Tobira Therapeutics Presents Data Supporting Anti-Fibrotic Activity of Cenicriviroc in Liver Disease Models at The Liver Meeting 2013

AASLD Annual Meeting 2013

November 04, 2013 08:30 AM Eastern Time 

SOUTH SAN FRANCISCO, Calif.--(EON: Enhanced Online News)--Tobira Therapeutics presented positive results from an evaluation of cenicriviroc (CVC) in two animal models of liver fibrosis at the American Association for the Study of Liver Diseases (AASLD) annual meeting (The Liver Meeting^®) in Washington, DC. CVC is a novel, oral, once-daily, dual CCR2 and CCR5 antagonist in late-stage clinical development for the treatment of HIV infection as part of fixed-dose combination regimens, and in planning for clinical development in liver fibrosis and other diseases in which antagonism of CCR2 and CCR5 may have a therapeutic effect.

“Significant Anti-Fibrotic Activity of Cenicriviroc, a Dual CCR2/CCR5 Antagonist in a Rat Model of Thioacetamide-Induced Liver Fibrosis and Cirrhosis”

“The data presented today illustrate the potential clinical utility of targeting CCR2 and CCR5 with CVC in the treatment of liver fibrosis, a disease for which there is currently no approved therapies,” said Scott Friedman, M.D., Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at Mount Sinai School of Medicine. “The safety and tolerability profile of CVC observed in Phase 2 studies in HIV makes it a good candidate for clinical evaluation in patients with liver disease.”

“These promising results in liver fibrosis build upon Phase 2 clinical safety and efficacy data from the HIV clinical program and demonstrate the multiple indications in which a CCR2 and CCR5 antagonist like CVC may play an important therapeutic role as an oral anti-fibrotic agent,” said Andrew Hindman, Tobira’s President and Chief Executive Officer.

Two experiments evaluated the effects of CVC at two doses in well-validated animal models of liver disease. CVC treatment was associated with an anti-fibrotic effect in both models. The first experiment evaluated a diet-induced mouse model of non-alcoholic steatohepatitis (NASH). These data were presented by Dr. Friedman during an oral presentation entitled “Anti-Fibrotic and Anti-Inflammatory Activity of the Dual CCR2 and CCR5 Antagonist Cenicriviroc in a Mouse Model of NASH” (Abstract ID #30). The second experiment evaluated a thioacetamide acid (TAA) induced rat model of liver fibrosis and cirrhosis. These data were presented in a poster session entitled, “Significant Anti-Fibrotic Activity of Cenicriviroc, a Dual CCR2/CCR5 Antagonist in a Rat Model of Thioacetamide-Induced Liver Fibrosis and Cirrhosis” (Abstract ID # LB-7).

NASH mouse model: CVC was evaluated in a streptozotocin-induced model of NASH. Over a nine-week experiment, three groups of animals (n=6/group) were administered CVC doses of 0 (vehicle), 20 (low dose) or 100 (high dose) mg/kg/day. After nine weeks biochemical, gene expression, and histologic evaluations of the liver were conducted. The primary finding showed the percentage of fibrosis area (by Sirius red staining) was significantly decreased by CVC treatment relative to vehicle control (0.29 ± 0.14, 0.20 ± 0.06 and 0.61 ± 0.23 for CVC low dose, CVC high dose and vehicle, respectively; p<0.01).

Liver fibrosis and cirrhosis rat model: CVC was evaluated in a TAA-induced model of liver fibrosis and cirrhosis. Over a twelve-week experiment, three groups of animals (n=4-8/group) received CVC doses of 0 (vehicle), 30 (low dose) and 100 (high dose) mg/kg/day, across three different periods of exposure to TAA to evaluate different degrees of liver damage. Biochemical, gene expression and histologic evaluations of the liver were conducted. When started concurrently with TAA (Group 1; Early Intervention), both the CVC low dose (Group 1a) and high dose (Group 1b) showed significantly reduced fibrosis by 49% and 38%, respectively (p<0.001), as assessed by collagen morphometry. When treatment started four weeks after TAA-induced injury (Group 2; Emerging Fibrosis), a statistically significant anti-fibrotic effect was observed for CVC low dose (Group 2a, 36% collagen reduction; p<0.001), but not for CVC high dose (Group 2b). When treatment was started at eight weeks (cirrhosis present) and continued for four weeks (Group 3; Cirrhosis Reversal), there was no significant effect of CVC on fibrogenic gene expression or fibrosis.

Chemokines and Liver Fibrosis: Chemokine receptor types 2 (CCR2) and 5 (CCR5) are expressed on monocytes, macrophages, Kupffer cells and hepatic stellate cells (HSCs), which contribute to inflammation in the liver. There is increasing evidence of the role of CCR2 and CCR5 in the pathogenesis of liver disease^1–7: these two co-receptors promote the recruitment of macrophages^3–5, play key roles in the migration of hepatic stellate cells (HSCs) during liver injury^3,4 and promote hepatic fibrosis in mice^3,4.

About Cenicriviroc

Cenicriviroc (CVC) is a novel, oral, once-daily, fixed-dose combinable, dual antagonist of chemokine receptors CCR2 and CCR5 with nanomolar potency. CVC is entering Phase 3 clinical development for the treatment of HIV-1 infection, and in planning for clinical development in liver fibrosis and other indications in which CCR2 and CCR5 play a role. The CCR2 receptor is found on monocytes, macrophages, dendritic and hepatic stellate cells, which are implicated in several inflammation-mediated diseases, including liver fibrosis. The CCR5 receptor is the target used by the HIV virus to infect human T-cells. CVC has been well tolerated with more than 500 subjects treated in single- and multiple-dose studies conducted to date, including 115 HIV-1 infected adults treated over a 48-week duration in Phase 2b (NCT01338883) ⁸. Tobira’s HIV Phase 3 development program will evaluate CVC in fixed-dose combination tablets with other antiretroviral agents, for use in the treatment of HIV infection.

About Tobira Therapeutics

Tobira Therapeutics is a privately held biopharmaceutical company developing innovative therapies for treatment of HIV infection, fibrosis, GVHD, and certain oncology indications. The company’s lead development candidate is cenicriviroc (CVC), a novel, oral, once-daily, fixed-dose combinable, dual inhibitor of chemokine receptors CCR2 and CCR5 in late-stage clinical development for the treatment of HIV. Tobira is backed by a syndicate of leading life science investors including Domain Associates, Frazier Healthcare Ventures, Montreux Equity Partners, Novo Ventures and Canaan Partners. Learn more at www.TobiraTherapeutics.com.

References

1. Saiman and Friedman, Frontiers in Physiology, June 2012; 2. Zimmermann and Tacke, Inflammation & Allergy – Drug Targets, 2011; 3. Seki et al., The Journal of Clinical Investigation, July 2009; 4. Seki et al. Hepatology, July 2009; 5. Miura et al. American Journal of Physiology – Gastrointestinal & Liver Physiology, June 2012; 6. Ochoa-Callejero et al. PLOS ONE, January 2013; 7. Mitchell et al., The American Journal of Pathology, May 2009; 8. Feinberg et al. EACS 2013, PS4/1

Contacts

Tobira Therapeutics
Caroline Loewy, 650-741-6625
EVP & CFO
cloewy@tobiratherapeutics.com
or
BCC Partners for Tobira Therapeutics:
Karen L. Bergman, 650-575-1509
kbergman@bccpartners.com
Michelle Corral, 415-794-8662
mcorral@bccpartners.com

Source

Global Burden of Liver Disease Substantial

Medscape Medical News > Conference News

Miriam E. Tucker

November 04, 2013

WASHINGTON, DC — Total deaths worldwide from cirrhosis and liver cancer rose by 50 million per year over 2 decades, according to the first-ever World Health Organization (WHO) study of liver disease mortality.

"Viral hepatitis specifically and liver disease in general have been underrepresented in the policy and the funding table," presenter Benjamin Cowie, PhD, told Medscape Medical News. "We're now increasingly recognizing that this is a substantial contributor to global mortality."

Dr. Cowie presented the liver disease-specific findings from the WHO Global Burden of Disease Study here at the Liver Meeting 2013.

