Gilead 2Q 2014 earnings press release., Sovaldi sales helped 2Q earnings increase to $ 6.4 billion in 2014 from $ 2.66 billion in 2Q2013, the increase coming from sofosbuvir sales.
Krishan Maggon 's insight:
With sales of $ 5.7 billion in the first half of 2014, Gilead hepatitis C drug is likely to emerge as the successor to Lipitor, unless government pressure forces company to reduce the price of 1000 dollar/pill. Projected sales in 2014 may reach $15 billion making it the best selling human medicine of all time.
Opinion from JAMA — New Expensive Treatments for Hepatitis C Infection (@Jama_current: The simple math is that #Sovaldi will add ~$300 to every insured person's premiums per yr over 5 yrs http://t.co/A4FLjYg9Sh)...
Recent studies have provided insight into the protective role of neutralizing antibodies in hepatitis C.
Neutralizing antibodies show broad reactivity for diverse HCV genotypes.
Recombinant HCV glycoproteins can elicit neutralizing antibodies.
The HCV E2 core structure can inform rational design of immunogens.
Krishan Maggon 's insight:
Volume 105, May 2014, Pages 100–111
Review The past, present and future of neutralizing antibodies for hepatitis C virusJonathan K. Balla, Alexander W. Tarra, Jane A. McKeatingb, , Show more DOI: 10.1016/j.antiviral.2014.02.013Open Access funded by Medical Research Council
Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host.
Most intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance.
Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide1. HCV infection often results in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. No vaccine is available and current therapies are effective against some, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies2, 3, 4. Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an antigen-binding fragment (Fab) at 2.4 Å resolution. The E2 core has a compact, globular domain structure, consisting mostly of β-strands and random coil with two small α-helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulphide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins, whereas sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements on exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.
Krishan Maggon 's insight:
Structural determination of the HCV may provide us with additional targets for new class of antiviral drugs
Last month, Eugene Groysman made the case that Gilead Sciences (NASDAQ:GILD) can double its stock price because of high demand for its new Hepatitis-C drug, Sovaldi, even though it costs $84,000 per treatment. Eugene has an exceptional long-term investment track record so when he tells me how a stock can double I pay attention, and then I verify. When I research stocks, the opinions I value most highly come from those who have taken a position in the stock and have made money on it. After all, if the person expressing an opinion about the stock does not have a strong enough conviction to make a trade on it, why should we? And, if they have made trades on the stock, but have not made any money, why should we follow their lead?
Therapy for hepatitis C is undergoing a revolution. Several new drugs against the hepatitis C virus (HCV) have reached the market and many others, including direct-acting antivirals and host-targeted agents, are in phase II or III clinical development. All-oral, interferon-free combinations of drugs are expected to cure more than 90% of infections. A vast amount of data from clinical trials are presented regularly at international conferences or released to the press before peer-review, creating confusion in the viral hepatitis field. The goal of this review is to clarify the current stage of HCV therapy and drug development. This review describes the different classes of drugs and their mechanisms and properties, as well as treatment strategies in development, including those that are interferon-based and interferon-free. HCV treatment options that will be available in 2014–2015 are presented for each genotype. A number of unanswered questions and challenges remain, such as how to treat special populations, the role of ribavirin in interferon-free regimens, the role of HCV resistance in treatment failures, and how to best re-treat patients who failed on treatment. Strategic choices, cost issues, HCV screening, and improving access to care in resource-constrained areas also are discussed.
