March 5, 2014

Biological Psychiatry

Article in Press

Kuan-Pin Su, Hsueh-Chou Lai, Hui-Ting Yang, Wen-Pang Su, Cheng-Yuan Peng, Jane Pei-Chen ChangHui-Chih Chang, Carmine M. Pariante

Received 24 September 2013; received in revised form 6 January 2014; accepted 11 January 2014. published online 27 January 2014.
Corrected Proof

Abstract

Background
Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression.

Methods
We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis.

Results
Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.

Conclusions
EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.

Key Words: Chronic hepatitis C virus (HCV), clinical trial, omega-3 polyunsaturated fatty acids (n-3 PUFAs), inflammation, interferon-alpha (IFN-α), major depressive disorder (MDD)

Source

Wednesday, March 5, 2014 4:15 pm EST

BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced new data from HIV/HCV co-infected patients in the ongoing C-WORTHY Study, a Phase 2 clinical trial evaluating the efficacy and safety of Merck's all-oral, once-daily regimen combining MK-5172, an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor. In these co-infected patients, the administration of MK-5172/MK-8742 for 12 weeks resulted in robust HCV suppression, and a safety profile consistent with that observed for patients infected with HCV Genotype 1 infection (GT1) alone.

At 12 weeks, 100 percent (29/29) of co-infected patients who received MK-5172/MK-8742 and ribavirin (RBV), and 90 percent (26/29) of co-infected patients who received MK-5172/MK-8742 alone had HCV RNA levels of less than 25 IU/mL, versus 100 percent (13/13) in patients with HCV alone treated with MK-5172/8742. The data were presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI).

“We are encouraged by the potential of MK-5172/MK-8742 for the treatment of people living with HIV/HCV co-infection, where there remains a need for additional therapeutic options,” said Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories.

About the MK-5172/MK-8742 Data Presented at CROI

After 4 weeks of treatment, all co-infected patients showed a reduction in HCV RNA levels to below 25 IU/mL with or without RBV administration. HCV kinetics over the first 4 weeks of therapy were similar in patients with or without HIV co-infection.

Virologic Response: Intent-to-Treat Population

Capture

*One HIV/HCV co-infected patient had not yet reached TW12; HIV/HCV co-infected (RBV-free) arm: 1 lost to follow-up (HCV RNA undetectable at the last visit on record); 2 breakthroughs with low blood levels of MK-5172 and/or MK-8742; HCV mono-infected (RBV-containing) arm: 3 early discontinuations (day 3 [detectable at the last visit] and days 22 and 35 [undetectable at the last visit]).

There were three treatment failures in the HIV/HCV co-infected study arms; one subject completed the treatment regimen but was lost to follow-up (HCV RNA undetectable at the last visit on record); and two co-infected subjects with low pharmacokinetic levels of MK-5172 and/or MK-8742 experienced virologic breakthrough at the 8 week time point (both cases with low blood levels of MK-5172 and/or MK-8742).

The most common adverse events observed in this cohort were fatigue (7%) and headache (8%). The incidence of these adverse events was not increased in patients with HIV. No co-infected patients discontinued due to either an adverse event or study medication intolerance.

About HIV/HCV Co-Infection

Globally, approximately seven million patients are co-infected with HIV and HCV. HCV is the leading cause of morbidity and mortality among those living with HIV-1, and compared to the general population, the overall prevalence of HCV infection is higher among those infected with HIV-1. Furthermore, HIV/HCV co-infected patients have a three times higher rate of progression to cirrhosis and a six times higher risk of hepatic decompression than HCV patients infected with HCV alone, underscoring the need for new therapeutic options for this patient population.

About the C-WORTHY Clinical Trial

C-WORTHY is a randomized, dose-responsive, parallel-group, multiple-site, open-label trial comparing different patient populations exposed to different durations of treatment of MK-5172 (100 mg QD) in combination with MK-8742 (50 mg QD) with or without RBV in patients with chronic HCV infection. A total of 450 patients with HCV GT1 and HCV RNA levels of ≥10,000 IU/mL have been enrolled in C-WORTHY and randomized across 16 arms to examine difficult-to-treat subpopulations.

The primary objective of C-WORTHY is to evaluate the safety and efficacy of MK-5172 in combination with MK-8742 with or without RBV as assessed by the proportion of patients achieving sustained virologic response at 12 weeks (SVR12) in treatment-naïve patients and more complex patient groups including prior peginterferon alfa and ribavirin treatment failures, cirrhotic patients and co-infected patients. The aim of the HIV/HCV co-infected arms is to compare on-treatment HCV RNA responses (defined as proportion of patients with HCV RNA <25 IU/mL) in GT1 HIV/HCV co-infected patients treated with MK-5712/MK-8742 with or without RBV with those in mono-infected patients.

