March 26, 2015

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-- Sovaldi Part of First All-Oral Treatment Regimen for Genotype 2 Patients in Japan --

-- 96 Percent Cure Rates and Shortened, 12-Week Course of Therapy --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Mar. 26, 2015-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Sovaldi® (sofosbuvir), a once-daily nucleotide analog polymerase inhibitor, for the suppression of viremia in patients with genotype 2 chronic hepatitis C virus (HCV) infection with or without compensated cirrhosis. Sovaldi is indicated for use in combination with ribavirin (RBV) for 12 weeks. Sovaldi (in combination with RBV) is the first all-oral, interferon-free treatment regimen for genotype 2 HCV infection. Sovaldi is also the first product to be marketed by Gilead in Japan.

“Today’s approval represents an important step forward in the management of hepatitis C in Japan, enabling genotype 2 infected patients the opportunity of a cure in 12 weeks with an all-oral regimen that eliminates the need for interferon,” said Masao Omata, MD, Yamanashi Prefectural Hospital Organization.

Primarily due to HCV, Japan has one of the highest rates of liver cancer of any industrialized country. Of the more than one million people chronically infected with HCV, 20-30 percent have the genotype 2 strain of the virus. Currently approved therapies in Japan for genotype 2 HCV infection involve 24-48 weeks of injections with pegylated interferon, which may not be suitable for many patients.

Sovaldi’s approval is supported by data from a Phase 3 clinical trial conducted in Japan (Study GS-US-334-0118) among treatment-naïve and treatment-experienced genotype 2 patients. Approval was based on 96 percent (n=135/140) of genotype 2 HCV-infected patients who received 12 weeks of an all-oral regimen of Sovaldi plus RBV 600–1,000 mg/day achieving a sustained virologic response 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV infection. The approval is also supported by SVR12 results from four international Phase 3 studies (FISSION, FUSION, POSITRON and VALENCE), which included genotype 2 HCV patients.

“There is a need in Japan for new HCV treatment options that are more effective and better tolerated and we have been pleased to partner with the medical community here in Japan to demonstrate the efficacy and safety of Sovaldi,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. “We look forward to making Sovaldi available in Japan as quickly as possible, while simultaneously continuing to work with the agency on its review of our second application for an all-oral sofosbuvir-based regimen for the treatment of genotype 1 HCV infection.”

Gilead filed a New Drug Application (NDA) in Japan for a single-tablet regimen of sofosbuvir and the NS5A inhibitor ledipasvir for the treatment of genotype 1 HCV infected patients on September 24, 2014. The ledipasvir/sofosbuvir single tablet regimen is an investigational product in Japan and its safety and efficacy have not yet been established.

IMPORTANT SAFETY INFORMATION

Use with potent P gp inducers: Drugs that are potent P-gp inducers in the intestine are expected to decrease sofosbuvir plasma concentration. Sovaldi is contraindicated in patients receiving the following substances: carbamazepine, phenytoin, rifampicin or St. John’s wort. Also, Sovaldi should be administered with care when coadministered with the following drugs: rifabutin, and phenobarbital.

Contraindications: Sovaldi is contraindicated in patients with severe renal function impairment (eGFR<30 mL/min/1.73m2) or patients with renal insufficiency requiring dialysis.

Anemia occurred in patients receiving Sovaldi in combination with ribavirin. Patients should be carefully observed and hemoglobin should be periodically monitored and appropriate measures should be taken including ribavirin dose adjusted according to the ribavirin package insert. If ribavirin is permanently discontinued, Sovaldi should also be discontinued.

Adverse reactions: In the Japanese Phase 3 clinical study, 61 of 140 (43.6 percent) patients experienced adverse reactions, including abnormal laboratory test values. The major adverse reactions were 21 anemia/hemoglobin decreased (15.0 percent), 7 headache (5.0 percent), 6 malaise (4.3 percent), 6 nausea (4.3 percent), and 6 pruritus (4.3 percent).

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 the risk that physicians and patients may not see advantages of Sovaldi over other therapies and may therefore be reluctant to prescribe the product, and the risk that payers may be reluctant to approve or provide reimbursement for the product. Further, the ledipasvir/sofosbuvir single tablet regimen may not be approved in Japan in the currently anticipated timelines or at all, and approval, if granted, may have significant limitations on its use. 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.
Investors:
Patrick O’Brien, +1 650-522-1936
Media:
Cara Miller, +1 650-522-1616
Seiko Noma, +81-3-6837-0790 (Japan)

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March 25, 2015

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

March 21, 2015

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.
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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.

March 20, 2015

Delay HCV Tx and Watch Patients Die

by Michael Smith
North American Correspondent, MedPage Today

Meeting Coverage 03.01.2015

-- Even successful treatment carries risk if it is delayed, model suggests.

SEATTLE -- Delaying hepatitis C (HCV) treatment in patients who also have HIV increases the risk of liver complications and death even if the therapy is successful, a researcher said.

In a computer modeling study, treating a patient in METAVIR stage F3 disease instead of stage F2 increased the risk of liver-related death from 5% to 10%, according to Cindy Zahnd, a research assistant at the University of Bern in Switzerland.

And if successful HCV treatment was delayed until stage F4, the risk of liver-related death rose to 25%, compared with therapy at stage F2, Zahnd said here at the 2015 Conference on Retroviruses and Opportunistic Infections.

That's because "people who are living with HIV have many other risk factors that maintain them at a certain risk even after HCV clearance," Zahnd said.

It might seem obvious that delayed treatment increases the risk of complications or death, Zahnd told MedPage Today, but there is little long-term follow-up of actual patients that quantifies that danger.

"The point of this exercise was to project the long-term risk," she said.

The issue is important, especially in the U.S. where there is "push-back" against paying for some of the new and expensive anti-HCV agents early in the disease course, commented David Thomas, MD, of Johns Hopkins University School of Medicine, who moderated a media conference at which the data was discussed.

"Sometimes drugs aren't paid for in patients in a lower stage of disease," he said, because of a "mental model that someone would have to go to F4 before they get into trouble."

So insurers and other payers are often content to wait, he said, especially since some newer agents have been controversial because of their costs.

What the study shows, he added, is that "this approach has consequences."

The researchers used data from the Swiss Hepatitis C Study for the period before the newer agents were available to obtain estimates of the risk of progression in coinfected patients, Zahnd said.

In those days, treatment was with pegylated interferon and ribavirin, only about 60% of patients attempted the treatment, and only about 40% were able to clear HCV, she noted.

Those data suggested, however, that successful treatment would reduce the risk of liver fibrosis progression by a factor of 10, the risk of decompensated cirrhosis by the same factor, and the risk of hepatocellular carcinoma by a factor of 2.6.