KeywordsDirect-Acting Antivirals; Interferon-Free Regimens; Sofosbuvir; Simeprevir; DaclatasvirAbbreviations used in this paperDAA, direct-acting antiviral; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTA, host-targeted agent; IFN, interferon; RdRp, RNA–dependent RNA polymerase; SVR, sustained virologic
Krishan Maggon 's insight:
Volume 146, Issue 5, May 2014, Pages 1176–1192
Reviews and Perspectives New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges Jean–Michel Pawlotsky, Show more DOI: 10.1053/j.gastro.2014.03.003
International Journal of Infectious Diseases, Volume null, Issue null, Pages null, null, Authors:Sabeen Sabri; Muhammad Idrees; Shazia Rafique; Amjad Ali; Muhammad Iqbal
Hepatitis C virus (HCV) is the causative agent of chronic liver diseases, which usually lead to liver fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). Among the non-structural genes of HCV, NS3 and NS5A play important roles in apoptosis. The NS3 and NS5A genes of HCV interact with the p53 tumor suppressor gene differentially. The objective of this study was to analyze the interaction of NS3 and NS5A genes of HCV genotype 3a with the p53 gene, subgenomic HCV replicons harboring NS3 and NS5A genes.
Huh-7 cell lines stably expressing NS3 and NS5A genes were generated. The stable cell lines were confirmed by Western blot, reverse transcriptase PCR, and immunofluorescence assay. HCV NS3- and NS5A-expressing cell lines were transfected with p53-expressing clone.
NS3 and NS5A both interact with p53 by down-regulating the expression of the p53 gene. In HCV subgenomic harboring cells, the interaction of NS3 and NS5A with p53 was observed consistently. The suppression of p53 gene expression by NS3 and NS5A was observed significantly as compared with NS3- and NS5A-negative control Huh-7 cells.
It is concluded that both of the non-structural genes, NS3 and NS5A, of HCV play important roles in the hepatocarcinogenesis of HCV by interacting directly or indirectly in different manners with the p53 gene.
Studies on the role of NS3 and NS5A non-structural genes of hepatitis C virus genotype 3a local isolates in apoptosisSabeen Sabria, Muhammad Idreesb, , , Shazia Rafiquec, Amjad Alid, Muhammad Iqbalc Show more International Journal of Infectious Diseases
A new meta-analysis published online in PLOS ONE by infectious disease and epidemiology specialists from the Perelman School of Medicine at the University of Pennsylvania highlights significant gaps in hepatitis C care that will prove useful as the...
First-in-class medicine to offer new treatment option for patients
The European Medicines Agency's Committee for Medicinal Products for Human Use(CHMP) has recommended granting a marketing authorisation for Daklinza (daclatasvir) in combination with other medicines for the treatment of chronic (long-term) hepatitis C virus (HCV) infection in adults.
HCV infection is a major European public-health challenge. It occurs in between 0.4% and 3.5% of the population in different European Union (EU) Member States and is the most common single cause of liver transplantation in the EU.
The treatment paradigm of hepatitis C is currently rapidly shifting with the development of several new classes of direct-acting antivirals. Among these is Daklinza, which is the first representative of a new class of antivirals that block the action of NS5A, a protein which is essential for HCV to replicate.
Until very recently, the standard of care for hepatitis C included a combination of the medicines pegylated interferon and ribavirin, with or without an inhibitor of the viral NS3/4A protease enzyme. However, interferon-based therapies are associated with potentially serious side effects, which are sometimes difficult to manage. One of the major benefits of the new antivirals is to provide an interferon-free treatment option for HCV infection.
There remains a public-health need to make such new treatment options available for patients where available interferon-free treatment regimens may have suboptimal effectiveness.
In November 2013, the CHMP gave an opinion on the conditions under which early access to daclatasvir, in combination with sofosbuvir, another direct-acting antiviral medicine, could be given in compassionate-use programmes.
The EMA is actively supporting the development of these new treatment options. The applicant for Daklinza, Bristol-Myers Squibb EEIG, received scientific advice from the CHMP during the development of this medicine. Daklinza was evaluated byaccelerated assessment, a regulatory tool to help speed up patient access to new medicines where there is an unmet medical need.