In the HIV/HCV co-infection arms, 59 treatment-naïve, non-cirrhotic, GT1 HIV/HCV co-infected patients on a stable antiretroviral regimen (raltegravir + tenofovir or abacavir with either 3TC or FTC) were examined. These subjects were randomized at a 1:1 ratio to receive 12 weeks of MK-5172 (100 mg QD) administered concomitantly with MK-8742 (50 mg QD), with or without twice daily (BID) RBV.

Additional data from Merck’s Phase 2 program for MK-5172/MK-8742 will be presented at the 49th Annual Meeting of the European Association of the Study of the Liver, April 9-13 in London. Details on the C-WORTHY Study, as well as additional Phase 2 trials for MK-5172 and MK-8742, can be viewed on www.merck.com/clinical-trials.

In October 2013, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to MK-5172/MK-8742 for treatment of chronic HCV infection.

About Merck

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

Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Contact:

Merck
Media:
Caroline Lappetito, 267-305-7639
or
Ian McConnell, 908-423-3046
or
Investors:
Carol Ferguson, 908-423-4465
or
Justin Holko, 908-423-5088

Source

PUBLIC RELEASE DATE: 5-Mar-2014
Contact: Vicki Cohn
vcohn@liebertpub.com
914-740-2100
Mary Ann Liebert, Inc./Genetic Engineering News

New Rochelle, NY, March 5, 2014—Chronic hepatitis C virus (HCV) infection can lead to serious diseases such as cirrhosis and cancer of the liver, so viral clearance and prevention of relapse are important treatment goals. Low-dose oral interferon may reduce the risk of HCV relapse in patients with mild liver fibrosis according to a study published in Journal of Interferon & Cytokine Research, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Interferon & Cytokine Research website.

In "A Double-Blind Randomized Controlled Study to Evaluate the Efficacy of Low-Dose Oral Interferon-Alpha in Preventing Hepatitis C Relapse," Chuan-Mo Lee and coauthors from several universities and hospitals in Taiwan present the results of a clinical trial comparing the effects of 24 weeks of treatment with two doses of oral interferon-alpha or placebo in patients who achieved viral clearance after successful HCV therapy.

"This is a highly significant study relevant to the optimal use of IFN for HCV treatment," says Co-Editor-in-Chief Ganes C. Sen, PhD, Chairman, Department of Molecular Genetics, Cleveland Clinic Foundation, Ohio.

###

About the Journal

Journal of Interferon & Cytokine Research (JICR), led by Co-Editors-in-Chief Ganes C. Sen, PhD, and Thomas A. Hamilton, PhD, Chairman, Department of Immunology, Cleveland Clinic Foundation, is an authoritative peer-reviewed journal published monthly online with Open Access options and in print that covers all aspects of interferons and cytokines from basic science to clinical applications. JICR is an official journal of the International Cytokine and Interferon Society. Complete tables of content and a sample issue may be viewed online on the Journal of Interferon & Cytokine Research website.

About the Publisher

Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Viral Immunology, AIDS Research and Human Retroviruses, and DNA and Cell Biology. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.

Source

New drugs trump interferon in HCV therapy

By: NEIL OSTERWEIL, Family Practice News Digital Network

03/05/14

The era of interferon and ribavirin in the treatment of hepatitis C viral infections appears to be drawing to a close, and few clinicians will mourn the passing of the effective but highly toxic combination, investigators said at the Conference on Retroviruses and Opportunistic Infections.

In patients with hepatitis C virus infection alone or HCV with HIV coinfection, a host of new interferon-free drugs and new combinations are transforming therapy, reported Dr. Jean-Michel Pawlotsky, professor of medicine at the University of Paris-Est.

"Hepatitis C is living a real therapeutic revolution. Everything is changing very fast. We’re now getting infection cure rates higher than 90% with the classes of drugs we have," he said at a briefing.

STARTVerso4

With all of the drugs, the sustained virologic response (SVR) rates "are exactly the same in coinfected patients as they are in monoinfected patients," said Dr. Douglas Dieterich of Mt. Sinai Medical Center, New York.

RTEmagicC_6cjxk9s8_99753.photo.jpg

Courtesy US. Dept of Veterans Affairs
A host of new interferon-free drugs and new combinations are transforming therapy for patients with hepatitis C viral infections, says Dr. Jean-Michel Pawlotsky.

For example, a combination of the protease inhibitor faldaprevir with pegylated interferon alfa-2a plus ribavirin (PR) produced SVR rates at week 4 of follow-up (SVR4) of 74% in HCV/HIV coinfected patients, said Dr. Dietrich, a principal investigator for the STARTVerso4 trial.