Their model assumed that uptake of treatment with newer agents would be 100% and that cure rates would be about 90%, Zahnd said.

In that scenario, if treatment is provided soon after diagnosis -- between a month and a year later -- less than 3% of patients would die of liver complications, the model showed.

On the other hand, if treatment was delayed until METAVIR stage F2 or higher, the risks gradually increased, reaching 25% in those treated at stage F4, Zahnd said.

The investigators were "a bit surprised" to find that the proportion of liver-related deaths was so high despite successful treatment in most patients, Zahnd said, and concluded that some of the events would have taken place after the HCV was cleared.

Indeed, at the higher stages, most liver-related deaths would occur after the patient had cleared HCV, she said. In some patients, she reported, fibrosis progression would be maintained through persistent risk factors, such as drug toxicity, coinfections, or metabolic liver disease.

One implication of the analysis, Zahnd said, is that delaying treatment -- aside from the individual risks -- also increases the risk of transmitting HCV to others.

Indeed, she said, delaying treatment until METAVIR stage F4 would quadruple the infectious period.

She cautioned that the study had heterogeneous data sources, and also explained that it modeled a closed cohort with no transmission so the analysis probably under-estimates the positive impact of early HCV treatment.

And the model did not include the possibility of re-treatment, Zahnd said, which might have led to an over-estimate of the number of people experiencing liver-related complications.

The analysis was part of the Swiss HIV and the Swiss Hepatitis C Cohort studies. Zahnd did not disclose any relevant relationships.

Thomas disclosed no relevant relationships.

Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 03.02.2015

Primary Source

Conference on Retroviruses and Opportunistic Infections

Source Reference: Zahnd C, et al "Impact of deferring HCV treatment on liver-related events in HIV+ patients" CROI 2015; Abstract 150.

Source

Annals of Internal Medicine

17 March 2015, Vol 162, No. 6>

Original Research | 17 March 2015

Jagpreet Chhatwal, PhD; Fasiha Kanwal, MD, MSHS; Mark S. Roberts, MD, MPP; and Michael A. Dunn, MD

[+-] Article and Author Information

Ann Intern Med. 2015;162(6):397-406. doi:10.7326/M14-1336

Background: Sofosbuvir and ledipasvir, which have recently been approved for treatment of chronic hepatitis C virus (HCV) infection, are more efficacious and safer than the old standard of care (oSOC) but are substantially more expensive. Whether and in which patients their improved efficacy justifies their increased cost is unclear.

Objective: To evaluate the cost-effectiveness and budget impact of sofosbuvir and ledipasvir.

Design: Microsimulation model of the natural history of HCV infection.

Data Sources: Published literature.

Target Population: Treatment-naive and treatment-experienced HCV population defined on the basis of HCV genotype, age, and fibrosis distribution in the United States.

Time Horizon: Lifetime.

Perspective: Third-party payer.

Intervention: Simulation of sofosbuvir–ledipasvir compared with the oSOC (interferon-based therapies).

Outcome Measures: Quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and 5-year spending on antiviral drugs.

Results of Base-Case Analysis: Sofosbuvir-based therapies added 0.56 QALY relative to the oSOC at an ICER of $55 400 per additional QALY. The ICERs ranged from $9700 to $284 300 per QALY depending on the patient's status with respect to treatment history, HCV genotype, and presence of cirrhosis. At a willingness-to-pay threshold of $100 000 per QALY, sofosbuvir-based therapies were cost-effective in 83% of treatment-naive and 81% of treatment-experienced patients. Compared with the oSOC, treating eligible HCV-infected persons in the United States with the new drugs would cost an additional $65 billion in the next 5 years, whereas the resulting cost offsets would be $16 billion.

Results of Sensitivity Analysis: Results were sensitive to drug price, drug efficacy, and quality of life after successful treatment.

Limitation: Data on real-world effectiveness of new antivirals are lacking.

Conclusion: Treatment of HCV is cost-effective in most patients, but additional resources and value-based patient prioritization are needed to manage patients with HCV.

Primary Funding Source: National Institutes of Health.

Source

Annals of Internal Medicine

17 March 2015, Vol 162, No. 6>

Original Research | 17 March 2015

Mehdi Najafzadeh, PhD; Karin Andersson, MD; William H. Shrank, MD, MSHS; Alexis A. Krumme, MS; Olga S. Matlin, PhD; Troyen Brennan, MD, JD, MPH; Jerry Avorn, MD; and Niteesh K. Choudhry, MD, PhD

[+-] Article and Author Information

Ann Intern Med. 2015;162(6):407-419. doi:10.7326/M14-1152

Background: New regimens for hepatitis C virus (HCV) have shorter treatment durations and increased rates of sustained virologic response compared with existing therapies but are extremely expensive.

Objective: To evaluate the cost-effectiveness of these treatments under different assumptions about their price and efficacy.

Design: Discrete-event simulation.

Data Sources: Published literature.

Target Population: Treatment-naive patients infected with chronic HCV genotype 1, 2, or 3.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: Usual care (boceprevir–ribavirin–pegylated interferon [PEG]) was compared with sofosbuvir–ribavirin–PEG and 3 PEG-free regimens: sofosbuvir–simeprevir, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir. For genotypes 2 and 3, usual care (ribavirin–PEG) was compared with sofosbuvir–ribavirin, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir–ribavirin (genotype 3 only).

Outcome Measures: Discounted costs (in 2014 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.

Results of Base-Case Analysis: Assuming sofosbuvir, simeprevir, daclatasvir, and ledipasvir cost $7000, $5500, $5500, and $875 per week, respectively, sofosbuvir–ledipasvir was cost-effective for genotype 1 and cost $12 825 more per QALY than usual care. For genotype 2, sofosbuvir–ribavirin and sofosbuvir–daclatasvir cost $110 000 and $691 000 per QALY, respectively. For genotype 3, sofosbuvir–ledipasvir–ribavirin cost $73 000 per QALY, sofosbuvir–ribavirin was more costly and less effective than usual care, and sofosbuvir–daclatasvir cost more than $396 000 per QALY at assumed prices.

Results of Sensitivity Analysis: Sofosbuvir–ledipasvir was the optimal strategy in most simulations for genotype 1 and would be cost-saving if sofosbuvir cost less than $5500. For genotype 2, sofosbuvir–ribavirin–PEG would be cost-saving if sofosbuvir cost less than $2250 per week. For genotype 3, sofosbuvir–ledipasvir–ribavirin would be cost-saving if sofosbuvir cost less than $1500 per week.

Limitation: Data are lacking on real-world effectiveness of new treatments and some prices.

