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.
Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from a Phase 3 clinical trial (GS-US-337-0113) in Japan evaluating the investigational once-daily fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) 90 mg and the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection. Among patients receiving 12 weeks of LDV/SOF without RBV, 100 percent (n=83/83) of treatment-naïve and 100 percent (n=88/88) of treatment-experienced patients achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Among patients receiving LDV/SOF plus RBV, 96 percent (n=80/83) of treatment-naïve and 100 percent of treatment-experienced patients (n=87/87) achieved SVR12. Across all arms of the study, patients with cirrhosis achieved a 99 percent (n=75/76) SVR12. The study met its primary endpoint of superiority compared to a predefined historical SVR12 rate. Patients who achieve SVR12 are considered cured of HCV infection.
Genotype 1 is the most common strain of HCV in Japan, accounting for approximately 70 percent of the more than one million people chronically infected with the disease. The majority of these infections are due to HCV genotype 1b. Current treatment options for genotype 1 HCV infection involve up to 48 weeks of therapy with pegylated interferon injections, RBV tablets and other oral medicines, which may not be suitable for certain patients.
In the study, 341 patients with genotype 1 HCV infection were randomized (1:1) to receive 12 weeks of all-oral therapy with LDV/SOF, with or without RBV. Of these, 166 patients were treatment-naïve, 175 were treatment-experienced and 76 had compensated cirrhosis. The intent-to-treat SVR12 rates in the study are summarized in the table below:
Overall, 338/341 patients (99 percent) in Study GS-US-337-0113 achieved SVR12. Of the three patients who failed to achieve SVR12, one patient relapsed after discontinuation of therapy, one patient discontinued therapy after one week of treatment due to rash and one patient died during the study.
Fewer adverse events were observed in the RBV-free arms compared to the RBV-containing arms in the study, most notably with regard to anemia, which was observed in 14 percent of patients taking LDV/SOF plus RBV compared to 2 percent of patients receiving LDV/SOF alone. Adverse events observed with LDV/SOF without RBV were generally mild and included nasopharyngitis (28 percent), headache (6 percent) and malaise (5 percent). Among those taking LDV/SOF plus RBV, in addition to anemia, the most common adverse events were nasopharyngitis (22 percent), pruritus (8 percent), rash (8 percent), headache (8 percent), stomatitis (6 percent), nausea (5 percent) and malaise (5 percent). No patients taking LDV/SOF and two patients taking LDV/SOF plus RBV discontinued treatment due to treatment-emergent adverse events. Full study results will be presented at a future scientific meeting.
Based on these data, Gilead plans to submit a New Drug Application for the LDV/SOF fixed-dose combination with the Japanese Pharmaceutical and Medical Devices Agency (PMDA) by the end of 2014. The product is currently under regulatory review in the United States and European Union.
On April 2, 2014, Gilead announced topline results from another Phase 3 study in Japan evaluating SOF as a single agent in combination with RBV for the treatment of genotype 2 HCV infection. The company plans to file for approval of SOF with the PMDA by mid-2014. SOF as a single agent has been approved by regulatory authorities in the United States, European Union and Canada under the tradename Sovaldi®.
LDV/SOF and SOF are investigational products in Japan and their safety and efficacy have not yet been established.
Achillion is currently conducting a Phase 2 clinical trial to evaluate the all-oral, interferon-free combination of sovaprevir and the 2nd generation NS5A inhibitor, ACH-3102 , with ribavirin, for a 12 treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients.
Krishan Maggon 's insight:
The clinical hold was imposed by the FDA in July 2013 after reports of liver toxicity in treated patients in Phase II. The hold has been lifted for single dosing and remains in force for multiple dosing
Sovaprevir is a Phase 2 NS3/4A protease inhibitor being developed for the potential treatment of chronic HCV infection. To date, approximately 550 subjects have been exposed to sovaprevir with clinical activity reported in two Phase 2 12-week treatment duration studies, one in combination with pegylated-interferon/ribavirin and one in combination with ACH-3102 in which the combination achieved 100% SVR12 in patients with genotype 1b HCV. The FDA removed the clinical hold to permit the conduct of therapeutic trials with a maximum of 200 mg once daily of sovaprevir in HCV patients and in single dose trials in healthy volunteers, but maintained a partial clinical hold for multiple dose studies that may be conducted in healthy volunteers, requiring prior review and approval of the protocol by the FDA. Achillion expects to continue to work collaboratively with the FDA on the continued clinical development of sovaprevir.
