U.S. Food and Drug Administration Grants Fast Track Designation to Can-Fite's CF102 in the Treatment of Liver Cancer
PETACH TIKVA, Israel, Sept. 17, 2015 /PRNewswire/ -- Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory and cancer diseases, today announced the U.S. Food and Drug Administration (FDA) has granted the Company's drug candidate CF102 Fast Track designation as a second line treatment for hepatocellular carcinoma (HCC), the most common form of liver cancer. CF102 had already received the FDA's Orphan Drug designation.
Can-Fite is currently conducting a Phase II study for this indication in the U.S., Europe and Israel. The randomized, double blind, placebo controlled study is expected to complete enrollment by the end of the first half of 2016 in 78 patients with Child-Pugh Class B cirrhosis who failed the only FDA approved drug on the market, Nexavar® (sorafenib). Patients are treated twice daily with 25 mg of oral CF102, which has been found to be the most efficacious dose in Can-Fite's earlier Phase I/II study resulting in the longest overall survival time, with excellent safety results.
Fast Track, aimed at getting important new drugs that meet an unmet need to patients earlier, is expected to expedite the development of CF102. Drugs that receive Fast Track designation benefit from more frequent meetings and communications with the FDA to review the drug's development plan to support approval. It also allows the Company to submit parts of the New Drug Application (NDA) on a rolling basis for review as data becomes available. Since the Fast Track Program started, from March 1998through June 30, 2015 a total of 318 Fast Track applications have been received by the FDA. The FDA has granted 202 of them, and denied 110, with 6 more pending.
"We are very pleased that the FDA recognizes the potential for CF102 to treat HCC patients who have tried, and not been responsive to Nexavar, the only FDA approved drug currently on the market for this indication," stated Can-Fite CEO Dr. Pnina Fishman. "We consider Fast Track designation to be a major catalyst for our CF102 development program and we believe it could shorten our time to market for CF102, thereby making a considerable difference for patients."
According to Global Industry Analysts, the global market for liver cancer drugs is projected to exceed $2 billion in 2015. Nexavar® annual sales, as reported by Bayer, were €773 million in 2014.
About CF102
CF102 is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). A3AR is highly expressed in tumor cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug. In Can-Fite's pre-clinical and clinical studies, CF102 has demonstrated a robust anti-tumor effect via deregulation of the Wnt signaling pathway, resulting in apoptosis of liver cancer cells.
Thursday, 17 September 2015
Wednesday, 16 September 2015
Benitec Initiates a Fourth Site in Hepatitis C Clinical Trial
Benitec Initiates a Fourth Site in Hepatitis C Clinical Trial
SYDNEY, Sept. 16, 2015 /PRNewswire/ -- Benitec Biopharma Limited (NASDAQ: BNTC; NASDAQ: BNTCW; ASX: BLT) a clinical-stage biotechnology company developing innovative therapeutics based on its gene-silencing technology, DNA-directed RNA interference (ddRNAi), is pleased to announce it has initiated a new site for its ongoing Phase 1/2a TT-034 trial at the Methodist Health System Clinical Research Institute in Dallas, Texas. The site has commenced pre-screening hepatitis C patients and is led by principal investigator Dr. Parvez Mantry, a gastroenterologist and hepatologist.
This brings the total number of trial sites to four, with Benitec already having established sites at the Duke Clinical Research Institute, the University of California San Diego and the Texas Liver Institute.
Benitec CEO and Managing Director Dr. Peter French said, "We are pleased to welcome a fourth site to join our first-in-man trial of TT-034, an innovative therapeutic based on Benitec's gene silencing technology, ddRNAi. The addition of this site reflects the growing interest from the medical community in Benitec's potentially transformational approach to treating and curing hepatitis C. Recruitment and dosing for the trial is proceeding well."
More detail on the TT-034 trial: TT-034 is a ddRNAi-based therapeutic, designed to treat and potentially cure hepatitis C (HCV) with a single administration. TT-034 targets the hepatitis C viral RNA at three separate, highly conserved sites. As such it acts as a "triple therapy" even though it is a monotherapy, and minimises the ability of the virus to mutate and escape the therapy. Once it reaches the liver cells it enters the nucleus and produces three separate short hairpin RNAs continuously for the lifetime of the cell. Thus it has the potential to not only treat the existing HCV infection but to guard against reinfection for months to years without the need to re-treat. It has been extensively tested in pre-clinical in vivo studies and no adverse effects were seen at any therapeutic dose. However, as it is regulated as a gene therapy, the trial design is to primarily ensure that treatment with TT-034 is safe, hence the gradual dose escalation.