Conclusion: From a societal perspective, novel treatments for HCV are cost-effective compared with usual care for genotype 1 and probably genotype 3 but not for genotype 2.

Primary Funding Source: CVS Health.

Source

Charity attacks Gilead over hepatitis C drug restrictions

Wed Mar 18, 2015 4:18pm EDT

(Reuters) - Charity Medecins Sans Frontieres has accused U.S. drugmaker Gilead Sciences Inc GILD.O of restricting access to its breakthrough hepatitis C drug Sovaldi in developing countries as it tries to protect profit margin in wealthier nations.

MSF, also known as Doctors Without Borders, said Gilead's restrictions aimed to stop discounted supplies of Sovaldi being diverted to patients from rich countries, but that the effort had resulted in "multiple restrictions and demands" on people receiving treatment in poor countries.

It said Gilead was excluding people without national identity documents, a move that hurts migrants, refugees and marginalized patients.

"We're seeing Gilead trying everything it can to squeeze every last drop of profit out of some middle-income and (high-income) countries, and millions of people with hepatitis C will have to pay the price," said Rohit Malpani, Director of Policy and Analysis at MSF's Access Campaign.

Gilead said in developing countries it operates a system of tiered pricing and voluntary generic licensing to help enable access to its hepatitis C medicines.

"As part of these efforts, the company works to ensure that the medicines reach their intended recipients with patient access our primary goal," a Gilead spokesman said.

Sovaldi, which is far more effective and better-tolerated than older treatments, has come under fire for its $1,000-a-pill price tag in the United States. It racked up $10.3 billion in sales for Gilead in its first year on the market.

Gilead said it is in discussions with 11 generic drugmakers to identify strategies for supplying 91 developing nations. But activists have said such deals would not ensure access to several middle-income countries where health authorities will struggle to provide treatment to patients.

"We will continue to seek input on all areas of our access program as it evolves, and make any improvements as needed," Gilead said.

In a statement on Wednesday ahead of a meeting between Gilead and the generics producers, MSF urged the companies to reject a program under which it says the U.S. drugmaker keeps people in developed and some middle-income countries, where Sovaldi's cost is "exorbitant," from accessing cheaper copies.

"MSF is greatly concerned that this program will establish an ugly precedent and will be introduced in all countries where the company and its generic licensees sell the drug," the charity said.

About 150 million people in the world live with chronic hepatitis C, most of them in low- and middle-income countries.

(Reporting by Zeba Siddiqui in Mumbai and Bill Berkrot in New York; Editing by Marguerita Choy)

Source

Hepatitis C: only a step away from elimination?

The Lancet

Editorial

Volume 385, No. 9973, p1045, 21 March 2015

Globally, an estimated 185 million people are infected with hepatitis C virus (HCV). Acute HCV infections are usually asymptomatic. However, about 75% of patients develop chronic infection, which can lead to liver cirrhosis and hepatocellular carcinoma. 700 000 deaths worldwide could be attributed to HCV in 2013. While most people affected live in low-income and middle-income countries in Asia, Africa, and the Middle East, in the UK an estimated 200 000 individuals are infected with HCV, and annual deaths from HCV have quadrupled since 1996. These figures are appalling, surely. But the extraordinary recent developments in treatment for hepatitis C offer substantial grounds for optimism. A series of new drugs—more effective in viral clearance with fewer side-effects—are changing the landscape for hepatitis C.

Today's Lancet gives a sense of the remarkable past few years it has been for hepatitis C. As described in Paul Webster and colleagues' comprehensive Seminar, until recently interferon in combination with ribavirin was the main treatment for hepatitis C, but eligibility, safety, tolerability, and effectiveness were limited. The development of direct-acting antiviral drugs towards NS3/4A protease, NS5B polymerase, and NS5A replication complex has progressed tremendously and now allows for interferon-free therapies. Four clinical trials with new regimens are published in today's issue. The C-WORTHY trial assessed a single-tablet once-daily regimen of grazoprevir (protease inhibitor) and elbasivir (NS5A inhibitor) with or without ribavirin for patients with HCV genotype 1. Eric Lawitz and colleagues report a sustained virological response (SVR) at 12 weeks, irrespective of ribavirin and duration of treatment. Similarly, Mark Sulkowski and colleagues report very encouraging results (SVR at 12 weeks: 87–97%) in patients co-infected with HIV. With about 25% of individuals infected with HIV being co-infected with HCV, inclusion of this group of patients in trials is also of utmost importance. In the PHOTON-2 trial, Jean-Michel Molina and colleagues specifically assessed the recently approved regimen sofosbuvir (NS5B inhibitor) plus ribavirin in patients infected with HCV genotypes 1–4 co-infected with HIV. They confirm the pan-genotypic potential of sofosbuvir (SVR 12 weeks: 84–89%), offering HIV co-infected patients a useful interferon-free option. The fourth trial published in today's issue goes a step further and assesses whether the addition of a third direct-acting antiviral drug to an interferon-free, ribavirin-free combination (sofosbuvir and ledipasvir) would allow shorter treatment duration—an important factor for a patient population in which treatment compliance and adherence can be an issue.

These trials are important because they offer new effective treatment options for HCV infection. “An opportunity now exists to almost eliminate this infection from the UK”, wrote Roger Williams and colleagues in The Lancet Commission on Addressing liver disease in the UK. Highly effective new antiviral drugs not only can cure those treated but also can reduce transmission of HCV and therefore its prevalence. The Commission estimated that with these new antiviral drugs we could contemplate the “eradication of infections from chronic hepatitis C virus in the UK by 2030”. Indeed, modelling studies for England showed that increasing diagnostic and number of people treated by 27 times would result in a 95% reduction in the prevalence of HCV infection, an 80% reduction in hepatocellular carcinoma, and avert 5200 deaths by 2030.

While new drugs offer new opportunities, new challenges also arise. Scaling-up treatment—in any country—will face important cost issues. But the high costs of these new medicines, which should be robustly scrutinised and, where appropriate, challenged, must not inhibit a careful and comprehensive analysis of the broader benefits they might bring. For example, as Melanie Calvert and colleagues argue this week, patient-reported outcomes offer the opportunity to have the patient's voice more forcefully heard in health policy decision making. The self-reported benefits to patients from these new anti-HCV regimens might prove to be substantial. And the financial returns from reduced health-care costs and higher economic activity might easily outweigh the expense of the medicines themselves. This kind of broader cost-effectiveness work needs to be urgently completed.

Next month, The Lancet Infectious Diseases is hosting its inaugural Viral Hepatitis Summit in Shanghai (April 10–12). We look forward to this meeting addressing the increasingly urgent need for a global plan to eliminate hepatitis C. With no vaccine in sight, if we are truly to contemplate elimination of hepatitis C by 2030, ensuring that treatments reach marginalised groups and are accessible to all those living with HCV will be crucial.