Achillion is a potential takeover target for its Hepatitis C drug pipeline
Merck (NYSE:MRK), known as MSD outside the United States and Canada, and Idenix Pharmaceuticals, Inc. (NASDAQ: IDIX), today announced that the companies have entered into a definitive agreement under which Merck will acquire Idenix for $24.50 per share in cash. The transaction, which values the purchase of Idenix at approximately $3.85 billion, has been approved by the boards of directors of both companies.
Idenix is a biopharmaceutical company engaged in the discovery and development of medicines for the treatment of human viral diseases, whose primary focus is on the development of next-generation oral antiviral therapeutics to treat hepatitis C virus (HCV) infection. The company currently has three HCV drug candidates in clinical development: two nucleotide prodrugs (IDX21437 and IDX21459) and a NS5A inhibitor (samatasvir). These novel candidates are being evaluated for their potential inclusion in the development of all oral, pan-genotypic fixed-dose combination regimens. -
Gileads curative but highpriced hepatitis C pill Sovaldi stirred payer frustration after its launch smashed sales records. Now firms from biotech to big pharma are gunning for their share of the HCV business.
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.
AbbVie (NYSE: ABBV) announced today that the Marketing Authorization Applications (MAAs) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection have been validated and are under accelerated assessment by the European Medicines Agency (EMA).
Accelerated assessment, which is designated to new medicines of major public health interest, was granted by the EMA for AbbVie's investigational HCV regimen in May. Validation of the MAAs confirms that the submissions are complete and starts the EMA's centralized review process. If approved, AbbVie's regimen could be available for marketing in the European Union (EU) in the first quarter of 2015.
The MAAs were submitted on May 8, 2014 and are supported by data from a large clinical program including six Phase III studies of more than 2,300 GT1 patients in over 25 countries. Review of the MAAs will be conducted under the centralized licensing procedure, which, when finalized, provides marketing authorizations in all 28 member states of the EU.
On June 13, AbbVie announced that the New Drug Application (NDA) for AbbVie's regimen was accepted and granted priority review by the U.S. Food and Drug Administration (FDA).
Krishan Maggon 's insight:
AbbVie all oral interferon free treatment cocktail high cure rate, FDA breakthrough drug designation, looming market war with Gilead, Merck for the booming hepatitis C market.
The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir co-formulated with ombitasvir (ABT-267), and dasabuvir (ABT-333) with or without ribavirin (RBV). The combination of three different mechanisms of action interrupts the hepatitis C virus replication process with the goal of optimizing sustained virologic response rates across different patient populations.
Previous scoops have covered Phase III results and data.
1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1–4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis).
Conclusions In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.
Krishan Maggon 's insight:
Full text open access French Study
Gut 2014;63:1150-1158 doi:10.1136/gutjnl-2013-305667
Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis CM Colombo1, I Fernández2, D Abdurakhmanov3, P A Ferreira4, S I Strasser5, P Urbanek6,C Moreno7, A Streinu-Cercel8, A Verheyen9, W Iraqi10, R DeMasi11, A Hill12, J M Läuffer13,I Lonjon-Domanec10, H Wedemeyer14
1Department of Medicine, Division of Gastroenterology, Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico, Universita` degli Studi di Milano, Milan, Italy2Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain3I.M. Sechenov First Moscow State Medical University, E. M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russia4Viral Hepatitis Division of Infectious Disease, Outpatient Clinic to HIV, Federal University of São Paulo, São Paulo, Brazil5AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia6Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic7Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium8Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases, "Prof. Dr. Matei Bals", Bucharest, Romania9Janssen Pharmaceutica, Beerse, Belgium10Janssen Pharmaceuticals, Paris, France11Janssen Research and Development, Titusville, New Jersey, USA12Janssen Research and Development, High Wycombe, UK13Janssen-Cilag AG, Zug, Switzerland14Medizinische Hochschule Hannover, Hannover, GermanyCorrespondence toProfessor Massimo Colombo, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, Milan 20122, Italy; email@example.comReceived 15 July 2013Revised 3 October 2013Accepted 15 October 2013Published Online First 7 November 2013
'Unprecedented' innovation comes at a price - Sanofi CEO PharmaTimes The EFPIA boss also slammed critics of the price of Gilead Sciences' hepatitis C treatment Sovaldi (sofosbuvir) for which a 12-week course costs $84,000.
ObjectiveTo investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens...