August 31, 2013

If You Can't Make Own Drug, Take Gilead's

Provided by The Big Red Biotech Blog

08/31/2013

Fierce Biotech reports that Gilead is getting a lot of attention from rivals Merck and Roche as its hepatitis C drug, sofosbuvir, approaches expected approval by FDA in December of this year.  Idenix is also claiming its place in line to grab for sofosbuvir by including the drug in a list of metabolites it claims in ints patents. 

You may remember that Gilead bought Pharmasset for a startling $11B a few years ago to gain control of this very drug. The drug is considered to be a potential game changer in hepatitis C treatment.  Analysts variously estimate peak sales to be in $4B to $5B range. 

Gilead says Roche's claim has no merit.  It says any agreement that it had with Pharmasset ended several years before it even purchased the company.  Gilead also says its own patent cover sofosbuvir and dismisses merit of any Idenix patents.  That leaves Merck which claims Gilead should pay it 10% royalties on sofosbuvir sales due to two patents it holds that it claims Gilead would need to practice.  It gave Gilead until today to respond to its claims. 

It's clear that this property is valuable so anyone -- even with a tenuous claim -- may find it to be well worth the legal investment to try to get in on the action.  Legal costs are much likely to be far less than costs that would be incurred to actually invent ones own drug, right? 

Posted by Bruce Lehr Aug 31st 2013.

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Also See: Gilead Sues Merck Saying New Drug Won’t Infringe Patents

Journal of Hepatology

Article in Press

Coilly Audrey, Roche Bruno, Dumortier Jérôme, Leroy Vincent, Botta-Fridlund Danielle, Radenne Sylvie, Pageaux Georges-Philippe, Si-Ahmed Si-Nafaa, Guillaud Olivier, Antonini Teresa Maria, Haim-Boukobza Stéphanie, Roque-Afonso Anne-Marie, Samuel Didier, Duclos-Vallee Jean-Charles

Received 18 February 2013; received in revised form 16 July 2013; accepted 15 August 2013. published online 30 August 2013.
Accepted Manuscript

Abstract

Background

Protease inhibitors (PI) with peg-interferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge.

Methods

This cohort study included 37 liver transplant recipients (male: 92%, age 57±11years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage > than or equal to F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%).

Results

Eighteen patients were treatment-naive, five were relapsers and 14 were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and 15 tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (P=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (P=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (P=0.24). Treatment was discontinued in 16 patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8±1.1-fold and 3.4±1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2±1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir.

Conclusions

Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections, require close monitoring.

Keywords: Abbreviations

Keywords: ALT, alanine aminotransferase, AFEF, French Association for the Study of the Liver, AUC, area under the curve, BID, twice daily (bis in die), BOC, boceprevir, cEVR, complete early virological response, CNI, calcineurin inhibitors, CYP, cytochrome P450, EPO, erythropoietin, EOT, end of treatment response rate, EVR, early virological response, F, female, FCH, fibrosing cholestatic hepatitis, G1, genotype 1, GGT, gamma-glutamyl transferase, HBV, hepatitis B virus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HIV, human immunodeficiency virus, IL, interleukin, INR, International Normalized Ratio, IS, immunosuppressive drugs, Kg, Kilogram, LT, liver transplantation, M, male, MELD, Model for End-stage Liver Disease, MMF, mycophenolate mofetil, NA, not available, NR, non-response, PCR, polymerase chain reaction, PEG-IFN, pegylated interferon, PI, protease inhibitors, QD, once a day (quaque die), RBV, ribavirin, RVR, rapid virological response, SVR12, sustained virological response 12 weeks after the end of therapy, TBC, trough blood concentration, TID, three times a day (ter in die), TVR, telaprevir, VB, virological breakthrough, VL, viral load, VR, virological response.

Keywords: Boceprevir, Drug-drug interaction, Early virological response, HCV recurrence, Liver transplantation, Protease inhibitors, Sustained virological response, Telaprevir

PII: S0168-8278(13)00613-2

doi:10.1016/j.jhep.2013.08.018

© 2013 Published by Elsevier Inc.

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Provided by MedicalXpress

August 30, 2013

livercancerd

Immunohistochemical stainings of Ki67 and pancytokeratin (Ki67 is stained brown, pancytokeratin is stained pink) indicate proliferation of hepatocytes (arrowheads) and biliary epithelial cells (arrows) in TAK1/RIP3-deficient mice. Credit: Helmholtz Zentrum München

The death of numerous liver cells in the context of chronic inflammation due to apoptosis, a form of programmed cell death, can promote the formation of tumour cells in the liver. This insight significantly contributes to a better understanding of cellular processes in liver cancer development and thereby opens up new therapeutic approaches. A research team including scientists from the Helmholtz Zentrum München has reported this in the current issue of the scientific journal Cell Reports.

Liver cancer (Hepatocellular Carcinoma, HCC) usually arises as the result of a chronic, inflammatory liver disease. The most common causes here are excessive alcohol consumption as well as a high-fat diet and also chronic infection with the hepatitis viruses B and C. In the course of the inflammatory process, the liver cells (hepatocytes) die more frequently due to programmed cell death. The result is increased cell growth, also referred to as compensatory proliferation, which can lead to tumour development.

A distinction is made between the two most important forms of self-induced cell death, namely apoptosis (programmed cell death) and necroptosis (programmed necrosis), which are based on different cellular mechanisms. Until now, it was not clear which form of cell death is decisive for the development of malignant liver tumours. The team working with Professor Dr. Tom Luedde from the RWTH Aachen University Hospital and Professor Dr. Mathias Heikenwälder from the Institute of Virology at the Helmholtz Zentrum München (HMGU) has now been able to verify that apoptosis precedes the development of abnormal liver cells. The scientists, including Florian Reisinger from the Institute of Virology (HMGU) and Dr. Kristian Unger from the Research Unit Radiation Cytogenetics (HMGU) showed this using mouse models. Moreover they discovered that in contrast, necroptosis prevents uninhibited cell proliferation and consequently the development of liver cancer.

These findings could form the basis for new approaches to therapy for liver cancer, which until now has been a form of cancer that cannot be adequately treated and that kills 800,000 patients around the world each year. "We now know which cellular signalling pathways are involved in liver tumour development", explains Heikenwälder. "In a further step we want to develop new treatment options, for example, by attempting to pharmaceutically block the apoptosis itself or its signalling pathways. But any new therapy can also cause undesirable effects: In our experiments, we saw that blocking apoptosis under inflammatory conditions can result in bililary obstruction (cholestasis) in the context of liver inflammation."

In upcoming investigations, the scientists want to verify their findings on the development of liver cancer and search for active substances that inhibit apoptosis while simultaneously causing the mildest possible side effects. The objective is to further develop the acquired knowledge in the sense of translational research in order to provide concrete benefits for society.

 Explore further: US liver-related deaths underestimated for decades

More information: Vucur, M. et al. (2013), RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling Caspase-8- and JNK-dependent compensatory cell proliferation, Cell Reports. DOI: 10.1016/j.celrep.2013.07.035

Journal reference: Cell Reports

Provided by Helmholtz Association of German Research Centres

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