"Certainly here in the United States, the number of people dying from liver disease and viral hepatitis is increasing quite steadily and concernedly rapidly," said Dr. Cowie, an infectious disease physician and epidemiologist at the Royal Melbourne Hospital in Australia.

Session comoderator Robert Fontana, MD, told Medscape Medical News that "there need to be better studies of viral hepatitis around the world to get better data. This is really a global health problem. We've been talking about AIDS and tuberculosis for a long time, but liver disease is also here. It's not coming, it's here already."

This is a substantial contributor to global mortality.

"We need to test people so we can treat them," added Dr. Fontana, who is from the University of Michigan Health System in Ann Arbor. "If you wait until they get liver cancer, the efficacy of everything we do is poor."

The report, supported by the Bill and Melinda Gates Foundation, was a collaboration of 486 researchers from 50 countries. The Institute for Health Metrics and Evaluation at the University of Washington led the work, which examined 291 diseases and injuries and 67 risk factors from 1990 to 2010 by region and country.

The report first listed hepatitis B as a leading cause of global death from infectious disease," but initial data did not include deaths from secondary infectious causes, such as liver cancer, cirrhosis, and other chronic diseases (N Engl J Med. 2012;366:454-461).

Cirrhosis and Liver Cancer on the Rise

"The morbidity and mortality of viral hepatitis is underrepresented in previous estimates because cirrhosis and cancer weren't included, but when you aggregate them, it moves up. I think that's a really important point," Dr. Fontana said.

As the number of annual liver cancer and cirrhosis deaths rose by 1.25 to 1.75 million from 1990 to 2010, an increasing proportion was due to liver cancer. In 2010, hepatitis B virus was associated with 45% of liver cancer and 30% of cirrhosis deaths, whereas hepatitis C and alcohol each caused about 25% of liver cancer and cirrhosis disease deaths.

In all, 1.3 million deaths worldwide are due to chronic viral hepatitis, which is comparable to the burden of HIV/AIDS, tuberculosis, and malaria, Dr. Cowie noted.

These proportions varied by country and region. In the United States, which had an estimated 19,500 liver cancer and 49,500 cirrhosis deaths in 2010 — an increase of 25,000 total liver disease deaths over 20 years — hepatitis C was a primary cause, accounting for 41% of liver cancer and 40% of cirrhosis deaths. Alcohol and hepatitis B were less common causes.

In China, by contrast, hepatitis B caused 54% of liver cancer and 46% of cirrhosis deaths in 2010. There were 370,000 liver cancer and 110,000 cirrhosis deaths in 2010. Those represented half the entire global burden of liver cancer deaths, but only 11% of the total deaths due to cirrhosis, Dr. Cowie noted.

Hepatitis B–associated cirrhosis was also more common in sub-Saharan Africa, where it accounted for 47% of liver cancer and 39% of cirrhosis deaths. The region also had a disproportionate burden of other cirrhosis deaths.

In Australia, cirrhosis deaths predominate, but liver cancer from hepatitis B is increasing relatively rapidly. There, hepatitis B is associated with 41% of liver cancer deaths and alcohol is responsible for 38% of cirrhosis deaths.

Dr. Cowie told Medscape Medical News that the recent baby boomer screening recommendations from the US Public Health Services Task Force and the Centers for Disease Control and Prevention are a step in the right direction.

"It's good to see the United States taking a leadership role from a clinical perspective, but there's still a lot to be done," he said. "Beyond diagnosis, what about access to care? In Australia, less than 5% of infected people have access to treatment."

Advancing Progress in Liver Diseases

Advancing progress in liver disease could follow the model of the HIV/AIDS movement, Dr. Cowie suggested. "That's one of the really encouraging messages from the Global Burden of Diseases project. HIV mortality has been falling since 2006 on a global basis. That's such a wonderful testament to what we can achieve when we harness our collective political will and donor funding and partnership responses with affected communities," he noted. "We can transform what was — and still is — a very substantial burden, but we're actually turning it around. That's so encouraging. We need to take those lessons and translate them into other areas that have been neglected, like viral hepatitis and liver disease."

Dr. Cowie pointed out that in poor countries, programs such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria, and the US President's Emergency Plan for AIDS Relief (PEPFAR) have brought lifesaving drugs to people in need. "In poor countries with HIV, there was a recognition that this was a substantial and evolving health emergency. As a consequence, the Global Fund and PEPFAR have transformed the lives of millions of people. Why can't we do that for liver disease?"

Dr. Cowie says he anticipates that the project will help many different diseases that have previously been underappreciated as major causes of morbidity and mortality. "All data are freely available on that site. It's an absolute treasure trove. It's not just about viral hepatitis or about any particular country. It's about all causes of human disease in an accessible format."

Dr. Cowie has disclosed no relevant financial relationships. Dr. Fontana reports receiving research support from Gilead and Vertex, and being a consultant for GlaxoSmithKline and Tibotec.

The Liver Meeting 2013: American Association for the Study of Liver Diseases (AASLD). Abstract 23. Presented November 3, 2013.

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Culture Shock: Magic Bullet for HCV?

Meeting Coverage

Published: Nov 4, 2013

By Michael Smith, North American Correspondent, MedPage Today

Culture Shock is a blog by Michael Smith for readers with an interest in infectious diseases.

WASHINGTON -- A few years back, a prominent liver researcher was asked if he was delaying hepatitis C treatment for patients not in urgent need. After all, new, less toxic, more effective treatments would soon be on stream. Why push patients into current regimens, often hard to take and always very toxic?

"Yes," the doc replied, deadpan. "In fact, I've had to add a new floor to my warehouse."

He and others may be running up whole new buildings if some preliminary research, presented here at the annual meeting of the American Association for the Study of Liver Diseases, comes to fruition.

Think of this -- a single infusion that cures HCV.

We're getting perilously close to magic bullet territory here. One doctor I spoke to here said she'd postpone therapy for most of her patients -- even with the newer, gentler drugs -- if there was a possibility that a single shot could cure the disease.

In a plenary presentation, David Suhy, PhD, of Tacere Therapeutics of San Francisco, outlined the idea: A recombinant virus vector that gives rise to hairpin RNA segments that target three parts of the HIV genome. Once integrated into liver cells, the RNAs interfere with HCV replication as long as the cells live.

Upside? It's a single infusion so there would be no compliance or adherence issues. And the treatment is over, just like that.

The downside is that there's no way to stop or reverse the therapy once it's administered.

The pre-clinical data look good and the stuff is intended to go into early human trials next year, Suhy said.

It's important to emphasize that this is not ready for prime time, not by a long shot. We all know of very promising drugs that have fallen to the ground during clincial trials.

But if it looks as if it's working, it could put all of the new HCV drugs off the shelf, even before they've had much of a chance to get on.

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VIDEO: 3-D liver reproduction offers new planning, educational opportunities

Provided by Healio

November 4, 2013

WASHINGTON — Nizar Zein, MD, of the gastroenterology and hepatology department at the Cleveland Clinic reports during The Liver Meeting that use of 3-D printers to generate highly accurate representations of individual livers may allow better preoperative planning.

The new method of viewing the organ also could avert unnecessary surgery in patients with potentially unsuitable anatomy and decrease complications related to surgery, he said.

Disclosure: Zein reports no relevant financial disclosures.

For more information:

Zein N. #1180: 3-Dimensional (3D) Print of Liver for Preoperative Planning in Live Donor Liver Transplantation. Presented at: The Liver Meeting 2013; Nov. 1-5, Washington.

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VIDEO: Complications of Cirrhosis - The Liver Meeting 2013

WebsEdgeHealth

Published on Nov 3, 2013

Theo Heller, MD, Chief, Translational Hepatology Unit, National Institutes of Health, talks to AASLD TV about the exciting new developments in this area of research and new information coming out of the Global Burden of Disease Studies.

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Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial

ABSTRACT FINAL ID: 215
CURRENT CATEGORY: Viral Hepatitis C
CURRENT DESCRIPTORS: S06. HCV Therapy and Trials: New Agents (phase 2 -3)
SESSION TYPE: Plenary Session
SESSION TITLE: Presidential Plenary: Viral Hepatitis

ABSTRACT FINAL ID: Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial

PRESENTER: Eric Lawitz

AUTHOR/INSTITUTIONS: E. Lawitz, F. Poordad, F.E. Membreno, The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, UNITED STATES|R.H. Hyland, X. Ding, C. Hebner, P.S. Pang, W.T. Symonds, J.G. McHutchison, Gilead Science, Inc, Fost

SPONSORSHIP: Gilead Sciences, Inc.

