The Tasmanian Hep C Buyers’ Club

The New York Times
The Tasmanian Hep C Buyers’ Club

Sophie Cousins

Jefferys, a tall man with a thick silver mustache and beard, knew Gilead Sciences had developed a better option: a highly tolerable 12-week oral treatment with high cure rates, called sofosbuvir and sold under the brand name Sovaldi.

While the drug had been approved in the United States and Europe, it wasn’t yet approved in Australia. And in the United States, the retail price was $1,000 per daily pill — $84,000 in total.

But Jefferys also read that in late 2014, Gilead issued India a voluntary license to allow the manufacture of generic versions of sofosbuvir...

Continue Reading .......

Related On This Blog 

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"  

Watch Action Hepatitis Canada - Why We Need a National Strategy for Hepatitis C

Published on Jul 24, 2017
Action Hepatitis Canada

Eisai Submits Applications In U.S. (FDA) And Europe (EMA) For Lenvatinib In Hepatocellular Carcinoma

Eisai Submits Simultaneous Applications In The United States And Europe For Lenvatinib In Hepatocellular Carcinoma

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Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") announced that it has submitted applications to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for its in-house discovered and developed anticancer agent lenvatinib mesylate (lenvatinib) for the treatment of hepatocellular carcinoma (HCC). This follows the application in Japan. Lenvatinib for the treatment of HCC is designated as an orphan drug by the FDA.

This application is based on the results of the REFLECT study (Study 304), a multicenter, open-label, randomized, global Phase III trial comparing the efficacy and safety of lenvatinib versus sorafenib, a standard treatment for HCC, as a first-line treatment for 954 patients with unresectable HCC.*1

In the REFLECT study, lenvatinib met the primary endpoint and demonstrated an overall survival (OS) treatment effect by the statistical confirmation of non-inferiority compared to sorafenib. Developing first-line treatments for HCC is challenging, and over the past 10 years, four previous first-line Phase III studies investigating other agents compared to sorafenib have failed to achieve this endpoint in OS.*2

Additionally, lenvatinib showed highly statistically significant and clinically meaningful improvements in the secondary endpoints of Progression Free Survival (PFS), Time To Progression (TTP), and Objective Response Rate (ORR). In this study, the five most common adverse events observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, weight loss and fatigue, which is consistent with the known side-effect profile of lenvatinib.

Liver cancer is the second leading cause of cancer related death and is estimated to be responsible for 750,000 deaths per year globally (27,000 per year in the US, 62,000 per year in Europe), with 780,000 cases newly diagnosed each year (30,000 per year in the US, 63,000 per year in Europe).*3 HCC accounts for 85% to 90% of liver cancer cases. Treatment options for unresectable HCC are limited and the prognosis is very poor, making this an area of high unmet medical need.

Lenvatinib is approved as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, and in Europe, under the brand name Lenvima(R). Additionally, lenvatinib in combination with everolimus is approved for the treatment of renal cell carcinoma (RCC) in over 35 countries, including the United States and in Europe. In Europe, lenvatinib was launched under the brand name Kisplyx(R) for RCC.

Eisai positions oncology as a key therapeutic area, and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai is committed to exploring the potential clinical benefits of lenvatinib as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to patients with cancer, their families, and healthcare providers.

1. About lenvatinib mesylate (generic name, “lenvatinib”, product name: Lenvima® / Kisplyx®)

Discovered and developed in-house, lenvatinib is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor proliferation.

Currently, Eisai has obtained approval for lenvatinib as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, and in Europe, under the brand name Lenvima®. Additionally, Eisai has obtained approval for the agent in combination with everolimus as a treatment for renal cell carcinoma (second-line) in over 35 countries, including the United States and in Europe. In Europe, the agent was launched under the brand name Kisplyx® for RCC.