Convincing efficacy with a good safety profile
The positive opinion granted by the CHMP for the marketing authorisation of Daklinza is supported by a pivotal trial in which the medicine was evaluated in HCV genotype-1, -2 and -3 infected patients, in combination with sofosbuvir with or without ribavirin. This study included a treatment arm with patients that previously failed on therapy with an NS3/4A inhibitor in combination with pegylated interferon and ribavirin. All such patients in the study reached a sustained virologic response, which is the goal of antiviral therapy for HCV. This trial is supported by a study of Daklinza in combination with pegylated interferon and ribavirin in patients with genotype 4 infection, and by several phase IIb trials of Daklinza with other combinations including with pegylated interferon and ribavirin.
The medicine showed convincing efficacy, in particular in combination with sofosbuvir, with an overall good safety profile.
The opinion adopted by the CHMP at its June 2014 meeting is an intermediary step on Daklinza’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will then take place at the level of each Member State considering the potential role/use of Daklinza in the context of the national health system of that country.
Boehringer Ingelheim Statement on Hepatitis C drug development
20 June, 2014 - Boehringer Ingelheim has re-evaluated its strategy in hepatitis C (HCV), and as a result the company has decided not to move forward in this therapeutic area. The HCV treatment environment has significantly and rapidly evolved since the submission of the faldaprevir marketing applications to regulatory bodies around the world. There are now several new treatment options available for patients and additional all-oral options are expected to be approved in 2014. This decision was taken as there is no longer an unmet medical need for the faldaprevir interferon-based regimen that was the subject of the application.
Boehringer Ingelheim will withdraw all pending marketing applications for faldaprevir worldwide and is discontinuing further development.
Boehringer Ingelheim is committed to developing new treatments that provide high therapeutic value in areas where medical need exists. The company is focusing its efforts on numerous promising development projects in immunology, cardiovascular, respiratory, metabolic diseases, diseases of the central nervous system and oncology.
How cost effective are protease inhibitors for hepatitisC? #Boceprevir #Telaprevir find out for FREE http://t.co/FJubvevOE5 #ThinkHepatitis
Introduction: Combination therapy with pegylated interferon, ribavirin and the two first-generation NS3/4A protease inhibitors (PIs), telaprevir (TVR) and boceprevir (BOC), is the new standard-of-care therapy for patients who are chronically infected with genotype 1 hepatitis C virus. These combinations significantly increase sustained virological response (SVR) rates, but they also increase the rates of adverse events (AEs). Appearance of significant AEs may necessitate dose reduction or discontinuation of treatment, and may impact on virological response.
Areas covered: In registration trials, IFN-related AEs were a dominant feature in both types of therapy. Some events were more frequent with PI-containing regimens, like anemia and dysgeusia with BOC and anemia, pruritus, rash and anorectal symptoms with TVR. This review addresses the early identification and management of AEs to improve tolerance, and to avoid reduction in SVR rates.
Expert opinion: Every patient will experience adverse effects to differing degrees; a systematic approach to their management can be very helpful. Early recognition and intervention can help clinicians ensure that patients are able to complete therapy where possible and achieve the goal of viral eradication. Treatment with the next generation of antivirals will improve safety and efficacy.
Great review concerning ADR of HCV antiviral drugs.
Open access full text
Safety of direct-acting antivirals in the treatment of chronic hepatitis C
March 2014, Vol. 13, No. 3 , Pages 307-319 (doi:10.1517/14740338.2014.884068)PDF (308 KB)PDF Plus (337 KB)ReprintsPermissionsEzequiel Ridruejo 1,2 MD1 Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”, Department of Medicine, Hepatology Section, Avda. Las Heras 2939, (C1425ASG) Ciudad Autónoma de Buenos Aires, Argentina +54 11 5299 1221; +54 11 5299 0600 ext 5900;email@example.com Hospital Universitario Austral, Hepatology and Liver Transplant Unit, Pilar, Argentina
The results of a new clinical trial were excellent news for Gilead, but women and patients with cirrhosis were underrepresented in the study. (.@GileadSciences' #Sovaldi is already the talk of the town.
Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.
The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/links/hcv/hcv-classification.htm). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond “w,” and the nomenclature of intergenotypic recombinant. Conclusion: This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields. (Hepatology 2014;59:318-327)
Krishan Maggon 's insight:
Increasing number of HCV genotypes makes it more complex for drug targeting.