ABSTRACT BODY:
Background: In a prior phase 2 study, patients with HCV genotype 1 who received sofosbuvir (SOF), an HCV-specific uridine nucleotide analog, together with ledipasvir (LDV), an NS5A inhibitor, plus ribavirin (RBV) for 12 weeks, achieved a high rate of sustained virologic response (SVR), irrespective of whether the patients were treatment-naïve or prior null responders. We therefore assessed the safety and efficacy of 8 and 12-week regimens of a fixed-dose combination (FDC) of SOF and LDV with and without RBV in treatment-naïve and protease inhibitor-experienced patients with HCV genotype 1.

Methods: 60 non-cirrhotic treatment-naïve patients with HCV genotype 1 were randomized 1:1:1 to receive: 1) FDC for 8 weeks, 2) FDC + RBV for 8 weeks, or 3) FDC for 12 weeks. In parallel, 40 patients who had not achieved SVR after previous treatment with a protease inhibitor regimen (50% of whom also had compensated cirrhosis) were randomized to receive twelve weeks of: 1) FDC or 2) FDC + RBV. The primary end point was SVR 12 weeks after completion of treatment.

Results: 100 patients were enrolled. The treatment-naïve group was 88% genotype 1a and 20% were IL28B CC. The protease-inhibitor experienced group was 85% genotype 1a and 7.5% were IL28B CC. Biopsy-confirmed cirrhosis was present in 22/40 (55%) of the PI-experienced subjects. Results are tabulated below. SOF/LDV FDC with or without RBV for 8 and 12 weeks was generally well tolerated; 1 patient discontinued treatment early. Adverse events were generally mild, and no SAEs attributed to treatment were reported. Grade 3/4 laboratory abnormalities were infrequent. Adverse events and laboratory abnormalities consistent with the safety profile of RBV were noted in groups receiving SOF/LDV FDC+RBV. SVR12 from all groups will be presented.

Conclusions: SOF/LDV FDC elicited rapid declines in HCV RNA and high rates of SVR regardless of the presence of RBV in all treatment groups with no viral breakthrough observed. 97% of patients achieved SVR, two relapsed, and one was lost to follow up. Further evaluation of SOF/LDV FDC in treatment-naïve and treatment-experienced patients in Phase 3 studies is in progress.

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Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial

ABSTRACT FINAL ID: 73
CURRENT CATEGORY: Viral Hepatitis C
CURRENT DESCRIPTORS: S06. HCV Therapy and Trials: New Agents (phase 2 -3)
SESSION TYPE: Parallel Session
SESSION TITLE: Parallel 11: HCV Therapeutics: New Agents

ABSTRACT FINAL ID: Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial

PRESENTER: Edward Gane

AUTHOR/INSTITUTIONS: E.J. Gane, Auckland Clinical Studies, Auckland, NEW ZEALAND|C.A. Stedman, Christchurch Clinical Studies Trust, Christchurch, NEW ZEALAND|R.H. Hyland, X. Ding, E.S. Svarovskaia, P.S. Pang, W.T. Symonds, Gilead Science, Inc, Foster City, Califor

SPONSORSHIP: Gilead Sciences, Inc.

ABSTRACT BODY:
Background: In previous Phase 2 studies, the addition of an NS5A inhibitor (either ledipasvir (LDV) or daclatasvir) to the combination of the HCV nucleotide analog sofosbuvir (SOF) plus ribavirin (RBV) for 12 weeks resulted in high rates of sustained viral response (SVR) in non-cirrhotic patients infected with HCV genotype 1 (GT-1). In the ELECTRON Phase 2 study, we evaluated the safety and efficacy of a fixed-dose combination (FDC) tablet of SOF plus LDV in additional patient populations, including those with cirrhosis and with non-GT-1 infection. We also evaluated the need for RBV and for 12 weeks’ duration.

Methods: We enrolled 4 arms: prior null-responder HCV GT-1 patients with compensated cirrhosis were randomized to receive open-label SOF/LDV FDC with or without RBV for 12 weeks; treatment-naïve HCV GT-1 patients without cirrhosis received SOF/LDV FDC plus RBV for 6 weeks; and treatment-naïve HCV non-GT-1 patients without cirrhosis were assigned to receive SOF/LDV FDC plus RBV for 12 weeks.

Results: 54 patients were enrolled. Of the GT-1 prior null-responder group, 79% were genotype 1a, and 32% were IL28B CC. Of the treatment-naïve GT-1 group, 84% were genotype 1a, and 20% were IL28B CC. Of the non-GT-1 group 20% were GT-2, and 80% GT-3. Efficacy results are tabulated. SOF/LDV FDC with or without RBV was generally well tolerated; There were no SAEs or treatment discontinuations. Adverse events were generally mild, and Grade 3/4 laboratory abnormalities were infrequent and consistent with the safety profile of RBV. No toxicity attributable to SOF/LDV FDC was identified.

Conclusions: SOF/LDV FDC elicited rapid decline in HCV RNA in all patient populations with no viral breakthrough observed. In treatment-naïve GT-1 patients without cirrhosis, reduction in duration from 12 to 6 weeks increased the rate of relapse. In the prior null responder GT-1 patients with cirrhosis, the addition of RBV to SOF/LDV FDC decreased the rate of relapse, suggesting that either RBV or a third DAA may be useful in this difficult-to-treat patient population. Promising SVR rates achieved in genotype 2 or 3 patients support further evaluation of SOF/LDV FDC in patients with HCV GT-2 or GT-3.

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“To share or not to share?” Serosorting by hepatitis C status in the sharing of drug injection equipment among NHBS-IDU2 participants

J Infect Dis. (2013) doi: 10.1093/infdis/jit520

First published online: October 16, 2013

Bryce D. Smith1,*, Amy Jewett2, Richard D. Burt3, Jon E. Zibbell1, Anthony K. Yartel4 and Elizabeth DiNenno5

+ Author Affiliations

1. ¹Centers for Disease Control and Prevention, Division of Viral Hepatitis, Atlanta, Georgia 30333
2. ²Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831
3. ³Public Health Seattle and King County, Seattle, WA 98104
4. ⁴Centers for Disease Control and Prevention Foundation, Atlanta, GA 30333
5. ⁵Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, GA 30333

1. ↵*Corresponding author: 1600 Clifton Rd, MS G-37, Atlanta, GA 30333. BSmith6@cdc.gov. Tel: 404-639-6277; Fax: 404-718-8595.

Abstract

Background. Persons who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV) infection. CDC estimates there are 17,000 new infections per year, mainly among PWID. This study examines injection equipment serosorting – considering HCV serostatus when deciding whether and with whom to share injection equipment.

Objective. To examine whether injection equipment serosorting is occurring among PWID in selected cities.

Methods. Using data from the National HIV Behavioral Surveillance System-Injection Drug Users (NHBS-IDU2, 2009), we developed multivariate logistic regression models to examine the extent to which participants' self-reported HCV status is associated with their injection equipment serosorting behavior and knowledge of last injecting partner's HCV status.

Results. Participants who knew their HCV status were more likely to know the HCV status of their last injecting partner, compared to those who did not know their status (HCV+: aOR 4.1, 95%CI 3.4-4.9; HCV-: aOR 2.5, 95%CI 2.0-3.0). Participants who reported being HCV+, relative to those of unknown HCV status, were five times more likely to share injection equipment with a partner of HCV-positive status (aOR 4.8, 95%CI 3.9–6.0).

Conclusion. Our analysis suggests PWID are more likely to share injection equipment with persons of concordant HCV status.

Received April 23, 2013.
Revision received June 12, 2013.
Accepted June 13, 2013.

Read Full Text (PDF) here – Free

Genotype-1 hep. C race heats up

Provided by MM&M

Deborah Weinstein November 04, 2013

Genotype-1 hep. C race heats up

Early reads from the American Association for the Study of Liver Diseases (AASLD) Boston conference indicates a tight race to treat the genotype 1 form of hepatitis C. The outlook is that Gilead and Merck are set for, if not a brawl, then a tight-fitting co-existence in which each company's offerings could be safety nets if patients fail on one medication and have to go in search of another.