SYDNEY, Sept. 16, 2015 /PRNewswire/ -- Benitec Biopharma Limited (NASDAQ: BNTC; NASDAQ: BNTCW; ASX: BLT) a clinical-stage biotechnology company developing innovative therapeutics based on its gene-silencing technology, DNA-directed RNA interference (ddRNAi), is pleased to announce it has initiated a new site for its ongoing Phase 1/2a TT-034 trial at the Methodist Health System Clinical Research Institute in Dallas, Texas. The site has commenced pre-screening hepatitis C patients and is led by principal investigator Dr. Parvez Mantry, a gastroenterologist and hepatologist.
This brings the total number of trial sites to four, with Benitec already having established sites at the Duke Clinical Research Institute, the University of California San Diego and the Texas Liver Institute.
Benitec CEO and Managing Director Dr. Peter French said, "We are pleased to welcome a fourth site to join our first-in-man trial of TT-034, an innovative therapeutic based on Benitec's gene silencing technology, ddRNAi. The addition of this site reflects the growing interest from the medical community in Benitec's potentially transformational approach to treating and curing hepatitis C. Recruitment and dosing for the trial is proceeding well."
More detail on the TT-034 trial: TT-034 is a ddRNAi-based therapeutic, designed to treat and potentially cure hepatitis C (HCV) with a single administration. TT-034 targets the hepatitis C viral RNA at three separate, highly conserved sites. As such it acts as a "triple therapy" even though it is a monotherapy, and minimises the ability of the virus to mutate and escape the therapy. Once it reaches the liver cells it enters the nucleus and produces three separate short hairpin RNAs continuously for the lifetime of the cell. Thus it has the potential to not only treat the existing HCV infection but to guard against reinfection for months to years without the need to re-treat. It has been extensively tested in pre-clinical in vivo studies and no adverse effects were seen at any therapeutic dose. However, as it is regulated as a gene therapy, the trial design is to primarily ensure that treatment with TT-034 is safe, hence the gradual dose escalation.
Friday, 11 September 2015
Treating Patients With Genotype 3 HCV Infection
Of Interest
HCV Genotypes and Treatment
HCV Genotypes and Treatment
A current collection of data extracted from news articles, peer-reviewed journals, as well as liver meetings/conferences, research manuscripts and interactive learning activities with a focus on treating HCV according to genotype.
Norah Terrault, MD, MPH - 9/10/2015
More from this author
Cirrhotic, treatment-experienced patients infected with genotype 3 HCV are among the most challenging HCV populations to treat....
Cirrhotic, treatment-experienced patients infected with genotype 3 HCV are among the most challenging HCV populations to treat....
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Following EASL and the approval of daclatasvir, we changed our protocols for this patient population: Our preferred treatment regimen for cirrhotic patients, especially those who are treatment experienced, is now peginterferon plus sofosbuvir and ribavirin for 12 weeks. For patients with cirrhosis who demonstrate intolerance to peginterferon, the combination of daclatasvir plus sofosbuvir and ribavirin for 24 weeks is used. For most other patients, we advocate the use of daclatasvir plus sofosbuvir for 12 weeks. I am very interested to see what additional data we will emerge from studies examining sofosbuvir plus other NS5A inhibitors, as well as with grazoprevir/elbasvir, particularly in our treatment-experienced cirrhotic patients.....
Learning Activity
Evolving HCV Management in Harder-to-Treat Populations In this recently updated module, Nancy Reau, MD, discusses evolving clinical data on the management of HCV infection in harder-to-treat patient populations, including patients with cirrhosis, renal impairment, genotype 3 HCV infection, and HIV coinfection. Please join us for the corresponding dinner meeting series, where Dr. Reau and other faculty members will apply the data shown here to the management of these key patient populations.
Faculty: Nancy Reau MD, FAASLD, AGAF
Released: 8/25/2015
Topics include:
Management of Compensated and Decompensated Cirrhosis in HCV
Impact of Reduced Renal Function on HCV Therapy
Selecting Treatment in Patients With Genotype 3 HCV Infection
Key Considerations for HCV/HIV Coinfection
Begin here....
Vancouver’s Downtown Eastside: Psychosis and hepatitis C-related liver dysfunction associated with increased mortality
DTES residents dying at more than eight times the national average: UBC study
Psychosis and hepatitis C-related liver dysfunction are the greatest risk factors for mortality for vulnerable residents in the Downtown
Marginalized residents of Vancouver’s Downtown Eastside are dying at more than eight times the national average, and treatable conditions are the greatest risk factors for mortality, researchers at the University of British Columbia have found.