Source

March 19, 2015

BMS-logo

The NDA contains data to support approval for daclatasvir in combination with sofosbuvir; would be the first 12-week regimen specifically for the treatment of hepatitis C genotype 3

The application is based on a Phase III clinical trial which tested a 12-week, ribavirin-free regimen and resulted in sustained virologic response (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced genotype 3 HCV patients

Thursday, March 12, 2015 3:00 pm EDT

"We also are continuing clinical trials to determine the potential of daclatasvir-based regimens in treating a range of other high unmet-need patients, including those coinfected with HIV, HCV patients with decompensated cirrhosis, and HCV recurrence in post-transplant patients."

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the resubmitted new drug application (NDA) for daclatasvir, an investigational NS5A replication complex inhibitor, has been accepted for review by the U.S. Food and Drug Administration (FDA) for use in combination with sofosbuvir for the treatment of chronic hepatitis C (HCV) genotype 3. The original NDA has been amended to include data from the Phase III ALLY-3 trial, which showed high cure rates for the combination, with sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naïve and 86% of treatment-experienced genotype 3 HCV patients. SVR12 rates were higher (96%) in non-cirrhotic genotype 3 patients, regardless of treatment history. The FDA will now review the submission within a six-month timeframe.

“The daclatasvir-based NDA seeks to address a high-unmet patient need that still exists despite recent hepatitis C treatment advances. Approximately 9-12% of HCV patients in the U.S. have genotype 3. That’s thousands of individuals in the U.S. who historically have had limited treatment options requiring at least 24 weeks of treatment,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “We also are continuing clinical trials to determine the potential of daclatasvir-based regimens in treating a range of other high unmet-need patients, including those coinfected with HIV, HCV patients with decompensated cirrhosis, and HCV recurrence in post-transplant patients.”

Genotype 3 is estimated to affect 54.3 million people worldwide, and is the second most common hepatitis C genotype after genotype 1 (83.4 million). The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with progressive disease, increased rates of steatosis and a disproportionately increased risk of hepatocellular carcinoma.

In the ALLY-3 study, the daclatasvir and sofosbuvir combination regimen was well tolerated, with no deaths, treatment-related serious adverse events, or discontinuations due to adverse events. The most frequent side effects (≥5%) were headache (19.7%), fatigue (19.1%), nausea (11.8%), diarrhea (8.6%), insomnia (5.9%), abdominal pain and arthralgia (both 5.3%). Additionally, there were 17 (11.2%) treatment failures, with 16 relapses post-treatment and 1 rebound at the end of treatment. There were no viral breakthroughs in this ribavirin-free regimen.

About ALLY-3: Study Design

This Phase III open-label clinical trial enrolled 152 genotype 3 HCV patients; 101 treatment-naïve patients and 51 treatment-experienced patients in 2 cohorts each received daclatasvir 60 mg and sofosbuvir 400 mg once daily for 12 weeks, with 24 weeks of follow-up. The primary endpoint was SVR12 rates, defined as HCV RNA < LLOQ target detected or not detected at follow-up week 12 in treatment-naïve and treatment-experienced patients.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Approximately 170 million people worldwide are infected with hepatitis C, with an estimated 2.7–3.9 million chronically infected in the United States. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 20 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a NS5A complex inhibitor, which continues to be investigated in multiple treatment regimens and in people with co-morbidities.

Daclatasvir was approved in Europe in August 2014, and more recently in Brazil in January 2015, for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Daclatasvir also is approved in Japan in combination with asunaprevir, a NS3/4A protease inhibitor. The daclatasvir+asunaprevir dual regimen is Japan’s first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that daclatasvir will receive regulatory approval in the United States, or if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Bristol-Myers Squibb Company
Media:
Robert Perry, Office: 609-419-5378
Cell: 407-492-4616
rob.perry@bms.com

or

Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com

Source

November 11, 2014

New England Journal of Medicine

Paul Y. Kwo, M.D., Parvez S. Mantry, M.D., Eoin Coakley, M.D., Helen S. Te, M.D., Hugo E. Vargas, M.D., Robert Brown, M.D., M.P.H., Fredric Gordon, M.D., Josh Levitsky, M.D., Norah A. Terrault, M.D., M.P.H., James R. Burton, M.D., Wangang Xie, Ph.D., Carolyn Setze, M.S., Prajakta Badri, Ph.D., Tami Pilot-Matias, Ph.D., Regis A. Vilchez, M.D., Ph.D., and Xavier Forns, M.D.

November 11, 2014DOI: 10.1056/NEJMoa1408921

Hepatitis C virus (HCV) presents a global health care challenge, with approximately 170 million people chronically infected.1 In 2012, approximately 24,000 liver transplantations were performed worldwide, with the largest proportion performed because of HCV-induced liver disease.2,3 In the United States, more than 40% of registrants on the liver-transplant waiting list are infected with HCV.3,4 After liver transplantation, recurrence of HCV infection is universal among recipients with viremia before transplantation.5,6 Fibrosis progression may be accelerated and HCV viral loads may be markedly increased in patients receiving post-transplantation immunosuppressive therapy as compared with patients not undergoing transplantation.7-9 Graft cirrhosis develops in 20 to 30% of HCV-infected persons within 5 years after transplantation.10,11 As a result of these complications, HCV infection has become the leading cause of death in liver-transplant recipients. Patient and graft survival rates are markedly lower among HCV-infected patients than among those who received a liver transplant owing to cholestatic or alcohol-related liver disease.3,12,13

Successful clearance of HCV after liver transplantation can reduce the risk of subsequent HCV-related complications such as progression to cirrhosis and graft loss.13-16 The standard of care in the treatment of recurrent HCV genotype 1 infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, though the response rates of 13 to 43% are generally lower than the rates of 40 to 52% among patients not undergoing transplantation, in part because of treatment-limiting toxic effects.8,15,17-19 In addition, interferon-based therapies can induce alloimmune graft injury, reducing patient and graft survival.16,20

Calcineurin inhibitors, such as tacrolimus and cyclosporine, are key components of most current post-transplantation immunosuppressive regimens. Long-term exposure to calcineurin inhibitors can progressively impair renal function, reducing ribavirin clearance. Consequently, augmented ribavirin exposure may increase the frequency and severity of ribavirin-associated hemolytic anemia, commonly requiring the use of hematopoietic growth factors, blood transfusion, or both. HCV treatment with a first-generation protease inhibitor, boceprevir or telaprevir, in combination with peginterferon and ribavirin results in a 20 to 71% response rate among liver-transplant recipients; however, clinically significant side effects of these regimens, especially anemia and infections, were reported to limit their use.21-24 In addition, drug interactions between protease inhibitors and calcineurin inhibitors may require dose modification and monitoring.25,26