Among the data:

Merck said a Phase II study of experimental protease inhibitor MK-5172, when combined with NS5A MK-8472 and ribavirin (RBV) as well as without RBV, showed a sustained response among genotype 1a and 1b patients. The company said it has extended the study beyond the 65-patient, 12-week format to include around 400 additional patients who have a variety of combined ailments, such as HCV and HIV, treatment-naïve non-cirrhotic, treatment-naïve cirrhotic, and RBV non-responders, among others.

ISI Group analyst Mark Schoenebaum wrote in a Monday assessment that “the most important take home message is that we now believe MRK may be just 18 months behind GILD in the race to develop an all oral regimen for genotype 1 Hep C.” Schoenebaum's Merck vs. Gilead reference refers to Gilead's much-heralded contender, sofosbuvir, which already has 15-0 FDA panel support for use in genotypes 1 and 4, in addition to sofosbuvir and ribavirin in genotypes 2 and 3.

Anticipation for sofosbuvir and other pipeline drugs has already started to sap enthusiasm for established products. Vertex's Incivek, for example, shot past its peak in 2011 and the company announced last week that it was shifting its focus to cystic fibrosis, in addition to laying off 370 employees.

Gilead's data release further cemented enthusiasm for sofosbuvir's prospects, but Credit Suisse analysts indicated in a Monday wrap-up that Gilead is not going to sweep the field. The roster of Credit Suisse analysts, which includes Ravi Mehrotra and Vamil Divan, highlighted that Merck's key to market share is competitive differentiation through both a successful expanded study, known as C-Worthy, and by tacking on additional genotypes to push it past a possible genotype-1 indication. The analysts say these two wins could mean sales of around $400 million by 2020, assuming a 2017 market launch.

ISI's Schoenebaum had a similar reaction, writing that Merck's MK-5172 regimen “could be the first that is truly clinically competitive with GILD.”

Getting less attention was Boehringer Ingelheim, which released Phase III data for its gentotype-1 treatment faldaprevir on Friday. The company said in a statement that the clinical trial indicates the drug is effective in patients with HIV and advanced liver disease, and that 84% of treatment-naïve patients could cut treatment time from 48 to 24 weeks, and that 83% of these patients were cured. The study also indicated a 70% cure rate among relapsed HCV patients who had tried other regimens.

Source

Results from the COSMOS study with Simeprevir and Sofosbuvir in cirrhotic and non-cirrhotic HCV genotype 1 patients presented at AASLD

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announced data from the interferon-free COSMOS study demonstrating safety and efficacy of the investigational protease inhibitor simeprevir (TMC435) in combination with the investigational nucleotide inhibitor sofosbuvir (GS-7977), with and without ribavirin, in genotype 1 chronic hepatitis C adult patients with compensated liver disease was presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C. during the late-breaking oral session on Monday, November 4.

“The high sustained virologic response (SVR) rates seen in genotype 1 patients with prior null response and in treatment-naïve and prior null response patients with advanced liver disease, in the COSMOS study, are highly encouraging. These difficult-to-cure patient groups are in urgent need of efficacious treatment options which today are lacking” says Charlotte Edenius, EVP Development, Medivir.

COSMOS - Study Design
COSMOS is a phase IIa, randomized, open-label study investigating the safety and efficacy of simeprevir in combination with sofosbuvir, with and without ribavirin, for either 12 or 24 weeks. The study enrolled HCV genotype 1 patients who were prior null responders to treatment with interferon and ribavirin with METAVIR F0-F2 scores (cohort 1, n=80), or treatment-naïve patients and prior null responders with METAVIR F3-F4 scores (cohort 2, n=87).

Final sustained virologic response 12 weeks after the end of treatment (SVR12) data from cohort 1 in previous null responder patients with METAVIR scores F0-F2 were presented, along with sustained virologic response 4 weeks after the end of treatment (SVR4) data from the 12 week arms of cohort 2 in treatment-naïve and previous null-responder patients with METAVIR scores F3-F4. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver. Liver fibrosis is scored on a four-point scale.

In cohort 1, 77 percent of the patients had genotype 1a (GT1a) subtype with 50 percent of those having baseline Q80K polymorphism. Seventy percent had IL28B CT genotype, 24 percent had IL28B TT genotype and 59 percent had METAVIR score F2.

In cohort 2, 78 percent of patients had GT1a subtype with 40 percent of those having baseline Q80K polymorphism. Fifty-six percent had IL28B CT genotype, 23 percent had IL28B TT genotype, 47 percent had METAVIR score F4 (cirrhosis) and 54 percent were prior null responders.

COSMOS – Efficacy Summary
In cohort 1, the SVR12 rate was 93 percent in genotype 1 null-responder patients with METAVIR scores of F0-F2 treated with simeprevir and sofosbuvir for either 12 or 24 weeks.

In an interim analysis of cohort 2, the SVR4 rate was 100 percent in both genotype 1 treatment-naive patients and prior null-responder patients with METAVIR scores of F3-F4 treated with simeprevir and sofosbuvir for 12 weeks.

In a pooled analysis of the 12-week treatment arms in cohorts 1 and 2, SVR4 was achieved among patients treated with simeprevir and sofosbuvir with or without ribavirin, in 96 percent of patients with IL28B non-CC genotype, 91 and 100 percent of patients with a METAVIR score of F4, respectively, and 95 percent of prior null responders.

All patients who completed treatment were HCV RNA undetectable at end of treatment and there were no viral breakthroughs in either cohort 1 or 2. The COSMOS study interim results show no benefit from adding ribavirin to simeprevir and sofosbuvir in this difficult to treat groups of hepatitis C patients and that 12 week treatment may confer similar clinical benefit to 24 week treatment.

Efficacy results with 150 mg simeprevir (SMV) and 400 mg sofosbuvir (SOF) once daily with or without ribavirin (RBV). Intent-to-treat (ITT) population.

Cohort 1: Prior null-responder HCV patients with METAVIR scores F0-F2
% (n)	SMV / SOF + RBV 24-week	SMV / SOF 24-week	SMV / SOF + RBV 12-week	SMV / SOF 12-week
SVR12	79* (19/24)	93 (14/15)	96 (26/27)	93 (13/14)

*17% (4/24) non-virologic failure

Cohort 2**: Prior null-responder and treatment-naïve HCV patients with METAVIR scores F3-F4
% (n)	SMV / SOF+ RBV Naive 12-week	SMV / SOF Naive 12-week	SMV / SOF + RBV Null response 12-week	SMV / SOF Null response 12-week
SVR4	100 (12/12)	100 (7/7)	93 (14/15)	100 (7/7)

**SVR4 data was only available for 12-week arms at time of interim analysis cut-off

- Summary Safety
The most common adverse events in both treatment arms were fatigue, headache, nausea and insomnia. Rash, itching, anemia and bilirubin increases occurred mainly in the ribavirin-containing arms of treatment. Four percent of patients (2/54) treated with simeprevir and sofosbuvir with ribavirin and 7 percent of patients (2/31) treated with simeprevir and sofosbuvir without ribavirin, respectively, discontinued treatment due to an adverse event in the 24 week arms, while no patients (0/82) in the 12 week arms discontinued treatment due to an adverse event at the time of this analysis.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR
Mobile: +46 708 537 292.

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 4.30 p.m. EST on 4 November 2013.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Simeprevir
Simeprevir (TMC435) is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and its affiliated companies and Medivir AB for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the viral protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except for the Nordic countries. Medivir AB will retain marketing rights for simeprevir in these Nordic countries under the marketing authorization held by Janssen-Cilag International NV.

On October 24, the U.S. Antiviral Drugs Advisory Committee of the FDA voted unanimously (19-0) to recommend approval of the new drug application filed by Janssen Research & Development, LLC for simeprevir administered once daily with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) in adult patients with compensated liver disease. Simeprevir was approved on September 27, 2013 in Japan for the treatment of genotype 1 hepatitis C. A Marketing Authorisation Application was submitted in April to the European Medicines Agency (EMA) by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C.

Simeprevir is also being studied in several interferon-free regimens using selected combinations of direct-acting antiviral agents with different mechanisms of action. To date, more than 43,700 patients have been treated with simeprevir in clinical trials.