When the researchers looked into the associated risk factors for mortality, they did not find any link with HIV or substance addiction. Instead, they found psychosis and hepatitis C-related liver dysfunction to be significantly associated with increased mortality, particularly among participants under the age of 55.In research outlined in the British Medical Journal Open, investigators recruited 371 study participants aged 23 to 72 from single room occupancy hotels and the Downtown Community Court. Over the course of nearly four years, 31 participants died—a mortality rate 8.29 times the average for Canadians of the same age and sex. For participants between the ages of 20 to 59, the mortality rates were even more astounding: more than 10 times the national rate.
“We were somewhat surprised because most people thinking about the Downtown Eastside think about HIV/AIDS or the possibility of overdosing on opioids like heroin,” said Dr. William Honer, professor and head of UBC’s Department of Psychiatry and co-author of the study. “Our system is not doing as well in getting treatments out there for psychosis and hepatitis C in this group, and it’s interesting that those two illnesses are causing risk for early mortality.”
While close to two-thirds of participants living with HIV were receiving antiretroviral treatment, not one of the 57 participants with active hepatitis C infection and related liver dysfunction was receiving treatment. Only one third of the 173 participants diagnosed with psychosis were receiving treatment.
“Psychosis is an extremely prevalent issue among inner city populations and we need to address this,” said lead author Andrea Jones, an MD/PhD candidate in mental health and addictions research at UBC. “We need to be ready to detect and treat mental illness in an integrated way that really meets the patients where they’re at. We need to improve the detection and treatment of psychosis and hepatitis C in marginalized people across Canada.”
BACKGROUND
About the study
About 3,800 people live in subsidized single room occupancy (SRO) housing in the DTES. The Downtown Community Court (DCC) is a partnership of justice, social and health care services, and processes 2,500 cases a year.
Between November 2008 and August 2012, researchers recruited 371 study participants, 81 of them women, from SROs and the DCC. The participants were followed for an average of 3.8 years. Mental and physical illnesses were identified and assessed with psychiatric evaluations, neuropsychological testing and MRI scans, as well as blood tests.
For the 31 participants who died during the study, Coroner’s reports were requested, healthcare providers were interviewed, and medical and mental-health related hospital records were obtained for the year prior to death.
The study, Mortality from treatable illnesses in marginally housed adults: a prospective cohort study, was funded by the Canadian Institutes of Health Research, and the BC Mental Health and Substance Use Services.
Find other stories about: Andrea Jones, Dept. of Psychiatry, downtown eastside, DTES, william honer
Public Affairs
310 - 6251 Cecil Green Park Road
Vancouver, BC Canada V6T 1Z1
Tel 604 822 6397
Fax 604 822 2684
Website http://news.ubc.ca
Email public.affairs@ubc.ca
Marginalized residents of Vancouver’s Downtown Eastside are dying at more than eight times the national average, and treatable conditions are the greatest risk factors for mortality, researchers at the University of British Columbia have found.
When the researchers looked into the associated risk factors for mortality, they did not find any link with HIV or substance addiction. Instead, they found psychosis and hepatitis C-related liver dysfunction to be significantly associated with increased mortality, particularly among participants under the age of 55.In research outlined in the British Medical Journal Open, investigators recruited 371 study participants aged 23 to 72 from single room occupancy hotels and the Downtown Community Court. Over the course of nearly four years, 31 participants died—a mortality rate 8.29 times the average for Canadians of the same age and sex. For participants between the ages of 20 to 59, the mortality rates were even more astounding: more than 10 times the national rate.
“We were somewhat surprised because most people thinking about the Downtown Eastside think about HIV/AIDS or the possibility of overdosing on opioids like heroin,” said Dr. William Honer, professor and head of UBC’s Department of Psychiatry and co-author of the study. “Our system is not doing as well in getting treatments out there for psychosis and hepatitis C in this group, and it’s interesting that those two illnesses are causing risk for early mortality.”
While close to two-thirds of participants living with HIV were receiving antiretroviral treatment, not one of the 57 participants with active hepatitis C infection and related liver dysfunction was receiving treatment. Only one third of the 173 participants diagnosed with psychosis were receiving treatment.
“Psychosis is an extremely prevalent issue among inner city populations and we need to address this,” said lead author Andrea Jones, an MD/PhD candidate in mental health and addictions research at UBC. “We need to be ready to detect and treat mental illness in an integrated way that really meets the patients where they’re at. We need to improve the detection and treatment of psychosis and hepatitis C in marginalized people across Canada.”
BACKGROUND
About the study
About 3,800 people live in subsidized single room occupancy (SRO) housing in the DTES. The Downtown Community Court (DCC) is a partnership of justice, social and health care services, and processes 2,500 cases a year.