Phase 3 trials of an all-oral, interferon-free, direct-acting antiviral regimen of ombitasvir coformulated as a single tablet with ritonavir-boosted ABT-450 (ABT-50/r) plus dasabuvir and ribavirin have shown high rates of sustained virologic response among patients with HCV genotype 1 infection, irrespective of prior treatment with peginterferon–ribavirin or the presence of cirrhosis.27-31 Ombitasvir is a potent NS5A inhibitor32; ABT-450 is an NS3/4A protease inhibitor coadministered with ritonavir to increase peak, trough, and overall drug exposure, permitting once-daily dosing33; and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Next-generation interferon-free treatment regimens have not been extensively examined in transplant recipients with recurrent HCV genotype 1 infection. The CORAL-I trial assessed the safety and efficacy of ombitasvir–ABT-450/r and dasabuvir with ribavirin in this population of patients with an unmet need for safe and efficacious therapy.

Methods

Patients

Patients 18 to 70 years of age were eligible for the study if they had HCV genotype 1 infection (HCV RNA level >10,000 IU per milliliter) and had received a liver transplant at least 12 months before screening because of chronic HCV infection. Patients could have received interferon-based treatment for HCV infection before transplantation but not after transplantation. Eligible patients had no evidence of advanced fibrosis (Metavir score ≤F2) on liver biopsy performed not more than 6 months before screening. A stable tacrolimus-based or cyclosporine-based immunosuppressive regimen was required, and glucocorticoids were permitted at a dose of no more than 5 mg per day. Patients were excluded if they were coinfected with the human immunodeficiency virus or hepatitis B virus or had undergone multiple-organ transplantation or liver retransplantation. Patients were enrolled from 10 transplantation centers in the United States and Spain between May and August 2013. Detailed eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design and Oversight

Patients in this phase 2, open-label trial received ombitasvir–ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir) and dasabuvir (250 mg twice daily) for 24 weeks. Ribavirin dosing was at the investigator's discretion because of the known risk of ribavirin-related hematologic toxic effects in transplant recipients. Patients were followed for up to 48 weeks after the treatment period (Figure S1 in the Supplementary Appendix).

On the basis of simulations based on pharmacokinetic data from a phase 1 study that evaluated drug interaction between the study drugs and tacrolimus or cyclosporine, the following dosages of calcineurin inhibitors were recommended: for cyclosporine, one fifth of the pretreatment total daily dose, administered once daily; for tacrolimus, 0.5 mg once weekly or 0.2 mg, where available, every 3 days. Modifications in tacrolimus or cyclosporine dosing during treatment were guided by scheduled testing of trough levels of calcineurin inhibitors. Details of the dosing of ribavirin and calcineurin inhibitors are provided in the Supplementary Appendix.

The study was conducted in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice, applicable regulations, and guidelines governing clinical-study conduct that have their origin in the Declaration of Helsinki. All patients provided written informed consent. The study was designed by the sponsor (AbbVie); the investigators and the sponsor jointly conducted the study and gathered the data. The sponsor conducted the data analyses. All authors signed a confidentiality agreement with the sponsor. The first draft of the manuscript was written by a sponsor-employed medical writer, with input from all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol, which is available at NEJM.org.

Efficacy and Safety Assessments

The primary efficacy end point was a sustained virologic response, defined as a plasma HCV RNA level of less than 25 IU per milliliter, 12 weeks after the end of treatment. Secondary assessments included the percentage of patients with a sustained virologic response at post-treatment week 24, virologic failure during treatment, and post-treatment relapse. A central laboratory used the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche), to test plasma samples for HCV RNA. Patients were monitored for clinical and laboratory evidence of adverse events at each study visit. Nonserious adverse events were recorded during the treatment period and until 30 days after the last dose. Serious adverse events were recorded from the time of informed consent until the end of the study. Details of plasma-sample collection, HCV RNA quantification, virologic-failure criteria, and resistance testing are provided in the Supplementary Appendix.

Statistical Analysis

Analyses of efficacy, safety, and baseline patient characteristics were performed on the intention-to-treat population, defined as all enrolled patients who received at least one dose of study drugs. The two-sided 95% confidence intervals for response rates were calculated with the use of the exact method based on the beta distribution. Patients with missing data at post-treatment week 12 or 24, including those who dropped out, were counted as having had virologic failure. Descriptive statistics are provided, such as the number of observations, mean, and standard deviation for continuous variables and counts and percentages for discrete variables. SAS software for the UNIX operating system (SAS Institute) was used for all analyses.

Results

Baseline Demographic and Clinical Characteristics

The CORAL-I study enrolled 34 patients, including 29 patients (85%) with HCV genotype 1a infection. The median time since liver transplantation was 3.3 years. Overall, 76% of patients had a non-CC IL28B genotype, 71% had previously been treated with peginterferon–ribavirin therapy, and 85% were receiving a tacrolimus-based immunosuppressive regimen (Table 1)

Treatment Efficacy

By week 4 of treatment, HCV RNA levels had decreased to less than 25 IU per milliliter in all 34 patients (Table 2); all the patients also had HCV RNA levels of less than 25 IU per milliliter at the end of treatment. With regard to the primary end point, 33 of 34 patients had a sustained virologic response at post-treatment week 12, for a rate of 97% (95% confidence interval [CI], 85 to 100). One patient did not have a sustained virologic response owing to a relapse on post-treatment day 3. No relapses occurred after post-treatment week 12; 33 of 34 patients (97%) had a sustained virologic response at post-treatment week 24. All 5 patients infected with genotype 1b (100%) and 28 of 29 patients infected with genotype 1a (97%) had a sustained virologic response. The remaining patient had resistance-associated variants R155K in NS3, M28T and Q30R in NS5A, and G554S in NS5B at the time of relapse, none of which were present at baseline. The NS3 variant Q80K was present in 11 of 29 patients (38%) with HCV genotype 1a infection at baseline, including the patient with a relapse, who had had a null response to prior peginterferon–ribavirin therapy. Variants at resistance-associated positions in NS3, NS5A, and NS5B were each observed in at least 1 patient at baseline (Table S1 in the Supplementary Appendix).

Safety

Adverse events were common, though the majority were mild or moderate in severity (Table 3). The most common adverse events were fatigue, headache, and cough. None of the patients had graft rejection and there were no deaths during the study. One patient discontinued the study drugs after week 18 owing to rash, memory impairment, and anxiety. These events were assessed as having a reasonable possibility of being related to the study drugs; they were moderate in severity. This patient had a sustained virologic response 12 weeks after ending treatment prematurely. Two patients (6%) had serious adverse events. Narratives on these two patients are provided in the Supplementary Appendix.