A Phase III study of lenvatinib in separate combinations with everolimus and pembrolizumab in renal cell carcinoma (first-line) was initiated and is underway. A Phase Ib/II study to investigate the agent in combination with pembrolizumab in select solid tumors (non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, head and neck cancer, and melanoma) and a Phase Ib study in HCC are also underway. Following the submission of applications in Japan (June 2017), the United States and Europe (July 2017), Eisai also plans to submit an application for lenvatinib for the treatment of HCC in China within the latter half of fiscal 2017.

2. About the RELECT study (Study 304) 1

The REFLECT study (A Multicenter, Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-Line Treatment of Subjects With Unresectable HCC) is a multicenter, open-label, randomized, global Phase III study comparing the efficacy and safety of lenvatinib versus sorafenib. In the study, 954 patients were randomized in a 1:1 ratio to receive lenvatinib 12 mg (≥60 kg) or 8 mg (<60 kg) once a day, depending on baseline body weight (n= 478) or sorafenib 400 mg twice a day (n= 476). Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoint of the study was Overall Survival (OS), with the goal of demonstrating non-inferiority. Other factors including Progression Free Survival (PFS), Time To Progression (TTP), Objective Response Rate (ORR) and Quality of Life (QOL) were assessed as secondary endpoints.

According to the results of the study, lenvatinib (13.6 months) met the statistical criteria for non-inferiority in the primary endpoint of median OS compared to sorafenib (12.3 months). (Hazard Ratio [HR] 0.92, 95% Confidence Interval [CI] = 0.79-1.06)

Additionally, lenvatinib showed statistically significant improvements in the three secondary efficacy endpoints, doubling sorafenib's median values and ratios: median PFS (lenvatinib 7.4 months versus sorafenib 3.7 months, HR 0.66, 95% CI = 0.57-0.77, P<0.00001), median TTP (lenvatinib 8.9 months versus sorafenib 3.7 months, HR 0.63, 95% CI = 0.53-0.73, P<0.00001) and ORR (lenvatinib 24% versus sorafenib 9%, P<0.00001).

Furthermore, EORTC QLQ-C30 and QLQ-HCC18 questionnaires were used to evaluate overall QOL. In both groups, scores decreased after the administration of the agents. However, within 3 categories in EORTC QLQ-C30 (role functioning, pain, diarrhea) and two categories in QLQ-HCC18 (nutrition, body image), it was found that Lenvatinib helped to delay deterioration of QOL compared to sorafenib (nominal P-value < 0.05)

In this study, the five most common adverse events observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, weight loss and fatigue, which is consistent with the known side-effect profile of lenvatinib.

3. About Hepatocellular Carcinoma (HCC)

Liver cancer is the second-leading cause of cancer death, estimated to be responsible for 750,000 deaths per year globally. Additionally, 780,000 cases are newly diagnosed each year. 3 There is a large regional difference, with about 80% of new cases occurring in Asian regions, including China and Japan. HCC accounts for 85% to 90% of liver cancer. HCC is associated with chronic liver disease, in particular cirrhosis. Major causes of cirrhosis include hepatitis B virus and hepatitis C virus. However, according to a recent investigation, non-B/non-C HCC is on the rise. Surgery is the first option for treatment, but patients with unresectable HCC who are not amenable for potentially curative therapeutic interventions, which include liver transplant, surgical resection, tumor ablation (typically radiofrequency ablation or cryotherapy), or who are not suitable for transarterial chemoembolization (TACE), are difficult to treat with a poor prognosis. Additionally, there is currently only one approved systemic therapy for frontline treatment of these patients, underscoring a great unmet medical need.

*1 Cheng A et al. "Phase 3 trial of lenvatinib vs sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma", the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO), (June 2017), Abstract No: 4001
*2 Llovet JM and Hernandez-Gea V. Hepatocellular carcinoma: Reasons for Phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20(8):2072-2079.
*3 GLOBOCAN2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/

NSW Podcast - Australia Hepatitis B and Hepatitis C

Sydney Sexual Health Centre

Welcome to the third episode of the new Sydney Sexual Health Centre podcast! This episode ties into Hepatitis Awareness Week, which is held at the end of July and incorporates World Hepatitis Day on July 28th. Two campaigns will run throughout July in the lead up to Hepatitis Awareness Week and World Hepatitis Day.