In October, Janssen Pharmaceuticals, Inc. acquired the investigational compound GSK2336805, an NS5a replication complex inhibitor in phase II development for the treatment of chronic HCV, from an affiliate of GlaxoSmithKline plc. Since being acquired, the compound has been renamed JNJ-56914845. Janssen Pharmaceuticals plans to initiate phase II studies to evaluate the use of JNJ-56914845 in interferon-free combinations with simeprevir and TMC647055, the company’s non-nucleoside polymerase inhibitor, for the treatment of chronic HCV in adult patients with compensated liver disease.

About Sofosbuvir
Sofosbuvir (formerly referred to as GS-7977) is a once-daily nucleotide analog polymerase inhibitor for the treatment of HCV infection being developed by Gilead Sciences, Inc. Sofosbuvir is being evaluated as part of multiple therapeutic regimens, including programs with RBV alone and in combination with peg-IFN and RBV.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

Source

Label Warnings Not Enough to Protect Consumer Safety When Taking Acetaminophen

Presented: November 5, 2013 -- Walter E. Washington Convention Center, Washington, DC

WASHINGTON, Nov. 4, 2013 /PRNewswire/ -- Acetaminophen is the leading cause of acute liver failure in the US. In January 2011, the Federal Drug Administration asked manufacturers to limit the strength of acetaminophen in prescription drug products. They also requested a Boxed Warning for severe liver injury to be added to the label of all prescription drug products that contain acetaminophen. The American Association for the Study of Liver Diseases (AASLD) has been a long-time proponent of these and other measures to improve the safety of acetaminophen, which if used properly, is a safe and effective drug.

Researchers from Northwestern University and Emory University concluded in a recent study that use of an enhanced icon on medication labels and additional written information were insufficient in ensuring the safe use of acetaminophen products. The study of enhanced communication strategies between healthcare providers and patients was conducted between August 2012 and February 2013. Patients at the general medicine clinics were either provided the usual care; provided enhanced bottle labeling with an icon identifying acetaminophen as an active ingredient and a flyer to explain safe use of the product (written strategy); or enhanced labeling, written brochure, and added verbal counseling (written and verbal strategy).

Patients in either of the enhanced information groups (written, written and verbal) were more likely to identify acetaminophen as an active ingredient. Only the verbal counseling strategy improved the understanding of the risk of concomitant use with other acetaminophen-containing products. Neither strategy improved understanding to greater than 50 percent. According to Marina Serper, MD, "The strategies we used were supposed to simulate what a patient may encounter in a typical pharmacy when picking up a prescription or choosing an over-the-counter product. We were somewhat surprised that these strategies improved comprehension but not to levels above 50 percent."

The study concluded that additional public health measures are needed to ensure the safe use of acetaminophen. "Acetaminophen is widely prescribed and is available in multiple over the counter products," said Dr. Serper. "Results of this study highlight the public's lack of knowledge of the potential dangers of acetaminophen and that broader public health campaigns may be needed to raise public awareness."

Dr. Serper also had some comments for healthcare providers, "We recommend that healthcare professionals routinely obtain detailed medication histories from their patients, counsel them on the maximum safe daily dose of acetaminophen, and the risks of combining multiple acetaminophen-containing products."

Abstract title:

Effect of Enhanced Risk Communication on Patient Comprehension of Concomitant Use Warnings for Acetaminophen-Containing Products: A Randomized Trial

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 Washington, November 2-5, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 1 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.

Media Contact: Gregory Bologna
703/299-9766  
gbologna@aasld.org
Press Room: November 1 – 5, 2013
Walter E. Washington Convention Center, Washington, DC
Telephone: (202) 249-4092

Researcher: Marina Serper, MD
Email: marina-serper@fsm.northwestern.edu
Phone: 215-718-4741

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.

SOURCE American Association for the Study of Liver Diseases (AASLD)

RELATED LINKS
http://www.aasld.org

Source

Risk-based screening misses hepatitis C in many pregnant women

11/04/13

By: DENISE FULTON, Ob.Gyn. News Digital Network

Gyn. News Digital Network

WASHINGTON – Programs to screen pregnant women for hepatitis C infection could go far to reduce a host of adverse outcomes, according to an analysis of a large national sample.

"Targeted HCV screening may overlook many pregnant women with chronic HCV infections, and that may contribute to the underdiagnosis of pediatric hepatitis C in the United States," study investigator Dr. Po-Hung Chen said at the annual meeting of the American Association for the Study of Liver Diseases.

^{Denise Fulton/IMNG Medical Media}

Dr. Po-Hung Chen

"Chronic hepatitis C is associated with adverse maternal/fetal consequences. In light of these findings, there seems to be a need to further evaluate universal hepatitis C screening as a part of antepartum care," he added.

Dr. Chen of the division of gastroenterology at Johns Hopkins University, Baltimore, and colleagues collected data on all births and spontaneous abortions recorded in the National Inpatient Sample between 2003 and 2010.

More than 28,000 of the 32 million deliveries or miscarriages recorded in the National Inpatient Sample were to mothers infected with HCV, he reported.

Of HCV-positive mothers, 72% had no traditional risk factors for the disease.

HCV-positive mothers were significantly more likely to experience obstetric pulmonary embolism (adjusted OR, 3.05), thyroid dysfunction (aOR, 1.37), and maternal death (aOR, 2.49). They also were significantly more likely to be white, less affluent, on Medicaid, substance abusers, and have more comorbidities.

Women who were HCV positive were significantly more likely to have labor before 37 weeks’ gestation (aOR, 1.36), antepartum hemorrhage (aOR, 1.44), and poor fetal growth (aOR, 1.61).

Cost of care and length of stay were significantly greater for mothers who were HCV positive, Dr. Chen said.

Previous analysis using data from the National Health and Nutrition Examination Survey (NHANES) showed that the prevalence of hepatitis C virus infection in women aged 20-39 years was 1%-1.6% in the period between 1999 and 2002. Dr. Chen noted that this could be an underestimation because NHANES is based on home health surveys and therefore does not include prison populations and homeless women, who are at high risk for HCV infection.

Currently, no definitive guidelines exist on how to manage chronic HCV in pregnant women, likely because of a dearth of suitable proven management options, Dr. Chen said, adding that ribavirin is contraindicated in pregnancy, interferon is generally not recommended, and the currently approved protease inhibitors are not options for single-drug management.

The American College of Obstetricians and Gynecologists does not recommend routine prenatal screening for HCV; instead, the college recommends screening only in women who are at high risk based on Centers for Disease Control and Prevention criteria.

Dr. Chen did not report financial conflicts of interest.

dfulton@frontlinemedcom.com

Source

HCV Drug Combo Cures Most in Select Group

Published: Nov 4, 2013

Coverage of Hepatitis C Virus is supported in part by an independent educational grant from AbbVie Pharmaceuticals.

This report is part of a 12-month Clinical Context series.

By Michael Smith, North American Correspondent, MedPage Today

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

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• This was an open-label, uncontrolled study of two novel direct-acting anti-HCV agents demonstrated high rates of remission 12 weeks post therapy.
• Be aware that all subjects had genotype 1b, which may carry a more favorable response to treatment than genotype 1a

WASHINGTON -- An investigational two-drug combination treatment for hepatitis C (HCV) -- using none of the standard medications -- led to cures in 90% or more of a selected group of patients, a researcher said here.

In an industry-sponsored clinical trial, the drugs reduced the viral load to an undetectable level 12 weeks after the end of treatment (the so-called SVR₁₂) in 95.2% of patients who had never been treated for the virus, according to Eric Lawitz, MD, of the University of Texas Health Science Center in San Antonio.

Among patients who had been previously treated but failed to respond, the SVR₁₂ rate was 90%, Lawitz reported at the annual meeting of the American Association for the Study of Liver Diseases.

While the results look good, it's important to realize the study was small and only included people with one of the HCV genotypes, cautioned Gary Davis, MD, of Baylor University Medical Center, who was not involved in the study but who moderated the session at which it was presented.

Because of that, the findings are not easily generalizable to the whole universe of HCV patients, he told MedPage Today.

Standard therapy for HCV has been based for several years on pegylated interferon and ribavirin, with the recent addition of the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis).