Grade 3 laboratory abnormalities were infrequent, and no grade 4 abnormalities were observed. Grade 3 elevations in the total bilirubin level were observed in two patients (6%), occurring within the first 8 days of treatment in both. No patient had jaundice or scleral icterus. Elevations in the total bilirubin level predominantly reflected elevated values for indirect bilirubin, a finding consistent with inhibition of the organic anion–transporting protein 1B1 by protease inhibitors. In one patient, total bilirubin levels were transiently elevated on day 92, to a value that was more than 2 times the upper limit of the normal range (predominantly accounted for by an elevated indirect bilirubin level), and alanine aminotransferase levels were transiently elevated on day 85, to a value that was more than 3 times the upper limit of the normal range. The values returned to the normal range on day 120 and on post-treatment day 4, respectively. Owing to persistent low-grade elevation of alanine aminotransferase levels during treatment, a liver biopsy was performed. The biopsy revealed markedly less necroinflammation than the prestudy biopsy, a finding consistent with a resolving HCV infection (Figure S2 in the Supplementary Appendix). This patient had a sustained virologic response at post-treatment week 12.

Grade 2 declines in hemoglobin levels (8 to <10 g per deciliter) occurred in nine patients (26%). One patient had a grade 3 decline in the hemoglobin level (6.5 to <8.0 g per deciliter) on day 15 and stopped ribavirin for 10 days. Erythropoietin was subsequently administered from day 26 to day 53; the hemoglobin level normalized by treatment day 42.

Ribavirin Dosing

The initial doses of ribavirin ranged from 400 to 1200 mg daily (Table 4.). The majority of patients received 600 or 800 mg daily at study initiation (19 of 34 [56%]) and also at the completion of treatment (23 of 34 [68%]). Overall, 19 patients (56%) had a modification in the ribavirin dose during treatment; 9 patients (26%) had modifications owing to declines in hemoglobin levels. Five patients (15%) received erythropoietin after detection of a nadir hemoglobin level of 7.6 to 9.1 g per deciliter. All 5 of these patients had initial ribavirin doses of 1000 to 1200 mg daily, and all 5 had a sustained virologic response at post-treatment week 12. No patient received a blood transfusion.

Dosing of Calcineurin Inhibitors

Modifications in the dose or dosing frequency of calcineurin inhibitors were made on the basis of blood levels of tacrolimus or cyclosporine. For most patients who received tacrolimus, 0.5-mg and 0.2-mg doses of tacrolimus were administered with a median dosing frequency of 10 days and 5 days, respectively. The geometric mean and range of trough blood concentrations of tacrolimus and cyclosporine during treatment were similar to those observed in the pretreatment period and were within the desired therapeutic range (Figure S3 in the Supplementary Appendix).

The mean creatinine clearance was 90.5 ml per minute at baseline and 85.9 ml per minute at week 24. No patient had a creatinine clearance of less than 50 ml per minute during treatment. Five of 29 patients (17%) had tacrolimus concentrations of more than 15.0 ng per milliliter during the treatment period, although dosing errors accounted for the elevations in 4 of the 5 patients. Only one adverse event (mild rash) was reported in a patient with an elevated tacrolimus level. Shortly after treatment completion, 8 patients (28%) had one or more tacrolimus measurements below the laboratory reference range; in all the patients, levels returned to the therapeutic range during subsequent follow-up, and no graft rejection occurred. The suggested adjustments in the cyclosporine dose maintained trough concentrations within the therapeutic range.

Neither tacrolimus nor cyclosporine substantially altered the trough concentrations of ombitasvir, ABT-450, dasabuvir, or ribavirin. The trough concentrations of the study drugs were within the range observed in phase 2 and 3 studies of this regimen.27-31,34

Discussion

Previous studies have shown that overall graft and patient survival rates are lower among liver-transplant recipients with HCV infection than among transplant recipients without HCV infection, owing to universal reinfection and accelerated disease progression. No existing therapeutic regimens are approved for HCV-infected liver-transplant recipients. In the phase 2 CORAL-I trial of a 24-week, interferon-free, all-oral antiviral regimen for HCV genotype 1 infection, a rate of sustained virologic response of 97% (95% CI, 85 to 100) at post-treatment weeks 12 and 24 was observed among liver-transplant recipients with no fibrosis or mild fibrosis. Sustained virologic responses of 96 to 100% have been reported in phase 3 studies of 12 weeks of treatment with ombitasvir–ABT-450/r and dasabuvir with ribavirin in nonimmunosuppressed patients not undergoing liver transplantation.27-30

Studies of a first-generation protease inhibitor (boceprevir or telaprevir) in combination with peginterferon and ribavirin have shown lower rates of sustained virologic response (20 to 71%) and high rates of toxic effects among immunosuppressed patients after transplantation, and some of these toxic effects can be life-threatening.21-24 In a phase 2 evaluation, treatment with the nucleotide polymerase inhibitor sofosbuvir and ribavirin for 24 weeks resulted in a sustained virologic response at post-treatment week 12 in 28 of 40 liver-transplant recipients (70%).35 The patients included in these studies generally had advanced fibrosis, which may be associated with a decreased response rate.

Treatment of liver-transplant recipients with telaprevir or boceprevir plus peginterferon and ribavirin is associated with high rates of treatment discontinuation owing to adverse events. Side effects of these regimens result in frequent use of erythropoietin (in 77 to 100% of patients), modifications in the ribavirin dose (in 70 to 100%), and blood transfusions (in 33 to 64%) to manage anemia.21-24 Grade 3 and grade 4 laboratory abnormalities were each observed in 28% of patients receiving treatment with sofosbuvir and ribavirin, including hemoglobin levels of less than 8.0 mg per deciliter in 20% of patients,35 although this study population included patients with cirrhosis, and such abnormalities may be observed more frequently in patients with cirrhosis than in those without cirrhosis.

In our study, doses of immunosuppressive calcineurin inhibitors were modified during the treatment period to maintain therapeutic levels. No deaths or episodes of graft rejection occurred in this population of difficult-to-cure transplant recipients with HCV infection. The rates of serious adverse events and study discontinuations due to adverse events observed in this small study were lower than the rates that have been observed with the interferon-based treatments that were the previous standard of care.36 Only one patient discontinued the study treatment owing to adverse events, and this patient had a sustained virologic response. In this immunosuppressed population, no new safety signals were identified, and events related to impairment of renal function and grade 3 laboratory abnormalities were similar to those observed in larger trials of this regimen involving patients not undergoing transplantation.27-31,34 However, this study was not large enough to accurately estimate rates of adverse events or to make comparisons with rates of adverse events in prior trials. No patient needed a blood transfusion; five patients (15%) required erythropoietin, all of whom had initially received ribavirin at a total daily dose of 1000 or 1200 mg. These five patients were among the first study participants to receive the study drugs, and this observation was communicated to the investigators with a suggestion to use a lower starting dose of ribavirin. Given the high response rate that was observed, regardless of the initial ribavirin dose, an initial dose of 600 to 800 mg may provide sufficient therapeutic benefit and minimize the risk of severe anemia.