Gilead Sciences’ (NASDAQ:GILD) drug portfolio has 16 medications, and generates gross margins over 70% with net margins consistently over 30%. It’s newest drug, Sovaldi, is dramatically boosting revenues and earnings, and two of our Masters, Eugene Groysman and Mike Koza, have noticed. This week I talked to Eugene to find out why he thinks GILD, which is up 49% in the last year, can double from here. Eugene has a 12-year track record with Marketocracy with his average annual return of 18.3%. You can view Eugene‘s top five holdings, learn more about his strategy, and track his progress with monthly Performance Insights emailed directly to you at the end of each month by visiting our website.
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the Japanese Ministry of Health, Labor and Welfare (MHLW) has approved Daklinza® (daclatasvir), a potent, pan-genotypic NS5A replication complex inhibitor (in vitro), and Sunvepra® (asunaprevir), a NS3/4A protease inhibitor, providing a new treatment that can lead to cure for many patients in Japan who currently have no treatment options. The Daklinza+Sunvepra Dual Regimen is Japan’s first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic hepatitis C virus (HCV) infection, including those with compensated cirrhosis.
The Daklinza+Sunvepra Dual Regimen
The indications for Daklinza and Sunvepra in Japan are for the improvement of viraemia in either of the following patients with chronic hepatitis C genotype 1, or chronic hepatitis C genotype 1 with compensated cirrhosis: (1) patients who are ineligible or intolerant to interferon-based therapy, and (2) patients who have failed to respond to interferon-based therapy.
The approval is supported by results from a Phase III study demonstrating that the 24-week regimen of Daklinza and Sunvepra achieved overall SVR24 (sustained virologic response 24 weeks after the end of treatment; a functional cure) among 84.7% of Japanese HCV patients with genotype 1b. Among patients 65 years of age or older who were either interferon-ineligible or intolerant, 91.9% achieved SVR24. Further, patients with compensated cirrhosis present at baseline had overall SVR24 rates of 90.9%.
The regimen used in the Phase III study resulted in low rates of discontinuation (5%) due to adverse events (AEs). In addition, the rate of serious adverse events (SAEs) was low (5.9%) and few SAEs were experienced by more than one patient. Nasopharyngitis was the most common AE in the study (30.2%).
Results from the HALLMARK-Dual study, the Phase III multinational clinical trial investigating the Daklinza+Sunvepra Dual Regimen among genotype 1b HCV patients, demonstrated similar results to the Japan registration study and support filings in countries that have a high prevalence of genotype 1b, such as Korea and Taiwan.
Daclatasvir, a potent pan-genotypic NS5A complex inhibitor (in vitro), which continues to be investigated in multiple treatment regimens and in people with co-morbidities, and is undergoing regulatory review in the U.S. and Europe.
Daclatasvir is being studied in combination with sofosbuvir in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients, and patients with genotype 3, as part of the ongoing Phase III ALLY Program.
In 2014 FDA granted Daclatasvir+Asunaprevir Dual Regimen Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b HCV infection.
In 2013, investigational all-oral 3DAA Regimen (daclatasvir/asunaprevir/BMS-791325) also received Breakthrough Therapy Designation in the U.S., which helped to expedite the start of the ongoing Phase III UNITY Program.
Hepatitis C, a bloodborne liver disease, primarily acquired via unscreened blood products or blood transfusions, IV drug use, or inadequate sterilization of medical equipment in the healthcare setting, can potentially result in a condition known as...
TheStreet.com Closer Look at Gilead's Slowing Hep C Prescriptions TheStreet.com NEW YORK (TheStreet) -- The number of prescriptions written for Gilead Sciences' (GILD) hepatitis C drug Sovaldi are showing signs of slowing growth, even a marginal...
Krishan Maggon 's insight:
Slowing prescriptions indicate price backlash against Gilead $1000 a pill price and may negatively impact $10 billion analysts sales projections for 2014.