We talk to Stuart Loveday from Hepatitis NSW about hepatitis B and hepatitis C, as well as the state-wide hepatitis B and hepatitis C awareness campaigns.



More on the hepatitis B campaign: www.hepB.org.au
More on the hepatitis C campaign: www.hepC.org.au
More on Hepatitis NSW: www.hep.org.au
More on Sydney Sexual Health Centre: www.sshc.org.au

Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life

Clinical Gastroenterology and Hepatology
August 2017 Volume 15, Issue 8, Pages 1271–1278.e6

Most Individuals With Advanced Cirrhosis Have Sleep Disturbances, Which Are Associated With Poor Quality of Life
Marwan Ghabril , Mollie Jackson, Raghavender Gotur, Regina Weber, Eric Orman, Raj Vuppalanchi, Naga Chalasani

In summary, we describe a high prevalence of disturbed sleep in patients with cirrhosis at a large transplant center. Disturbed sleep was predicted by muscle cramps, which is an important although poorly understood complication of end-stage liver disease. Disturbed sleep in this population appears to be multifactorial in etiology and may be associated with neurocognitive dysfunction. Disturbed sleep is strongly associated with decreased quality of life, and its severity may be meaningfully categorized on the basis of PSQI. Further studies to elucidate the pathogenesis and therapies for disturbed sleep in patients with cirrhosis are needed in the face of this significant and unmet need.

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Abstract

Background & Aims
Sleep disturbances are common in patients with cirrhosis, but their determinants and effects on health-related quality of life are not well-understood. We investigated the prevalence of disturbed sleep in these patients, factors associated with sleep disruption, and effects on quality of life.

Methods
We performed a prospective, cross-sectional study of 193 stable ambulatory patients with cirrhosis (154 with decompensated cirrhosis). Participants completed the Pittsburgh Sleep Quality Index (to assess sleep quality), the Chronic Liver Disease Questionnaire (CLDQ), and muscle cramp questionnaires and underwent neurocognitive testing. Actigraphy was performed in a subset of patients with normal and disturbed sleep. We collected serum samples from subjects with normal and disturbed sleep and performed non-targeted metabolomic analyses.

Results
Of the study subjects, 157 (81%) had disturbed sleep, with Pittsburgh Sleep Quality Index scores >5. Disturbed sleep was associated with muscle cramps, daytime somnolence, and decreased quality of life on the basis of CLDQ scores. Factors independently associated with disturbed sleep in logistic regression analysis included hypoalbuminemia, opiate therapy, and muscle cramps. Disturbed sleep was independently associated with CLDQ score (correlation parameter, –36.6; 95% confidence interval, –24 to –49; P < .001) on linear regression. Disturbed sleep was associated with neurocognitive impairment and with significantly delayed bedtime and decreased total sleep time, measured by actigraphy. Disturbed sleep was associated with metabolome signatures of alterations to the intestinal microbiome and lipid, arginine, and urea cycle metabolism.

Conclusions
Most patients with advanced cirrhosis (81%) have disturbed sleep. This has negative effects on quality of life and is associated with disruptions of several metabolic pathways, including metabolism by the intestinal microbiota.

Full Text....

Princeton researchers report new system to study chronic hepatitis B

Princeton researchers report new system to study chronic hepatitis B

Princeton University

Scientists from Princeton University's Department of Molecular Biology have successfully tested a cell-culture system that will allow researchers to perform laboratory-based studies of long-term hepatitis B virus (HBV) infections. The technique, which is described in a paper published July 25 in the journal Nature Communications, will aid the study of viral persistence and accelerate the development of antiviral drugs to cure chronic hepatitis B, a condition that affects over 250 million people worldwide and can cause severe liver disease, including liver cancer.