Between November 2008 and August 2012, researchers recruited 371 study participants, 81 of them women, from SROs and the DCC. The participants were followed for an average of 3.8 years. Mental and physical illnesses were identified and assessed with psychiatric evaluations, neuropsychological testing and MRI scans, as well as blood tests.
For the 31 participants who died during the study, Coroner’s reports were requested, healthcare providers were interviewed, and medical and mental-health related hospital records were obtained for the year prior to death.
The study, Mortality from treatable illnesses in marginally housed adults: a prospective cohort study, was funded by the Canadian Institutes of Health Research, and the BC Mental Health and Substance Use Services.
Find other stories about: Andrea Jones, Dept. of Psychiatry, downtown eastside, DTES, william honer
Public Affairs
310 - 6251 Cecil Green Park Road
Vancouver, BC Canada V6T 1Z1
Tel 604 822 6397
Fax 604 822 2684
Website http://news.ubc.ca
Email public.affairs@ubc.ca
Thursday, 10 September 2015
MODELLING THE HELICASE TO UNDERSTAND HEPATITIS
MODELLING THE HELICASE TO UNDERSTAND HEPATITIS
NS3 BEHAVES LIKE A “CATERPILLAR” AND HELPS THE VIRUS TO REPLICATE
NS3 is an enzyme specific to the hepatitis C virus. If developed, a drug capable of recognizing and selectively attacking it could fight the disease without side effects for the body. However, to be able to develop one we need to know more about the behavior of this important protein in the virus replication process. Some SISSA scientists have provided a detailed and comprehensive view of the behavior of NS3. The study has been published in the journal Nucleic Acids Research.
According to the WHO, a good 140 million people are affected by hepatitis C (3/4 million new cases per year). This is still a subtle disease which, in the event of chronic infection, heavily affects the patients' quality of life and whose complications can lead to death. One of the molecules involved in the reproduction mechanism of the virus in the body is a helicase, NS3, an enzyme that interacts with the RNA (the viral genome, which is not like our DNA) by climbing onto it and helping the pathogen's replication process.
"By knowing in detail how this helicase works, in the future we could try to block the viral replication, and thus stop the disease from proliferating in the body" explains Giovanni Bussi, SISSA professor and among the study authors. NS3 facilitates the work of the polymerases, the molecules that build a replica of the RNA strand, by "opening" and preparing the RNA to the action of the second enzyme. "NS3 crawls along the RNA strand contracting and extending like a caterpillar and, as it does so, it releases the part of the virus to which the polymerase then attaches" explains Andrea Pérez-Villa, SISSA student and first author of the paper. "We decided to analyze this protein because, unlike others, it is only present in the hepatitis C virus. This way, any drug capable of targeting its interaction with the RNA would not damage other proteins, for example, those belonging to the body being attacked by the virus. This means that, theoretically, the drug would have no side effects".
"Our work was based on a computer simulation, starting from the available experimental data", explains Pérez-Villa. So far, crystallography studies succeeded in obtaining a limited number of "images" of NS3, too few to be able to reconstruct the whole process. Based on existing data, Pérez-Villa and Bussi (as well as Maria Darvas, SISSA research scientist who took part in the study) created a model of the protein and had it interact with the viral RNA. But not only that.
"During the process, ATP, the "fuel" utilized by proteins, is consumed. Therefore our simulation also reproduced the system's interaction with ATP and subsequently with ADP, a waste product together with phosphate, after ATP had been utilized" concludes Bussi. So for the first time we provided a detailed description of the process, which will serve as a guide for future steps forward, whether theoretical or experimental.
NS3 BEHAVES LIKE A “CATERPILLAR” AND HELPS THE VIRUS TO REPLICATE
NS3 is an enzyme specific to the hepatitis C virus. If developed, a drug capable of recognizing and selectively attacking it could fight the disease without side effects for the body. However, to be able to develop one we need to know more about the behavior of this important protein in the virus replication process. Some SISSA scientists have provided a detailed and comprehensive view of the behavior of NS3. The study has been published in the journal Nucleic Acids Research.
According to the WHO, a good 140 million people are affected by hepatitis C (3/4 million new cases per year). This is still a subtle disease which, in the event of chronic infection, heavily affects the patients' quality of life and whose complications can lead to death. One of the molecules involved in the reproduction mechanism of the virus in the body is a helicase, NS3, an enzyme that interacts with the RNA (the viral genome, which is not like our DNA) by climbing onto it and helping the pathogen's replication process.
