.

Sovaldi treats hepatitis C genotypes 1, 2, and 3, and was approved for sale by Health Canada in late 2013. Harvoni treats genotype 1, and was approved for sale in late 2014.

Many older hepatitis C treatments often have difficult side effects; one such treatment, peginterferon, is injected under the skin as well. Older drugs also have various cure rates for those able to tolerate the side effects. Both Harvoni and Sovaldi are swallowed as a pill, and have far fewer side effects.

“This is incredibly welcome news for people living with hepatitis C in B.C. and their families,” said Daryl Luster, president of the board of the Pacific Hepatitis C Network. “As a person who treated with interferon and ribavirin, I know how difficult those older therapies are. The hepatitis C community is excitedly anticipating the change these new game-changing medications will bring to thousands of people living with hepatitis C in British Columbia.”

PharmaCare will cover Sovaldi or Harvoni for people who meet certain criteria. For example, people who have never before been treated for hepatitis C or who have failed treatment with older drugs may be eligible for coverage.

The B.C. Ministry of Health expects to cover treatment for about 1,500 people in the first year. PharmaCare will monitor and evaluate the effectiveness of the drugs and the outcomes for patients as part of its coverage program.

“These publically funded drugs will bring the hepatitis C cure to infected British Columbians, improve their health, and prevent needless deaths from liver disease,” said Dr. Mel Krajden, medical head, hepatitis for the B.C. Centre for Disease Control and professor at the Department of Pathology and Laboratory Medicine at the University of British Columbia. “This begins the path to eliminate hepatitis C in British Columbia.”

In order to fund these drugs and other new therapies, the ministry will continue its overall efforts to lower drug costs for PharmaCare. Some recent examples include: the recent single-sourcing of seven generic drugs; participation in the pan-Canadian price initiative, which has brought ten common generic drugs to 18% of the brand name price; and PharmaCare coverage changes for DPP-4 inhibitor diabetes drugs. These efforts have saved tens of millions of dollars for PharmaCare.

Sovaldi and Harvoni are the second and third new hepatitis C drugs PharmaCare has covered in the past six months. In October, PharmaCare began coverage of Galexos (simeprevir) for certain people after successful negotiations to lower its price.

PharmaCare also covers Victrelis (boceprevir) and peginterferon/ribavirin, for the treatment of chronic hepatitis C.

March is Liver Health Month, which provides an opportunity to raise awareness of the signs and risk factors for liver disease, including hepatitis C.

Quick facts:

• Hepatitis C is a serious, communicable disease that is spread through direct contact with the blood of an infected person. Symptoms may include fatigue, jaundice, abdominal pain, and joint pain. In some people, it can cause liver damage (cirrhosis) or liver cancer.
• There are about 80,000 people living with hepatitis C in B.C. However, many people with the virus have no symptoms; about 33% of people living with hepatitis C do not know they have it.
• About a quarter of people with hepatitis C do not need treatment, as their body fights off the infection.
• For those with persistent chronic infections and disease in B.C., about 50,000 in B.C. may eventually require treatment.
• People who are successfully treated and cured of hepatitis C infection are then not able to pass the disease on to others.
• In 2013-14, about 1,200 people in B.C. were treated for chronic hepatitis C with medication.

Learn more:

For more information on PharmaCare coverage of hepatitis C drugs, please visit: http://www.health.gov.bc.ca/pharmacare/formulary/dds.html

For more information about liver health, please visit: www.liver.ca

Media Contacts:

Laura Heinze
Media Relations Manager
Ministry of Health
250 952-1887 (media line)

Source

FDA Safety Alert on Sovaldi/Harvoni Label Change

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

Serious and Life-Threatening Cases of Symptomatic Bradycardia as well as One Case of Fatal Cardiac Arrest Reported with Coadministration of amiodarone with either Harvoni® (ledipasvir and sofosbuvir fixed-dose combination) or with Sovaldi® (sofosbuvir) in combination with another direct acting antiviral.

On March 20, 2015, FDA approved changes to the Harvoni (ledipasvir/sofosbuvir fixed dose combination) and Sovaldi (sofosbuvir) labels to update the WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and DRUG INTERATIONS sections of the labeling and the patient package insert with information on post-marketing cases of symptomatic bradycardia when co-administered with amiodarone. Additionally, Gilead Sciences has issued a Dear Healthcare Provider letter (see attachment).

The specific changes to the each label are summarized below.

Harvoni label changes:

5   WARNINGS AND PRECAUTIONS

5.1 Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Postmarketing cases of symptomatic bradycardia, including fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI. Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with HARVONI is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered HARVONI:

• Counsel patients about the risk of serious symptomatic bradycardia

• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking HARVONI who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting HARVONI should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately.

6   ADVERSE REACTIONS

6.2 Postmarketing Experience

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of HARVONI.