But interferon -- a general immune system booster -- is regarded as both difficult to take and dangerous, while ribavirin, a general antiviral, has its own suite of adverse effects, including anemia, that make it difficult to tolerate.

So investigators have been searching for so-called direct-acting agents -- drugs that target aspects of the virus itself -- that would be sufficiently powerful to cure the disease.

In the PEARL-1 study, Lawitz and colleagues studied ABT-450/r, an HCV NS3/4A protease inhibitor boosted with the protease inhibitor ritonavir (Norvir), and ABT-267, which blocks the viral nonstructural protein NS5A.

In an earlier study, the two drugs showed promise with and without ribavirin; the current study is intended to test how well they will do without the older drug.

Lawitz presented results for 82 patients with genotype 1b infection (with or without cirrhosis) treated for 12 weeks. Data for other patient groups is to be presented later, he said.

The primary endpoint of the study was the proportion of patients who reached an SVR₁₂ -- defined as no detectable virus 12 weeks after stopping treatment.

He reported that 41 of the 42 treatment-naive patients had no detectable virus at the end of treatment and 40 reached the SVR₁₂; the two who did not were lost to follow-up rather than suffering virologic failure..

Moreover, 39 of 40 null responders had no detectable virus at the end of treatment and 36 reached SVR₁₂; one patient had viral breakthrough during therapy and three relapsed, Lawitz said.

The regimen was generally well tolerated, he said -- the most common adverse event was headache -- there were no serious adverse events related to the study drugs, and no patients stopped treatment because of adverse events or abnormal laboratory findings.

The study was supported by AbbVie. Lawitz reported financial links with AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals, Kadmon, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix, and Theravance. Several authors are employees of AbbVie.

Davis reported financial links with Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Gilead, Johnson&Johnson, Merck & Co, Novartis, Pharmasset, and Vertex.

Primary source: American Association for the Study of Liver Diseases
Source reference: Lawitz E, et al "Interferon- and ribavirin-free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naïve patients and prior null responders" AASLD 2013; Abstract 75.

Source

Also See: New GT-1b Data from ABT-450 Containing Regimen Being Presented at The Liver Meeting

Babies Do OK if Mom on Tenofovir for Hepatitis B

Meeting Coverage

Published: Nov 4, 2013 | Updated: Nov 4, 2013

By Ed Susman , Contributing Writer, MedPage Today

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

WASHINGTON -- Pregnant women being treated for hepatitis B virus infections with the nucleotide inhibitor tenofovir (Viread) appeared to avoid transmission of the pathogen to their unborn children, researchers reported here.

Of the 14 pregnancies followed through to delivery, no cases of positive hepatitis B surface antigens were found among the infants, and no birth defects were observed even among the 12 women who took tenofovir throughout the pregnancy -- including the first trimester, said Christiane Stern, MD, senior medical scientist for Gilead Sciences, Boulogne, France, who presented the poster on behalf of a consortium of French doctors and hospitals who participated in the VIREAL study.

"In a hepatitis B virus real-life cohort, tenofovir treatment during pregnancy was well-tolerated, including in patients treated from the first trimester. No safety issues were reported for breastfeeding while on tenofovir up to 1 year," Stern told MedPage Today, at the American Association for the Study of Liver Diseases meeting.

She said five women reported breastfeeding, including three women taking tenofovir.

The researchers from three dozen hospitals in France recruited 441 chronic hepatitis B patients who were treated with tenofovir from June 2008 to April 2010. There were 16 pregnancies in the study cohort, and in 14 of them there was enough follow-up data for analysis.

In 11 of the 14 cases women were on tenofovir throughout the pregnancy; in one case treatment with tenofovir was commenced at 4 weeks of gestation. The other two cases involved women whose high level of hepatitis B status was discovered late in pregnancy who were given tenofovir after 20 weeks and 30 weeks to prevent mother-to-child transmission.

"As clinicians, this is information that we need to tell our patients," said Alexander Lalos, MD, a private practice gastroenterologist and a member of the adjunct faculty of Commonwealth Medical College in Scranton, Pa. "Many women want to know if it is safe to take certain medications while they are pregnant. Now we can say that there is a study which shows that it is safe."

Lalos told MedPage Today that preventing mother-to-child transmission of hepatitis B virus is crucial in breaking the cycle in which women pass on infection to their children, creating chronic infection which can then be passed on to others. "About 10% of mothers with hepatitis B virus infection transmit the virus to their newborns if they are not treated," he said.

Stern illustrated that all but two of the babies were full term (37 weeks or greater); one child was born at 34 weeks and one at 35 weeks. There were two Cesarean deliveries. In 11 cases where Apgar scores were recorded, all received scores of 10 at 10 minutes.

"Mother-to-child transmission is one of the main routes of hepatitis B virus transmission and the risk of transmission increases if the pregnant woman has virus DNA greater than 6-7 log IU/mL at delivery," Stern said. "Antiviral therapy given during the last trimester of pregnancy, in association with serovaccination of the newborn, can reduce the risk of mother-to-child transmission. However, tenofovir use from the first trimester has not been well-documented in patients with hepatitis B virus monoinfection."

The study was funded by Gilead Sciences.

Stern is an employee of Gilead.

Lalos had no disclosures.

Primary source: American Association for the Study of Liver Diseases
Source reference: Ganne-Carrie N, et al "Efficacy and safety results of tenofovir DF (TDF) treatment from the first trimester in HBV pregnant women in real-life clinical practice" AASLD 2013.

Source

More HCV Patients on Transplant Lists

Meeting Coverage

Published: Nov 4, 2013

By Michael Smith, North American Correspondent, MedPage Today

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

WASHINGTON -- An increasing number of patients on liver transplant waiting lists have hepatitis C (HCV), researchers found.

But the increase is almost entirely due to an increasing number of HCV patients wait-listed for transplant because of hepatocellular cancer (HCC), according to Jennifer Flemming, MD, of Queen's University in Kingston, Ont.

The proportion of wait-listed patients whose viral infection led to end-stage liver disease (ESLD) remained roughly stable over an 8-year period ending in 2010, Flemming reported at the annual meeting of the American Association for the Study of Liver Diseases.

The trend is likely to continue, Flemming concluded, and could "further strain our already limited donor pool."

An important element in the changes over time is the Model for End-stage Liver Disease (MELD), which is used by the United Network of Organ Sharing to allocate organs, Flemming said. The model is based mainly on the degree of hepatic decompensation but has been modified to give patients with liver cancer a higher priority than they would otherwise get.

Flemming and colleagues looked at data from the Scientific Registry of Transplant Recipients for January 2003 through December 2010 to estimate longitudinal trends in liver transplantation secondary to HCV.

The issue is important, because the prevalence of HCV-related cirrhosis is rising and is expected to peak in 2020 at about a million Americans, she said. At the same time, the prevalence of ESLD and HCC is also expected to peak in 2020 at 150,000 and 14,000 patients, respectively.

Over the 8 years of the study, Flemming said, 20,325 HCV patients were wait-listed for transplant, including 12,724 with ESLD and 7,061 with HCC.

The yearly totals rose steadily from 2,074 in 2003 to 3,053 in 2020. But the number of those with ESLD only rose from 1,451 to 1,674, while the numbers with HCC more than doubled, from 623 in 2003 to 1,379 in 2010.

Compared with the general population, she said, the overall rate rose from 6.9 to 10.2 wait-listed patients per 100,000 and the rate for those with ESLD went from 4.8 to 5.6 per 100,000.

On the other hand, the rate for patients with HCC rose from 2.1 to 4.6 per 100,000.

In other words, Flemming said, the overall rise is "all due to the increased listing of patients with hepatocellular carcinoma."

Overall, the yearly increase was 4.7% and was statistically significant at P<0.001, while the yearly increase for ESLD was 0.7% and did not reach significance.

The yearly increase for HCC was 11.8% and was again significant at P<0.001.

Physicians involved with liver transplantation have noticed they are transplanting more HCV patients with cancer, commented Kenneth Chavin, MD, PhD, of the Medical University of South Carolina in Charleston, who was not part of the study but who moderated the session at which it was presented.

"But this is a very well-done study that confirms what we're seeing," Chavin told MedPage Today.