HBV specifically infects the liver by binding to a protein called sodium-taurocholate co-transporting polypeptide (NTCP) that is only present on the surface of liver cells. Once inside the cell, HBV hijacks its host's cellular machinery to convert the virus's DNA into a stable "mini-chromosome." This allows the virus to establish persistent, long-term infections that can ultimately cause liver fibrosis, cirrhosis and hepatocellular carcinoma. The World Health Organization estimates that 600,000 people die every year as a result of HBV infection.

Researchers have so far failed to develop drugs that can cure chronic HBV infections, partly because they have not been able to study the long-term infection of liver cells grown in the laboratory. Liver cells--also known as hepatocytes--lose their function within days of being isolated from donor livers, preventing researchers from studying anything other than the acute stage of HBV infection. Hepatocytes can be maintained for longer when they are co-cultured with other, supportive cells.

"In previous studies using hepatocytes and cells known as fibroblasts grown on micro-patterned surfaces, HBV infections worked with only a few donors, and infection lasted for no longer than 14-19 days and required the suppression of antiviral cell signaling pathways, which poses problems for studying host-cell responses to HBV and for antiviral drug testing," said Alexander Ploss, an assistant professor of molecular biology at Princeton University.

Dr. Ploss and colleagues at Princeton and the Hurel Corporation, led by graduate student Benjamin Winer, tested a different system, in which primary human hepatocytes are co-cultured with non-parenchymal stromal cells, which are cells that support the function of the parenchymal hepatocytes in the liver. When plated in collagen-coated labware, the co-cultures self-assemble into liver-like structures. These self-assembling liver-like cultures could be persistently infected with HBV for over 30 days, without the aid of antiviral signaling inhibitors. Moreover, the system worked with hepatocytes grown from a variety of donors and with viruses isolated from chronically-infected patients, which are harder to work with than lab-grown strains of HBV.

"The establishment of a co-culturing system of human primary hepatocytes and non-parenchymal stromal cells for extended HBV infection is a valuable addition to the armamentarium of cell culture model systems for the study of HBV biology and therapeutic development, which has been hampered by a relative lack of efficient infectious cell culture systems," said T. Jake Liang, a senior investigator at the National Institute of Diabetes and Digestive and Kidney Diseases, who was not involved in the research.

Ploss and colleagues were able to scale down their co-culture infections to volumes as small as a few hundred microliters. This will be important for future high-throughput screens for anti-HBV drug candidates. As a proof-of-principle for these screens, the researchers found that they could block HBV infections in their co-culture system using drugs that either prevent the virus' entry into hepatocytes or inhibit a viral enzyme that is essential for the virus' replication. "The platform presented here may aid the identification and testing of novel therapeutic regimens," Ploss said.

This study is supported in part by grants from the National Institutes of Health (R21AI117213 to Alexander Ploss and R37GM086868 to Tom W. Muir), a Burroughs Wellcome Fund Award for Investigators in Pathogenesis (to Alexander Ploss) and funds from Princeton University (to Alexander Ploss). Benjamin Y. Winer is a recipient of F31 NIH/NRSA Ruth L. Kirschstein Predoctoral awarded from the National Institute of Allergy and Infectious Diseases. Felix Wojcik is supported by a German Research Foundation (DFG) postdoctoral fellowship.

The study, "Long-term hepatitis B infection in a scalable hepatic co-culture system," by Benjamin Y. Winer, Tiffany S. Huang, Eitan Pludwinski, Brigitte Heller, Felix Wojcik, Gabriel E. Lipkowitz, Amit Parekh, Cheul Cho, Anil Shrirao, Tom W. Muir, Eric Novik, Alexander Ploss, was published in Nature Communications on July 25, 2017.

https://www.eurekalert.org/pub_releases/2017-07/pu-pr072417.php

Stopping cholesterol-lowering drugs could be deadly

Stopping cholesterol-lowering drugs could be deadly
Andrew M. Seaman
(Reuters Health) - Stopping a cholesterol-lowering drug because of a muscle ache or stomach pain can be dangerous in the long run, suggests a new study.