This study has limitations. Patients were excluded if they had advanced fibrosis (Metavir score >F2) or had received interferon-based treatment after transplantation; thus, the study selected patients with cases of HCV infection that have historically been easier to treat than those characterized by advanced fibrosis. In addition, patients underwent transplantation at least 12 months before study initiation, so the study excluded those with early, aggressive forms of recurrent HCV infection (e.g., fibrosing cholestatic hepatitis) that can complicate treatment. Another limitation of the study was that immunosuppressive agents other than tacrolimus and cyclosporine were not evaluated; we assessed only these two agents because previous studies of interactions between drugs were restricted to these two agents.

In light of the worldwide organ shortage, a safe and effective antiviral regimen is needed for the treatment of HCV-infected liver-transplant recipients, who have lower survival rates than other liver-transplant recipients. Treatment of recurrent HCV infection after liver transplantation is associated with improved outcomes in patients who have a sustained virologic response,13-15 including improvements in graft and patient survival, changes that may potentially reduce the demand for retransplantation.8 We found that the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin resulted in a 97% response rate among immunosuppressed liver-transplant recipients with recurrent HCV genotype 1 infection. This all-oral, interferon-free regimen was efficacious in eradicating HCV infection in a patient population who are at high risk for severe illness and death and for whom treatment options are currently limited.

Supported by AbbVie.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on November 11, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made this study possible; Anthony “Jake” Demetris, M.D., at the University of Pittsburgh and Christine Collins, Ph.D., Barbara McGovern, M.D., Rajeev Menon, Ph.D., Preethi Krishnan, Ph.D., Gretja Schnell, Ph.D., Rakesh L. Tripathi, M.S., Michelle Irvin, and Thomas Reisch, employees of AbbVie, for contributions to the study; and Douglas E. Dylla, Ph.D., of AbbVie for medical-writing support.

Source Information

From Indiana University, Indianapolis (P.Y.K.); the Liver Institute at Methodist Dallas, Dallas (P.S.M.); AbbVie, North Chicago, IL (E.C., W.X., C.S., P.B., T.P.-M., R.A.V.); University of Chicago Medical Center (H.S.T.) and Northwestern University Comprehensive Transplant Center (J.L.) — both in Chicago; Mayo Clinic, Phoenix, AZ (H.E.V.); Columbia University Medical Center, Center for Liver Disease and Transplantation, New York (R.B.); Lahey Hospital and Medical Center, Burlington, MA (F.G.); University of California, San Francisco, San Francisco (N.A.T.); University of Colorado Denver, Aurora (J.R.B.); and the Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (X.F.).

Address reprint requests to Dr. Kwo at the Gastroenterology/Hepatology Division, Indiana University School of Medicine, 975 W. Walnut, IB 327, Indianapolis, IN 46202-5121, or at pkwo@iu.edu.

Source

(Ref: Merck & Co., The Lancet, StreetInsider, NASDAQ)

November 11th, 2014
By: Joe Barber

Merck & Co. said Tuesday that it plans to submit a marketing application for its investigational combination regimen of grazoprevir and elbasvir to the FDA in 2015 for the treatment of chronic hepatitis C. The company also reported results from the Phase II C-WORTHy trial, showing that the treatment combination, either with or without ribavirin, was associated with sustained virologic response rates at 12 weeks of 90 percent or greater in both treatment-naïve and -experienced patients. Eliav Barr, vice president of infectious diseases at Merck Research Laboratories, commented "we are encouraged by the findings for grazoprevir/elbasvir in the C-WORTHy trial and look forward to advancing our broad Phase III programme."

Source

Does Screening Baby Boomers for Hepatitis C Work?

Attention: Medical & Science Editors/Producers

Media Contact: Gregory Bologna
703-299-9766
gbologna@aasld.org
Press Room: November 7 – 11, 2014
Hynes Convention Center, Boston, MA
Telephone: 617-954-2977

Researcher: National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
+1 404-639-8895
NCHHSTPMediaTeam@cdc.gov

For Immediate Release
Presented: Tuesday, November 11 2015, 8:15 am Eastern

Does Screening Baby Boomers for Hepatitis C Work?

A study presented at the annual meeting of the American Association for the Study of Liver Diseases reported that the current age-based screening recommendation from the Centers for Disease Control and Prevention (CDC) is five times more effective in identifying people currently or previously infected with hepatitis C virus when compared to the previous screening strategy.

The CDC currently recommends a one-time birth cohort or age-based screening for hepatitis C virus (HCV). All baby boomers -- those born between 1945 and 1965 -- should be tested for HCV. Older screening strategies relied on identifying populations at greater risk for having HCV.

While the study did not evaluate the uptake of the CDC recommendation, the study authors conclude that the results demonstrate that the implementation of birth cohort testing in the primary care setting is feasible and can be effective.

A vast majority (81 percent) of Americans living with chronic HCV are baby boomers. In that group, 2.6 percent -- or 2.16 million people -- have chronic infection yet many don’t know they have it and cannot benefit from life-saving care and treatment.

Researchers conducted birth cohort testing trials for 14 months (December 2012-February 2014) at three large primary care healthcare centers. Baby boomer patients were randomly assigned to a group and automatically tested based on the birth cohort screening recommendation or to a control group based on the previous screening strategies. Almost 33,000 patients were screened using the birth cohort recommendation or control group.

While this is the first clinical study that provides real-world evidence that the baby boomer recommendations can be implemented in practice and will result in a significant increase in new HCV diagnoses, monitoring of the recommendations will continue to be important.
Abstract title:
Effectiveness of hepatitis C virus (HCV) testing for persons born during 1945-1965 -- Summary results from three randomized controlled trials

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AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. This year's Liver Meeting®, held in Boston, November 7-11, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 7 at the annual meeting. For copies of abstracts and press releases, or to arrange researcher interviews, contact Gregory Bologna at 703-299-9766.

Press releases and all abstracts are available online at www.aasld.org.