7 DRUG INTERACTIONS

Added amiodarone information to Table 3, 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	Clinical Comment
Antiarrhythmics: amiodarone	Effect on amiodarone, ledipasvir, and sofosbuvir concentrations unknown	Coadministration of HARVONI with amiodarone may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with HARVONI is not recommended; if coadministration is required, cardiac monitoring is recommended [see Warnings and Precautions (5.1)]

 

Sovaldi Label Changes:

5 WARNINGS AND PRECAUTIONS

5.1 Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral

Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with SOVALDI in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (HARVONI (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with SOVALDI in combination with another direct acting antiviral (DAA) is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered SOVALDI and another DAA:

• Counsel patients about the risk of serious symptomatic bradycardia

• Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.

Patients who are taking SOVALDI in combination with another DAA who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting SOVALDI in combination with a DAA should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems [See Adverse Reactions (6.2), Drug Interactions (7.2)].

6 ADVERSE REACTIONS

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of SOVALDI. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with SOVALDI in combination with another HCV direct acting antiviral [See Warnings and Precautions (5.1), Drug Interactions (7.2)].

7 DRUG INTERACTIONS

Added amiodarone information to Table 5, 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	Clinical Comment
Antiarrhythmics:                       amiodarone	Effect on amiodarone and sofosbuvir concentrations unknown	Coadministration of amiodarone with SOVALDI in combination with another DAA may result in serious symptomatic bradycardia. The mechanism of this effect is unknown. Coadministration of amiodarone with SOVALDI in combination with another DAA is not recommended; if coadministration is required, cardiac monitoring is recommended [See Warnings and Precautions (5.1), Adverse Reactions (6.2)].

Updated labeling will be posted soon at DailyMed

Please see Gilead Sciences has issued a Dear Healthcare Provider letter: 

SVD HVN - DHCP Letter 20March15 - FINAL.DOCX

Harvoni and Sovaldi are products of Gilead Sciences.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Steve Morin
Office of Special Health Issues 
Food and Drug Administration

If you are interested in receiving information about a broader range of FDA topics, consider subscribing to the FDA Patient Network News, a twice monthly newsletter containing FDA-related information on a variety of topics, including new product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings, proposed regulatory guidances and opportunity to comment, and other information of interest to patients and patient advocates.

Gilead Announces Harvoni Study Results in Chronic Hepatitis C Patients with Advanced Liver Disease and Those Who Failed Prior Treatment

Published: Nov 11, 2014 8:02 a.m. ET

- High Cure Rates in Nearly 800 HCV Patients with Advanced Liver Disease -

BOSTON, Nov 11, 2014 (BUSINESS WIRE) -- Gilead Sciences, Inc. GILD, +0.55% today announced results from several Phase 2 and Phase 3 studies evaluating investigational uses of Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) for the treatment of chronic hepatitis C virus (HCV) infection in patients with limited or no treatment options, including patients with decompensated cirrhosis, patients with HCV recurrence following a liver transplant and patients who failed previous treatment with other direct acting antivirals. These data will be presented this week at the 65th Annual Meeting of the American Association for the Study of Liver Diseases (The Liver Meeting2014) in Boston.

“Chronic hepatitis C patients with advanced liver disease are among the most difficult to cure and traditionally have had limited or no treatment options,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “The data presented this week demonstrate that Harvoni provides high cure rates for patients with advanced liver disease, as well as for those who failed prior treatment with other antivirals, including sofosbuvir-based regimens.”

Harvoni was approved by the U.S. Food and Drug Administration and Health Canada in October 2014 and is the first once-daily single tablet regimen for the treatment of chronic HCV genotype 1 infection in adults. Applications are pending in the European Union, Japan and New Zealand.

Advanced Liver Disease

In a pooled analysis of Phase 2 and Phase 3 open-label studies (Oral #82) in more than 500 genotype 1 HCV infected patients with compensated cirrhosis who received Harvoni alone or with ribavirin (RBV) for 12 or 24 weeks, 96 percent of patients achieved sustained virologic response (SVR12). Patients who achieve SVR12 are considered cured of HCV infection.

Two prospective analyses from a Phase 2 open-label study (Study GS-US-337-0123) evaluating patients with decompensated cirrhosis and those with HCV recurrence following liver transplantation also are being presented. In the first subgroup (Oral #239), 108 genotype 1 and 4 infected patients with decompensated cirrhosis, including those with moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Class B) and severe hepatic impairment (CPT Class C), received Harvoni plus RBV for 12 or 24 weeks. Overall, SVR12 rates were 87 percent (n=45/52) in the 12-week arm and 89 percent (n=42/47) in the 24-week arm.

The second subgroup (Oral #8) evaluated 12 or 24 weeks of Harvoni plus RBV among 223 genotype 1 and 4 patients who developed HCV recurrence following liver transplantation. Among non-cirrhotic patients, SVR12 rates were 96 percent (n=53/55) and 98 percent (n=55/56) following 12 and 24 weeks of treatment, respectively. For patients with compensated cirrhosis, SVR12 rates were 96 percent for both 12 weeks (n=25/26) and 24 weeks (n=24/25) of therapy. SVR12 rates among patients with decompensated cirrhosis were 81 percent for both 12 weeks (n=25/31) and 24 weeks (n=17/21) of therapy.