Researchers found that people who stopped taking statins after reporting a side effect were 13 percent more likely to die or have a heart attack or stroke over the next four years than people who kept taking the drugs.

Statins include the drugs atorvastatin, known commercially as Lipitor; rosuvastatin, also known as Crestor, and simvastatin, or Zocor.

They work by inhibiting the liver's ability to produce cholesterol while also helping the organ remove existing fats in the blood, according to the U.S. Centers for Disease Control and Prevention.

Continue reading @ Reuters Health

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Statins reduce risk of decompensation for people with HCV- and HBV-related cirrhosis

Michael Carter / 18 April 2017
Treatment with statins reduces the risk of decompensated liver disease for people with cirrhosis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV), investigators from Taiwan report in the online edition
Continue reading.....

Study Finds 275,000 Calls to Poison Control Centers for Dietary Supplement Exposures from 2000 through 2012

Study Finds 275,000 Calls to Poison Control Centers for Dietary Supplement Exposures from 2000 through 2012

Researchers calling for FDA regulation of yohimbe and energy products

Columbus, OH - 7/24/2017

U.S. Poison Control Centers receive a call every 24 minutes, on average, regarding dietary supplement exposures, according to a new study from the Center for Injury Research and Policy and the Central Ohio Poison Center, both at Nationwide Children’s Hospital.

The study, published online today in the Journal of Medical Toxicology, found the rate of calls regarding dietary supplement exposures increased (46.1%) during 2000 to 2002, decreased (8.8%) during 2002 to 2005 and increased again (49.3%) from 2005 to 2012. The decrease from 2002 to 2005 most likely resulted from the U.S. Food and Drug Administration’s (FDA) ban of the botanical stimulant ma huang previously found in some dietary supplements.

Seventy percent of dietary supplement exposure calls occurred among children younger than six years old and the majority of these were unintentional. Most exposures (97.3%) occurred at home, and in more than 97 percent of the cases, the child swallowed the substance. Serious medical outcomes accounted for 4.5 percent of exposures and the most serious outcomes (95%) occurred among children six years and older.

“Many consumers believe dietary supplements are held to the same safety and efficacy standards as over-the-counter medications,” said Gary Smith, MD, DrPH, senior author of the study and director of the Center of Injury Research and Policy at Nationwide Children’s. “However, dietary supplements are not considered drugs, thus they are not required to undergo clinical trials or obtain approval from the FDA prior to sale, unless the product is labeled as intended for therapeutic use.”

Miscellaneous substances found in commonly used dietary supplements accounted for the majority of exposure calls (43.9%). Other substances involved in exposures included botanicals (31.9%), hormonal products (15.1%), and other supplements (5.1%). Amino acids, cultural medicines and energy products each account for less than (2%) of exposures.

The dietary supplements with the highest proportion of serious medical outcomes were energy products, botanical and cultural medicines. Within the botanical category, yohimbe accounted for the largest proportion of serious medical outcomes (28.2%).

Nearly 30 percent of yohimbe exposure calls resulted in moderate or major effects. Yohimbe can cause heart beat rhythm changes, kidney failure, seizures, heart attack, and death.

Energy products, including drinks, advertised to increase energy and mental performance, can cause bad clinical effects as well. Many energy product exposures were unintentional and occurred among young children, causing heart and breathing problems, seizures, and other clinical problems. Findings support the need for improved energy product regulation, child-resistant packaging, and caregiver information, according to the study authors.
Nationwide Children's Hospital

Abstract

Journal of Medical Toxicology

pp 1–11

An Increase in Dietary Supplement Exposures Reported to US Poison Control Centers