"By knowing in detail how this helicase works, in the future we could try to block the viral replication, and thus stop the disease from proliferating in the body" explains Giovanni Bussi, SISSA professor and among the study authors. NS3 facilitates the work of the polymerases, the molecules that build a replica of the RNA strand, by "opening" and preparing the RNA to the action of the second enzyme. "NS3 crawls along the RNA strand contracting and extending like a caterpillar and, as it does so, it releases the part of the virus to which the polymerase then attaches" explains Andrea Pérez-Villa, SISSA student and first author of the paper. "We decided to analyze this protein because, unlike others, it is only present in the hepatitis C virus. This way, any drug capable of targeting its interaction with the RNA would not damage other proteins, for example, those belonging to the body being attacked by the virus. This means that, theoretically, the drug would have no side effects".
"Our work was based on a computer simulation, starting from the available experimental data", explains Pérez-Villa. So far, crystallography studies succeeded in obtaining a limited number of "images" of NS3, too few to be able to reconstruct the whole process. Based on existing data, Pérez-Villa and Bussi (as well as Maria Darvas, SISSA research scientist who took part in the study) created a model of the protein and had it interact with the viral RNA. But not only that.
"During the process, ATP, the "fuel" utilized by proteins, is consumed. Therefore our simulation also reproduced the system's interaction with ATP and subsequently with ADP, a waste product together with phosphate, after ATP had been utilized" concludes Bussi. So for the first time we provided a detailed description of the process, which will serve as a guide for future steps forward, whether theoretical or experimental.
Original paper Nucleic Acid Research: http://goo.gl/DAuCPt
http://www.sissa.it/news/modelling-helicase-understand-hepatitis
http://www.sissa.it/news/modelling-helicase-understand-hepatitis
Hepatitis C Genotype 3 - Updated Label for Daklinza (daclatasvir) Approved by the European Commission
Updated Label for Daklinza (daclatasvir) for the 12-week Treatment of Non-cirrhotic Patients with Chronic Hepatitis C Genotype 3 Approved by the European Commission
Daklinza in combination with sofosbuvir is the first 12-week all-oral therapy for genotype 3 patients without cirrhosis in Europe
Hepatitis C genotype 3 progresses faster than genotype 1 and is one of the most difficult-to-treat genotypes
Thursday, September 10, 2015 7:00 am EDT
"The burden of hepatitis C – and genotype 3, specifically – remains significant in many parts of Europe"
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the European Commission has approved an updated label for Daklinza for the treatment of genotype 3 chronic hepatitis C (HCV). The update allows the use of Daklinza in combination with sofosbuvir for 12 weeks in patients without cirrhosis in all 28 Member States of the European Union, and marks the first time these patients with genotype 3 HCV have a once-daily, all-oral treatment regimen of this shorter duration.
“The burden of hepatitis C – and genotype 3, specifically – remains significant in many parts of Europe,” said Graham R. Foster, FRCP, Ph.D., Professor of Hepatology, Blizard Institute, Queen Mary University of London, London, United Kingdom. “Despite advances in therapy, genotype 3 HCV patients are still some of the most challenging to treat with direct-acting antivirals. The cure rates achieved by Daklinza in combination with sofosbuvir for 12 weeks represent a positive step forward for genotype 3 patients without cirrhosis.”
Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A and P-glycoprotein transporter, as this may lead to lower exposure and loss of efficacy of Daklinza. Daklinza must not be administered as a monotherapy.
In August 2014, Daklinza was approved by the European Commission for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic HCV infection in adults. The original label included treatment of patients with genotype 3 (with or without compensated cirrhosis and/or treatment-experienced) with Daklinza and sofosbuvir and ribavirin, for 24 weeks. The updated label, which removes the requirement for ribavirin and reduces treatment duration to 12 weeks for patients without cirrhosis, is based on data submitted to the European Medicines Agency and the Committee for Medicinal Products for Human Use from the ALLY-3 clinical trial. The updated treatment regimen for patients with cirrhosis is forDaklinza plus sofosbuvir with the optional use of ribavirin, which may be added based on clinical assessment of the patient. The treatment duration for these patients has not changed.
Affecting an estimated 54.3 million people (30% of all HCV patients) worldwide, genotype 3 is the second most common HCV genotype globally and is considered one of the most difficult to treat. The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with accelerated fibrosis progression. Recent research has also shown the risk of cirrhosis for patients infected with HCV genotype 3 is 31% greater than for those with HCV genotype 1.
ALLY-3 Study Design
The European Commission’s approval is based on data from the Phase 3 open-label ALLY-3 clinical trial, which was published in Hepatology in April 2015. In the trial, 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naïve patients and 51 treatment-experienced patients) received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post-treatment. The co-primary endpoints were defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in each treatment group. Most treatment-experienced patients had failed prior treatment with peginterferon/ribavirin, but seven patients were treated previously with a sofosbuvir regimen and two patients with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. In the trial, the Daklinzaplus sofosbuvir regimen demonstrated overall SVR12 in 90% of treatment-naïve and 86% of treatment-experienced chronic HCV genotype 3 patients. SVR12 rates were higher (96%) in genotype 3 patients without cirrhosis, regardless of treatment history. In the more difficult-to-treat patients with cirrhosis, SVR12 rates were reduced (63%) following the 12 weeks of treatment with the Daklinza plus sofosbuvir regimen.