In this phase III open-label trial, 308 patients with HCV/HIV coinfection who were treatment naive or relapsed after prior interferon-based therapy were randomly assigned to receive faldaprevir 120 mg daily for 24 weeks or 240 mg for 12 or 24 weeks according to on-treatment response. In both arms, faldaprevir was given on a PR backbone, with duration guided by response to therapy.

For the primary endpoint of SVR12, the investigators saw a 72% rate, with no significant difference between the two dose groups, compared with approximately 80% in monoinfected patients in other phase III studies. There was also no difference in efficacy between patients with or without cirrhosis, he said.

Adverse events included mild hyperbilirubinemia in some patients and interferon side effects.

Simeprevir in coinfection

Dr. Dietrich was also the lead on study C212, which looked at simeprevir (Olysio) on a PR backbone in coinfected patients. The results were similar to those seen with faldaprevir (73.6% overall SVR12).

Interestingly, the presence of the simeprevir-resistant q80K polymorphism did not make a difference in response rates, he said. Among monoinfected patients in prior studies, those with q80k polymorphism had significantly lower SVR rates. The adverse events were also similar to those seen in patients with monoinfection.

PHOTON-1

The PHOTON-1 trial evaluated the first interferon-free regimen (sofosbuvir plus ribavirin) in patients with HCV genotypes 1-3 and HIV.

In this study, patients with HCV and stable HIV infection received sofosbuvir 400 mg and ribavirin 1,000-1,200 mg daily. Treatment-naive patients with HCV genotype 1 and treatment-experienced patients with genotypes 2 or 3 received treatment for 24 weeks, while treatment-naive genotype 2/3 patients received 12 weeks of treatment. Patients on multiple antiretroviral (ART) regimens and those with compensated cirrhosis were included in the study.

The primary efficacy endpoint, SVR12, was achieved in 88% of treatment-naive genotype 2 patients and 67% of genotype 3 patients. In genotype 1 patients, the SVR was approximately 70%, Dr. Dietrich said.

Adverse events were general and limited to anemias, headache, and other symptoms commonly seen with HCV therapies, he added.

SYNERGY trial

Dr. Anita Kohli presented final results from the SYNERGY trial, which looked at combination oral HCV therapy for 6 or 12 weeks (SVR4 results from this trial were presented at the 2013 Liver Meeting).

In this phase II prospective cohort study, 60 treatment-naive patients with HCV genotype 1 were enrolled into one of three arms to receive either sofosbuvir 400 mg with ledipasvir 90 mg once daily in a fixed-dose combination for 12 weeks (arm A); the same fixed-dose combination plus the non-nucleoside NS5B inhibitor GS-9669 500 mg/day for 6 weeks (arm B); or the fixed-dose combination plus the NS3 protease inhibitor GS-9451 80 mg/day for 6 weeks.

The SVR12 rate among the patients on sofosbuvir/ledipasvir alone (arm A) was 100%, the rate in arm B was 95%, and the rate in arm C was 100%.

"We find these results very promising," said Dr. Kohli of the National Institutes of Health.

She noted that all patients in the trial were treatment naïve, and that all stages of liver disease were included in the 12-week treatment arm, but cirrhotic patients were excluded from the 6-week arms.

"These regimens are very simple. They’re one, two, or three pills a day," she noted. In addition, "our patient population is one that has been historically very difficult to treat, that is, predominantly African American," she noted.

Most of the patients had genotype 1a with a high viral load, and 25%-30% of patients in all treatment arms had advanced-stage liver disease, she added.

PEARL-III

The PEARL III trial looked at 419 treatment-naive, noncirrhotic patients with HCV genotype 1b, who were randomly assigned to receive either a ritonavir-boosted protease inhibitor (ABT-450) with ABT-267, which is an inhibitor of HCV NS5A, coformulated into a single pill; or ABT-333, a non-nucleoside polymerase inhibitor, with or without ribavirin.

In the ribavirin-containing arm, SVR12 was 99.5%, compared with 99% among controls. There was only one virologic failure in the study, and two patients who did not achieve SVR4 were lost to follow-up at week 12, noted Dr. Daniel Cohen of AbbVie Pharmaceuticals.

Adverse events included predominantly mild headache and fatigue in about 25% of patients, with slightly more events seen in the ribavirin combination arm.

STARTVerso4 was sponsored by Boehringer Ingelheim. C212 was sponsored by Janssen. SYNERGY was supported by the National Institutes of Health and Gilead Sciences. Dr. Cohen is employed by AbbVie, which sponsored PEARL III.

Source