He added that there is active consideration to changing the rules for transplant to redress the imbalance. And, he said, the advent of new, more effective treatments for HCV might also change the pattern.

Source

Interdisciplinary Primary Care Model Achieves Sustained Virologic Response in Hepatitis C

Provided by HCPLive

By Kari Oakes, PA-C | November 04, 2013

As the worldwide disease burden increases and the need for expanded access to care rises concomitantly, primary care clinics utilizing an interdisciplinary staffing model offer a promising alternative to treating patients with hepatitis C (HCV), according to a poster presented by Samuel Ho, MD, of the VA San Diego Healthcare System and the University of California-San Diego.

At the annual meeting of the American Association for the Study of Liver Disease, held November 1-5, 2013, in Washington, DC, Ho and his co-authors offered a retrospective analysis of the outcomes and productivity at a once-weekly primary care HCV clinic.

In that clinic, which was held one half-day per week in a primary care outpatient facility, 4 primary care physicians (PCPs), 2 nurse practitioners, 1 nurse case manager, and 1 to 2 hepatologists were able to provide 215 patient slots per month. A pharmacist and a psychiatrist also participated in the clinic, as well as in team meetings that were held 2 times per month. Over the 18-month study period, the clinic completed 1,690 patient visits — for a total pool of 1,890 HCV patients — and initiated direct-acting antiviral (DAA) treatment in 75 patients. The clinic, which was initiated in 2000, was structured in a way that made same-day appointments available, as well.

PCPs treated 48 of the 75 patients who received DAA therapy, while hepatologists provided care for the rest. Patient characteristics varied by provider, as 32% of primary care patients were cirrhotic, compared to 44% of the hepatologists’ patients.  In terms of treatment, 27.6% of all patients were able to complete more tthan 36 weeks of antiviral therapy, 10.3% completed 29 to 36 weeks of treatment, 36.2% achieved 20 to 28 weeks of treatment, and 25.9% completed just 0 to 19 weeks of treatment. Adverse events necessitated early termination of treatment in 6.6% of patients, while virologic non-response was the reason for treatment termination in 21.6% of patients.

The researchers reported that final sustained virologic response (SVR) was 46% overall, with an SVR rate of 60% for PCPs and 25% for hepatologists.  The authors said the lower SVR rate for the hepatologists’ patients was probably attributable to the greater number of cirrhotic patients treated by the hepatologists. As expected, the SVR was lower for the pool of cirrhotic patients (33.3%) when compared to individuals without cirrhosis (55.2%).

In a discussion regarding the real-world implications of the study, Ho and a nurse case manager noted that PCPs were able to help patients achieve SVR rates comparable to those seen in published clinical trials.  The patient population seen in the clinic had a high incidence of comorbidities, and treatment regimens were challenging, as they included triple therapy consisting of boceprevir or telaprevir plus pegylated interferon alfa and ribavirin.

The authors noted that as many as 170 million people worldwide may have HCV infection, though most of those patients have never been treated.  As the need for HCV treatment increases and newer therapies raise the potential for initiation and compliance with treatment, new care delivery models may be necessary.  Thus, the poster authors proposed that the collaborative clinic model described in their study offers potential for expanding access to care for HCV patients.\

The authors reported funding support by the Research Service of the Department of Veterans Affairs and the VA HIV/HCV QERI program.

Source

First Study of Its Kind Shows That All-oral Treatment Regimen Prevents Hepatitis C Recurrence in Liver Transplant Recipients Who Received Allografts

Presented: November 5, 2013 at the Walter E. Washington Convention Center, Washington, DC

WASHINGTON, Nov. 4, 2013 /PRNewswire/ -- For the first time, researchers have been able to prevent the recurrence of hepatitis C virus (HCV) infection in a large proportion of patients (64 percent, n=25/39) who undergo liver transplantation for cirrhosis complicated by hepatocellular carcinoma (HCC). This success was achieved with an interferon-free treatment regimen containing the oral antivirals sofosbuvir, an investigational agent, and ribavirin.

Chronic HCV is the most common indication for liver transplantation. HCV recurrence is universal when a transplant recipient has detectable virus at the time of the procedure. Interferon-based treatments prior to transplantation are poorly tolerated and prevent post-transplant HCV recurrence in only 25 percent of these hard-to-treat patients. Recurrence of HCV can result in accelerated progression to cirrhosis, loss of the graft, and death.

In a Phase 2 study, 44 patients with chronic HCV who also had cirrhosis and HCC were treated with a combination of sofosbuvir and ribavirin for up to 48 weeks prior to liver transplantation. Of these patients, follow-up was possible for 41 individuals who were HCV undetectable at the time of transplantation. In this group, 25 patients achieved a virologic response (remained HCV undetectable) 12 weeks post-transplant (pTVR12).

Researcher Michael Curry, MD, points out that, "The very high SVR rate is in a population of patients with cirrhosis, predominantly HCV genotype 1, non IL28b CC, and prior treatment failure. This study is the first of its kind to prevent posttransplant HCV recurrence in a large number of patients, most of whom have previously failed prior treatments and could be considered 'difficult to treat.'"

Researchers concluded that the use of an interferon-free, all-oral treatment regimen of sofosbuvir and ribavirin is safe and effective in this challenging patient population. Dr. Curry addressed the subject of retransplantation, "HCV is the most common indication for liver transplantation, and it poses a major problem for transplantation resulting in graft dysfunction, cirrhosis, graft loss, and death or the need for retransplantation. Prevention of HCV recurrence after liver transplant will virtually eliminate the need for retransplantation for this indication and will significantly reduce the resource utilization in transplant units in investigating and treating graft dysfunction in HCV patients."

Abstract title:
Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation

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 Washington, November 2-5, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 1 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.

Media Contact: Gregory Bologna
703/299-9766
gbologna@aasld.org
Press Room: November 1 – 5, 2013
Walter E. Washington Convention Center, Washington, DC
Telephone: (202) 249-4092

Researcher: Michael Curry, MD
Email: mcurry@bidmc.harvard.edu
Phone: 617-632-9852

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.

SOURCE American Association for the Study of Liver Diseases (AASLD)

RELATED LINKS
http://www.aasld.org

Source

Also See: Gilead Announces Phase 2 Results for Sofosbuvir-Based Regimens in Hepatitis C Patients Before and After Liver Transplantation

All-oral, Combination Therapy for Patients with Hepatitis C Provides High Sustained Virologic Response Rate

Presented: November 5, 2013 -- Walter E. Washington Convention Center, Washington, DC

WASHINGTON, Nov. 4, 2013 /PRNewswire/ -- In this abstract to be presented at the annual meeting of the American Association for the Study of Liver Diseases, researchers from Japan provided 12-week results from their phase III study of an all-oral treatment regimen. In their presentation at The Liver Meeting® they will also provide 24-week results.

The group administered a combined treatment of daclatasvir and andasunaprevir. The treatment did not include peg-interferon/ribavirin. The treatment group were infected with hepatitis C genotype 1b, and they were either ineligible, naive or intolerant to treatment with peginterferon/ribavirin or they were nonresponders to such treatment.

For the 24-week study, 222 patients were studied, and 85.6 percent of those patients had a sustained virologic response (SVR) by week 12. According to Kazuaki Chayama, MD, PhD, "Only around 75 percent of patients treated with peg-interferon /ribavirin/telaprevir had a SVR but that therapy was associated with severe side effects and high cost. New oral-only drug therapy is quite safe and the eradication rate is so high."

Dr. Chayama continues, "These results, which were quite amazing, were expected after conducting the phase II trial, and we are very happy to confirm them in the phase III trial. I think further development of direct acting antivirals (DAAs) such as polymerase inhibitors will improve the SVR even more. Further research is necessary to develop an even higher SVR rate -- possibly 100 percent. Combination therapy with polymerase inhibitors is one way. Combination of these DAAs with peg-interferon (or interferon lambda) with or without ribavirin should be considered for patients with multi-drug resistance."

It was also noted that response rate was independent of baseline factors such as gender, age, baseline HCV RNA, etc. Although no death occurred during the study, 26 patients discontinued treatment due to adverse events or lack of efficacy.

Abstract title:

All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial

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 Washington, November 2-5, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 1 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.