In the trial, there were no treatment-related serious adverse events (SAEs), no discontinuations due to adverse events (AEs), and no new safety signals. The most common treatment-related AEs were headache (20%), fatigue (19%), nausea (12%) and diarrhea (9%). The updated Summary of Product Characteristics will be available atwww.ema.europa.eu.
About Bristol-Myers Squibb in HCV
Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is daclatasvir, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden, such as pre- and post-transplant patients and HIV/HCV coinfected patients, as part of the ongoing Phase 3 ALLY Program.
In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in North, Central and South America, the Middle East and the Asia-Pacific region.
U.S. Indication and Important Safety Information (ISI) - Daklinza™ (daclatasvir)
The following ISI is based on information from U.S. Prescribing Information for Daklinza. Please consult the full Prescribing Information for all labeled safety information.
INDICATION
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.
Limitations of Use:
Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).
WARNINGS and PRECAUTIONS
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
Bradycardia generally resolved after discontinuation of HCV treatment.
Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
ADVERSE REACTIONS
The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).
DRUG INTERACTIONS
CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.
Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.
Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.
Please click here for the Daklinza full prescribing information.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that Daklinza’s approval for the updated label mentioned above will lead to increased commercial success. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Contact:
Bristol-Myers Squibb Company
Media:
Robert Perry, 407-492-4616
rob.perry@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill Szablewski, 609-252-5894
william.szablewski@bms.com
Daklinza in combination with sofosbuvir is the first 12-week all-oral therapy for genotype 3 patients without cirrhosis in Europe
Hepatitis C genotype 3 progresses faster than genotype 1 and is one of the most difficult-to-treat genotypes
Thursday, September 10, 2015 7:00 am EDT
"The burden of hepatitis C – and genotype 3, specifically – remains significant in many parts of Europe"
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that the European Commission has approved an updated label for Daklinza for the treatment of genotype 3 chronic hepatitis C (HCV). The update allows the use of Daklinza in combination with sofosbuvir for 12 weeks in patients without cirrhosis in all 28 Member States of the European Union, and marks the first time these patients with genotype 3 HCV have a once-daily, all-oral treatment regimen of this shorter duration.
“The burden of hepatitis C – and genotype 3, specifically – remains significant in many parts of Europe,” said Graham R. Foster, FRCP, Ph.D., Professor of Hepatology, Blizard Institute, Queen Mary University of London, London, United Kingdom. “Despite advances in therapy, genotype 3 HCV patients are still some of the most challenging to treat with direct-acting antivirals. The cure rates achieved by Daklinza in combination with sofosbuvir for 12 weeks represent a positive step forward for genotype 3 patients without cirrhosis.”
Daklinza is contraindicated in combination with medicinal products that strongly induce CYP3A and P-glycoprotein transporter, as this may lead to lower exposure and loss of efficacy of Daklinza. Daklinza must not be administered as a monotherapy.
In August 2014, Daklinza was approved by the European Commission for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic HCV infection in adults. The original label included treatment of patients with genotype 3 (with or without compensated cirrhosis and/or treatment-experienced) with Daklinza and sofosbuvir and ribavirin, for 24 weeks. The updated label, which removes the requirement for ribavirin and reduces treatment duration to 12 weeks for patients without cirrhosis, is based on data submitted to the European Medicines Agency and the Committee for Medicinal Products for Human Use from the ALLY-3 clinical trial. The updated treatment regimen for patients with cirrhosis is forDaklinza plus sofosbuvir with the optional use of ribavirin, which may be added based on clinical assessment of the patient. The treatment duration for these patients has not changed.
Affecting an estimated 54.3 million people (30% of all HCV patients) worldwide, genotype 3 is the second most common HCV genotype globally and is considered one of the most difficult to treat. The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with accelerated fibrosis progression. Recent research has also shown the risk of cirrhosis for patients infected with HCV genotype 3 is 31% greater than for those with HCV genotype 1.