Retreatment of Patients Who Failed Prior Therapy

Study GS-US-337-0121 (Late Breaker Oral #LB-6) evaluated 155 genotype 1 patients with compensated cirrhosis who had failed prior treatment with pegylated interferon (PegIFN)/RBV and subsequently PegIFN/RBV plus a protease inhibitor. In this study, patients were randomized (1:1) to receive Harvoni plus RBV for 12 weeks or Harvoni alone for 24 weeks. Ninety-six percent (n=74/77) of those receiving Harvoni plus RBV for 12 weeks and 97 percent (n=75/77) of those receiving Harvoni for 24 weeks achieved SVR12.

In a second study (Oral #235), 51 genotype 1 patients who previously failed SOF/PegIFN/RBV, SOF/RBV or a SOF placebo/PegIFN/RBV treatment regimen received Harvoni plus RBV for 12 weeks. Twenty-nine percent of study patients (n=15/51) had cirrhosis. Ninety-eight percent (n=50/51) achieved SVR12 following 12 weeks of treatment with Harvoni plus RBV.

In all of these studies, Harvoni was well tolerated and its safety profile was generally consistent with that observed in clinical trials of Harvoni. Adverse events included fatigue, headache, nausea and anemia, which was more common among patients taking RBV. Grade 3/4 laboratory abnormalities were infrequent and included decreases in hemoglobin, which is consistent with RBV-associated anemia.

The safety and efficacy of Harvoni have not been established for the investigational uses described above.

Additional information about these studies can be found at www.clinicaltrials.gov.

Important Safety Information About Harvoni

Warnings and Precautions

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (greater-than or equal to 10 percent, all grades) adverse reactions were fatigue and headache.

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable longer-term results from these studies and other ongoing and subsequent clinical trials involving Harvoni, alone or in combination with other products, for the treatment of HCV in other patient populations. As Harvoni is used over longer periods of time, Gilead may find new issues such as safety or drug resistance, which may require it to provide additional warnings or contraindications in the label, which could reduce the market acceptance of Harvoni. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. Full Prescribing Information for Harvoni is available at www.gilead.com.

Harvoni is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

SOURCE: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Source

Advantages of Gilead’s Harvoni over emerging hepatitis C treatments

10-11-2014

US surveyed specialists anticipate prescribing Gilead Sciences’ (Nasdaq: GILD) Harvoni to a high proportion of their genotype-1 infected hepatitis C virus (HCV) patients, including those with cirrhosis of the liver, even if it is listed on a non-preferred formulary tier (tier 3 or higher).

Harvoni, a fixed-dose combination of Gilead’s nucleotide polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir, is the first once-daily single tablet regimen for HCV infections. According to physicians surveyed for a news report from Decision Resources Group, Harvoni has advantages over other emerging treatment options on all efficacy, treatment duration, safety and tolerability attributes considered.

Surveyed MCOs have prioritized Sovaldi over Olysio

Furthermore, surveyed Managed Care Organization (MCO) pharmacy and medical directors have prioritized formulary inclusion of Gilead’s Sovaldi over (sofosbuvir) Janssen/Medivir’s Olysio (simeprevir), suggesting that Sovaldi’s broad label and excellent clinical profile have allowed it to defend its higher cost.

Other key findings from the US Physician & Payer Forum report, titled Hepatitis C Virus: How will More Efficacious Direct-Acting Antivirals Influence US Prescribing and Reimbursement for this Dynamic Indication, include:

• Impact of new HCV treatment guidelines on MCO reimbursement: Among the almost two-thirds of surveyed MCO pharmacy and medical directors who are aware of the American Association for the Study of Liver Diseases’ treatment guidelines, more than two-thirds are aware of recommended treatments, and some indicated reducing formulary restrictions and streamlining prior authorization approvals for prescribed regimens recommended in the guidelines. These findings underscore the critical importance of treatment guidelines in favorable positioning of HCV therapies for reimbursement by MCOs.
• Concerns over increased risk of relapse following shortened course of therapy: Food and Drug Administration labeling recommends an eight-week course of Harvoni in treatment-naive, non-cirrhotic patients with lower baseline viral loads. Strikingly, nearly half of surveyed experts are concerned that short treatment duration increases risk of viral relapse following completion of HCV therapy with a high proportion indicating that durations of eight weeks or less are too short.

Decision Resources Group analyst Seamus Levine-Wilkinson commented: “Physicians report that discontinuation rates for Sovaldi and/or Olysio are higher than expected from clinical trials. Notably, the elevated “real world” discontinuation rates do not appear to stem from low efficacy or unexpected safety issues but are rather driven by high out-of-pocket cost associated with these therapies. Our findings may also have implications for the recently launched Harvoni as well as other novel therapies expected to enter the market in the near future. Approximately four out of five surveyed physicians have either already contacted or plan to reach out to patients regarding the newest HCV treatment options. As a result, uptake of novel HCV agents could surge as physicians treat the sizeable number of warehoused patients.”

Source