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- In adult patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) type 1 infection, TURQUOISE-I demonstrated sustained virologic response rates 12 weeks post-treatment (SVR(12)) of 93.5 percent after 12 weeks of treatment and 90.6 percent after 24 weeks of treatment, respectively

- In adult liver transplant patients with recurrent chronic GT1 HCV infection and new to treatment after transplantation, CORAL-I demonstrated 97.1 percent SVR rates at 12 and 24 weeks post-treatment after 24 weeks of treatment

- CORAL-I results published online today in The New England Journal of Medicine

Nov 11, 2014

BOSTON, Nov. 11, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced results from studies in chronic hepatitis C patients with human immunodeficiency virus type 1 (HIV-1) co-infection (TURQUOISE-I) and liver transplant recipients (CORAL-I) at The Liver Meeting®2014.

New, detailed results from part one of the Phase 2 portion of AbbVie's Phase 2/3 open-label study, TURQUOISE-I, showed patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) and HIV-1 receiving AbbVie's investigational treatment and ribavirin (RBV) for 12 weeks or 24 weeks achieved sustained virologic response rates 12 weeks post-treatment (SVR12) of 93.5 percent (n=29/31) and 90.6 percent (n=29/32), respectively. These data were presented today, November 11, as a "Poster of Distinction."

"Patients living with both chronic HCV and HIV have been historically considered more difficult to treat," said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "TURQUOISE-I is one of the few dedicated studies looking specifically at this population, who are seen in everyday clinical practice. These data will help us gain a better understanding of how our investigational treatment works in this subpopulation of genotype 1 patients." 

Additionally, results from the first cohort of AbbVie's ongoing open-label Phase 2 study, CORAL-I, were presented today during an oral session and published online in The New England Journal of Medicine. Results showed that non-cirrhotic liver transplant patients with recurrent GT1 HCV and new to treatment after transplantation achieved a SVR12 rate of 97.1 percent (n=33/34) and a sustained virologic response rate 24 weeks post-treatment (SVR24) of 97.1 percent (n=33/34) after 24 weeks of treatment.

"Recurrence of HCV infection in the new graft post-liver transplantation is universal in those that have the virus prior to transplantation, and can be associated with an aggressive disease course," explained Dr. Paul Kwo, medical director of liver transplantation and professor of medicine, Indiana University School of Medicine. "The high SVR rates seen in CORAL-I are promising and offer valuable information as we continue to assess this regimen within this specific patient population."

About TURQUOISE-I

TURQUOISE-I is an ongoing Phase 2/3, multi-center, randomized, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (weight based dosing of 1000 mg or 1200 mg per day divided twice daily) for 12 or 24 weeks in adult patients with chronic GT1 HCV infection with or without compensated liver cirrhosis who are also infected with HIV-1. Study patients were either new to therapy (treatment naïve) or had failed previous treatment with pegylated interferon and RBV (treatment-experienced), had a stable immune status (CD4+ counts of ≥200 cells/mm3 or CD4+ % ≥14%) and had HIV-1 ribonucleic acid levels suppressed on a stable atazanavir- or raltegravir-based antiretroviral HIV therapy.

No patients discontinued treatment due to adverse events in either the 12-week or 24-week arm. In the 12-week arm, no virologic breakthroughs were observed while on treatment. One patient (3.3 percent) experienced post-treatment relapse after 12 weeks of treatment. In the 24-week treatment arm, one virologic breakthrough was observed (3.1 percent). Two patients in the 24-week treatment group were believed to have been re-infected post-treatment by a different strain of HCV than the original infection. The most commonly reported adverse events (greater than 15 percent in both treatment arms combined) were fatigue (47.6 percent), insomnia (19 percent), nausea (17.5 percent), and headache (15.9 percent). Elevations in total bilirubin were the most common laboratory abnormality (68.3 percent), were mainly composed of indirect bilirubin, and were not associated with aminotransferase elevations. Reductions in RBV dose because of anemia or reduced hemoglobin occurred in 9.5 percent of patients (n=6/63); all six patients achieved SVR12.

About CORAL-I

CORAL-I is an ongoing Phase 2, multi-center, two-cohort, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (RBV dosing left up to the discretion of the investigator) for 24 weeks in adult non-cirrhotic (screening biopsy Metavir score ≤F2) liver transplant recipients with recurrent chronic GT1 HCV infection. Patients in the study initiated therapy at least 12 months after receiving a liver transplant, had not received other HCV therapy since their liver transplant, and were on a stable immunosuppressant regimen based on either tacrolimus or cyclosporine, for which dose adjustments were advised. Enrollment in the second cohort of the study is ongoing.

One patient (2.9 percent) discontinued the study due to adverse events but still achieved SVR12. Two patients experienced serious adverse events. The most commonly reported treatment-emergent adverse events (greater than 20 percent) were fatigue (50 percent), headache (44.1 percent), cough (32.4 percent), anemia (29.4 percent), diarrhea (26.5 percent), insomnia (26.5), asthenia (23.5 percent), nausea (23.5 percent), muscle spasms (20.6 percent), and rash (20.6 percent). No patients experienced virologic breakthrough while on treatment; however, one patient experienced post-treatment relapse. Nine patients had a grade 2 reduction in hemoglobin, and one patient had a grade 3 reduction. Five patients with hemoglobin decreases (anemia) received a medication to boost their red blood cell production at the investigator's discretion. No patients discontinued study drugs because of anemia, required a blood transfusion, or experienced a rejection of their transplanted liver.

About AbbVie's Investigational Three Direct-Acting Antiviral Treatment

AbbVie's investigational treatment consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (25mg), dosed once daily, and dasabuvir (250mg) dosed twice daily with or without ribavirin. The combination of three direct-acting antivirals, each with a distinct mechanism of action, targets and inhibits specific hepatitis C virus proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program

The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's multinational program using an investigational treatment combining three direct-acting antivirals includes more than 2,300 patients in over 25 countries. The program is designed to identify ways to maximize response rates in a broad spectrum of patient populations, including those with compensated cirrhosis, liver transplant recipients and those with human immunodeficiency virus type 1 co-infection.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

AbbVie's New Drug Application to the U.S. Food and Drug Administration (FDA) and Marketing Authorization Applications to the European Medicines Agency (EMA) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 HCV infection have been accepted and granted priority review by the FDA and validated and granted accelerated assessment by the EMA.

Safety Information for Ribavirin and Ritonavir

Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995.  The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements.  AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements.  Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.  Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K and in Item 1A, "Risk Factors" of Part II of AbbVie's second quarter 2014 Quarterly Report on Form 10-Q, which have been filed with the Securities and Exchange Commission.  AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie

For further information: Media, Stefanie Prodouz, +1 (224) 637-0971, stefanie.prodouz@abbvie.com, Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com, Investor Relations, Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

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