ALLY-3 Study Design
The European Commission’s approval is based on data from the Phase 3 open-label ALLY-3 clinical trial, which was published in Hepatology in April 2015. In the trial, 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naïve patients and 51 treatment-experienced patients) received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post-treatment. The co-primary endpoints were defined as HCV RNA below the lower limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in each treatment group. Most treatment-experienced patients had failed prior treatment with peginterferon/ribavirin, but seven patients were treated previously with a sofosbuvir regimen and two patients with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. In the trial, the Daklinzaplus sofosbuvir regimen demonstrated overall SVR12 in 90% of treatment-naïve and 86% of treatment-experienced chronic HCV genotype 3 patients. SVR12 rates were higher (96%) in genotype 3 patients without cirrhosis, regardless of treatment history. In the more difficult-to-treat patients with cirrhosis, SVR12 rates were reduced (63%) following the 12 weeks of treatment with the Daklinza plus sofosbuvir regimen.
In the trial, there were no treatment-related serious adverse events (SAEs), no discontinuations due to adverse events (AEs), and no new safety signals. The most common treatment-related AEs were headache (20%), fatigue (19%), nausea (12%) and diarrhea (9%). The updated Summary of Product Characteristics will be available atwww.ema.europa.eu.
About Bristol-Myers Squibb in HCV
Bristol-Myers Squibb’s research efforts are focused on advancing compounds to deliver the most value to HCV patients with high unmet needs. At the core of our portfolio is daclatasvir, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with high disease burden, such as pre- and post-transplant patients and HIV/HCV coinfected patients, as part of the ongoing Phase 3 ALLY Program.
In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic HCV. Since then, daclatasvir-based regimens have been approved in more than 50 countries, including the United States, across Europe, and in numerous other countries in North, Central and South America, the Middle East and the Asia-Pacific region.
U.S. Indication and Important Safety Information (ISI) - Daklinza™ (daclatasvir)
The following ISI is based on information from U.S. Prescribing Information for Daklinza. Please consult the full Prescribing Information for all labeled safety information.
INDICATION
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3 infection.
Limitations of Use:
Sustained virologic response (SVR) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
Drugs Contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).
WARNINGS and PRECAUTIONS
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
Bradycardia generally resolved after discontinuation of HCV treatment.
Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
ADVERSE REACTIONS
The most common adverse reactions were (≥ 5%): headache (14%), fatigue (14%), nausea (8%), and diarrhea (5%).
DRUG INTERACTIONS
CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
See Section 7 of the Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations.
Daklinza in Pregnancy: No data with Daklinza in pregnant women are available to inform a drug-associated risk. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity. Consider the benefits and risks of Daklinza when prescribing Daklinza to a pregnant woman.
Nursing Mothers: Daklinza was excreted into the milk of lactating rats; it is not known if Daklinza is excreted into human milk. Consider the benefits and risks to the mother and infant when breastfeeding.
Please click here for the Daklinza full prescribing information.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that Daklinza’s approval for the updated label mentioned above will lead to increased commercial success. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.
Contact:
Bristol-Myers Squibb Company
Media:
Robert Perry, 407-492-4616
rob.perry@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bill Szablewski, 609-252-5894
william.szablewski@bms.com
Wednesday, 15 April 2015
Using Clomid and HCG for Post Cycle Therapy
Clomid is a generic name for Clomiphene Citrate and is a synthetic estrogen. It is prescribed medically to aid ovulation in low fertility females. Another generic name is Serophene.
Most anabolic steroids, especially the androgens, cause inhibition of the body's own testosterone production. When a bodybuilder comes off a steroid cycle, natural testosterone production is zero and the levels of the steroids taken in the blood are diminishing. This leaves the ratios of catabolic : anabolic hormones in the blood high, hence the body is in a state of catabolism, and, as a result, much of the muscle tissue that was gained on the cycle is now going to be lost.
Clomid stimulates the hypothalamus to, in turn stimulant the anterior pituitary gland (aka hypophysis) to release gonadotrophic hormones. The gonadotrophic hormones are follicle stimulating hormone (FSH) and luteinizing hormone (LH - aka interstitial cell stimulating hormone (ICSH)). FSH stimulates the testes to produce more testosterone, and LH stimulates them to secrete more testosterone. This feedback mechanism is known as the hypothalamic-pituitary-testes axis (HPTA), and results in an increase of the body's own testosterone production and blood levels rise, to, in part, compensate for the diminishing levels of exogenous steroids. This is vital to minimise post cycle muscle losses.
Not all steroids do cause shut down of the feedback mechanism. Everyone is different and you must also take into account how long you have been using a certain steroid and at what dose in order to determine if you need Clomid or not.
Clomid also works as an anti-estrogen. As it's a weak synthetic estrogen, it binds to estrogen receptors on cells blocking them to estrogen in the blood. This minimises the negative effects like gynecomastia and water retention that may be a result of estrogen that has aromatised from testosterone.