Media Contact: Gregory Bologna
703/299-9766   
gbologna@aasld.org
Press Room: November 1 – 5, 2013
Walter E. Washington Convention Center, Washington, DC
Telephone: 202-249-4092

Researcher: Kazuaki Chayama, MD, PhD
Email: chayama@hiroshima-u.ac.jp
Phone: +81-82-257-5190

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.

SOURCE American Association for the Study of Liver Diseases (AASLD)

RELATED LINKS
http://www.aasld.org

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Also See: BMS Submits First All-Oral, Interferon-Free and Ribavirin-Free Treatment Regimen for Regulatory Review in Japan for Patients with Chronic Hepatitis C Infection

Positive Preclinical Profile of RG-101, a GalNAc-conjugated anti-miR Targeting microRNA-122, Supports Clinical Development for the Treatment of HCV

PRESS RELEASE   November 4, 2013, 8:07 a.m. ET

- Late-Breaking Poster to be Presented at AASLD -

- Regulatory Application for RG-101 to be Filed in the Near Term: Clinical Studies in Man Expected to Commence in Early 2014 -

LA JOLLA, Calif., Nov. 4, 2013 /PRNewswire/ -- Regulus Therapeutics Inc. (NASDAQ: RGLS), a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs, today announced that data demonstrating the positive preclinical profile of RG-101 will be presented in a late-breaking poster session at the 64th Annual Meeting of the American Association for the Study of Liver Disease (AASLD) being held in Washington, D.C. on Monday, November 4, 2013 from 8:00 a.m. Eastern Standard Time (EST) to 5:30 p.m. EST. The poster is available on the Company's website at http://www.regulusrx.com.

"RG-101 utilizes a unique mechanism of action by targeting microRNA-122, a liver-specific host factor for stability, replication and translation of HCV. We believe that therapies that target host-encoded factors essential for HCV replication may act as attractive combination agents because they may demonstrate activity across all HCV genotypes and may have a high barrier to resistance," said Neil W. Gibson, Ph.D., Chief Scientific Officer of Regulus. "We continue to be encouraged by the preclinical data seen to date and believe that RG-101 has the potential to be a best-in-class host factor agent. In the near term, we expect to file our application with regulatory authorities and look forward to commencing clinical trials in man in early 2014."

Late-Breaking Poster on RG-101 -- Monday, November 4, 2013, 8:00 a.m. EST -- 5:30 p.m. EST

-RG-101, a GalNAc-conjugated anti-miR Employing a Unique Mechanism of Action by Targeting Host Factor MicroRNA-122 (miR-122), Demonstrates Potent Activity and Reduction of HCV in Preclinical Studies-

In the late-breaking poster, Regulus will present positive data from completed preclinical studies evaluating RG-101 for in vitro and in vivo potency, pharmacokinetic/pharmacodynamics, toxicology and safety pharmacology and inhibition of HCV replication.

Potency and Pharmacokinetics/Pharmacodynamics of RG-101

Pharmacologic potency of RG-101 was significantly enhanced by approximately 20 fold in vivo in both mice and non-human primates, relative to the unconjugated oligonucleotide of RG-101 (RG-101-N). RG-101 is rapidly taken up in the liver and metabolized to the active oligonucleotide, which has an approximately 14 day tissue half-life. Additionally, potency as measured by AldoA (a miR-122 target gene) de-repression in the liver is achieved at significantly lower liver concentrations of oligonucleotide following efficacious doses of RG-101 of 1mg/kg-10mg/kg, compared to similar doses of RG-101-N. In addition to the potency studies, Regulus tested the efficacy of RG-101 to reduce HCV viral load titer in a human chimeric liver mouse model infected with HCV, as these mice are estimated to contain greater than 80 percent human hepatocytes. Genotype 1a HCV infected mice were subcutaneously administered a single dose of RG-101 at 3 mg/kg, 10mg/kg or 30 mg/kg and monitored for up to 36 days. Up to a 2 log reduction in HCV viral load titer was observed, which is similar to that observed for oral direct-acting antivirals as monotherapy in this mouse model. Additionally, the duration of action observed for RG-101 supports the potential for a once-a-month dosing regimen.

Regulus believes these preclinical data will assist the Company in determining the most efficacious dose of RG-101, including optimal dosing frequency, for clinical studies in man.

Toxicology and Safety Pharmacology of RG-101

RG-101 has demonstrated an excellent preclinical safety profile to date, with no findings observed up to 450 mg/kg in mice and 45 mg/kg in non-human primates. AldoA levels in non-human primates were maximally elevated at 1 mg/kg. These data demonstrate that RG-101 is safe and well tolerated with a high therapeutic index. Additionally, these data provide support that the chemistry and conjugation approach for RG-101 may mitigate the potential for pro-inflammatory effects.

Currently, additional preclinical toxicology and safety pharmacology studies are ongoing in which multiple doses of RG-101 are being evaluated.

About RG-101 for the Treatment of HCV

RG-101 is a key program in Regulus' 'Road to the Clinic' Strategy for 2013, in which the Company expects to nominate two microRNA candidates for clinical development, be positioned to file its first applications with regulatory authorities by the first half of 2014 and maintain a strong year-end cash position to support these goals. RG-101 was the first microRNA candidate nominated for clinical development under this strategy.

microRNA-122 (miR-122) is the most abundant microRNA in hepatocytes and is a critical host factor for survival and replication of all know HCV genotypes. RG-101 is a novel anti-miR-122 oligonucleotide therapeutic that is effectively targeted to hepatocytes for the treatment of HCV through conjugation to GalNAc, a carbohydrate-based chemistry approach for asialoglycoprotein receptor-mediated delivery of oligonucleotides to hepatocyte cells of the liver. Utilizing the GalNAc conjugate chemistry has significantly improved the potency of the active oligonucleotide of RG-101 by achieving targeted delivery of the oligonucleotide to the infected hepatocytes. Given its attractive properties and positive preclinical profile seen to date, Regulus believes that RG-101 may be an attractive agent to add to existing HCV therapeutic regimens. The Company plans to develop RG-101 as a key component of an HCV combination regimen for patients who have failed, or are intolerant of, the current standard of care and specific patient populations such as HCV/HIV co-infection. In the near term, Regulus expects to submit an application with regulatory authorities and to commence clinical studies in man in early 2014.

About Regulus

Regulus Therapeutics Inc. (NASDAQ:RGLS) is a biopharmaceutical company leading the discovery and development of innovative medicines targeting microRNAs. Regulus is uniquely positioned to leverage a mature therapeutic platform that harnesses the oligonucleotide drug discovery and development expertise of Alnylam Pharmaceuticals, Inc. and Isis Pharmaceuticals, Inc., which founded the company. Regulus has a well-balanced microRNA therapeutic pipeline entering clinical development, an emerging microRNA biomarkers platform to support its therapeutic programs, and a rich intellectual property estate to retain its leadership in the microRNA field. Regulus intends to focus its proprietary efforts on developing microRNA therapeutics for oncology indications and orphan diseases and is currently advancing several programs toward clinical development in oncology, fibrosis and metabolic diseases. Regulus is also developing RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122, for the treatment of chronic hepatitis C virus infection. Regulus' commitment to innovation and its leadership in the microRNA field have enabled the formation of strategic alliances with AstraZeneca, GlaxoSmithKline and Sanofi. In addition, Regulus has formed a research collaboration with Biogen Idec around its emerging microRNA biomarkers platform.

For more information, please visit http://www.regulusrx.com.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements associated with Regulus' expectations regarding future therapeutic and commercial potential of Regulus' business plans, including the belief that RG-101 is the best-in-class anti-HCV host factor agent and its expectations regarding future clinical studies, and technologies and intellectual property related to microRNA therapeutics being discovered and developed by Regulus. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Regulus' current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. These and other risks concerning Regulus' programs are described in additional detail in Regulus' SEC filings. All forward-looking statements contained in this press release speak only as of the date on which they were made. Regulus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

SOURCE Regulus Therapeutics Inc.

/CONTACT: Amy Conrad, Director, Investor Relations and Corporate Communications, aconrad@regulusrx.com, 858-202-6321; or Media: Liz Bryan, Spectrum Science, lbryan@spectrumscience.com, 202-955-6222 x2526

/Web site: http://www.regulusrx.com

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