It's effect as an anti-estrogen are quite weak though, and it should not be relied upon if you are going to be using androgenic steroids that aromatise at a rapid rate, or if you are pre-disposed to gynecomastia. Arimidex and Nolvadex (Tamoxifen) are far more effective anti-estrogens.
Important note: Clomid does not, as is often thought, stimulate the release of natural testosterone, but rather works at reducing the estrogenic inhibition caused by the steroid cycle. It does this in a similar manner to the way it and Nolvadex block estrogen receptors in nipples to combat gyno development, i.e. by blocking the estrogen receptors in the hypothalamus and pituitary thus reducing the inhibition from the elevated estrogen. This allows LH levels to return to normal, or even above normal levels, and in turn, natural testosterone levels to also normalise.
Inhibition of the HPTA is caused by either elevated androgen, estrogen or progesterone levels. On cessation of the steroid cycle, androgen levels begin to fall and Clomid dosing is normally commenced according to the half-life of the longest acting drug in the system (see below).
This may also explain the reason individuals often find post-deca recovery more difficult, as the progesterone presence is untouched by the Clomid. We know that Clomid and Nolvadex (being very similar chemically) are both ineffective with regard to reducing progesterone related gyno, so it is reasonable to assume that Clomid has little effect against progesterone levels.
Clomid During A Cycle
When we use anabolic steroids, the level of androgens in the body rises causing the androgen receptors to become more highly activated, and through the HPTA, a signal tells our testes to stop producing testosterone. During a cycle the body has far higher than normal levels of androgens and, as long as this level is high enough, Clomid will not help to keep natural testosterone production up. It will be almost all but completely shut off, in theory.
Some heavy androgen users, however, do advocate a small burst of Clomid mid-cycle, though it must be hard for them to say if it really of any benefit, due to the amount of gear they are using. Therefore, the only purpose of Clomid during a cycle is as an anti-estrogen.
When To Start Clomid
The correct time to commence Clomid depends on the type and cycle of steroids you have been using. Different steroids have different half-lifes (indicates the time a substance diminishes in blood), and Clomid administration should be taken accordingly.
As we have seen above, Clomid taken when androgen levels in our blood are still high will be a waste. It is crucial to wait for androgen levels to fall before implementing our Clomid therapy. However, if taken too late we could possibly lose gains.
The list below determines when you should start Clomid. Select from the list any steroids you've used in your cycle and whichever one has the latest starting point is the time to commence Clomid. For example, if Dianabol, Sustanon and Winstrol were cycled, the time for administering Clomid should be 3 weeks post cycle, as Sustanon remains active in the body for the longest period of time.
Steroid Time after last administration Length of Clomid Cycle
Anadrol50/Anapolan50: 8 - 12 hours 3 weeks
Deca durabolan: 3 weeks 4 weeks
Dianabol: 4 - 8 hours 3 weeks
Equipoise: 17 - 21 days 3 weeks
Finajet/Trenbolone: 3 days 3 weeks
Primabolan depot: 0 - 14 days 2 weeks
Sustanon: 3 weeks 3 weeks
Testosterone Cypionate: 2 weeks 3 weeks
Testosterone Enanthate/Testaviron: 2 weeks 3 weeks
Testosterone Propionate: 3 days 3 weeks
Testosterone Suspension: 4 - 8 hours 2-3 weeks
Winstrol 8 - 12 hours 2-3 weeks
How To Take Clomid
Clomid has a long half-life (possibly 5 days), so there is no need to split up doses throughout the day. If Sustanon has been used and Clomid is commenced 3 weeks after the last injection, I would estimate that androgen levels are low enough to start sending the correct signals. If androgen levels are still a little high, we need to start at a high enough amount that will work or help, even if androgen levels are still a little high. Try 300mg on day 1; then use 100mg for the next 10 days; followed by 50mg for 10 days.
Using HCG
It is our opinion that HCG is probably one of the most misunderstood and misused compounds in bodybuilding. Hopefully this information will go some way towards rectifying that for the members of MuscleTalk. HCG stands for Human Chorionic Gonadotrophin and is not a steroid, but a natural peptide hormone which develops in the placenta of pregnant women during pregnancy to controls the mother's hormones. (Incidentally, this is the reason you may hear of people testing for growth hormone (HGH) with a pregnancy testing kit - If their HGH shows 'pregnant', they've been ripped-off with cheaper HCG - but we digress slightly).
Its action in the male body is like that of LH, stimulating the Leydig cells in the testes to produce testosterone even in the absence of endogenous LH. HCG is therefore used during longer or heavier steroid cycles to maintain testicular size and condition, or to bring atrophied (shrunken) testicles back up to their original condition in preparation for post-cycle Clomid therapy. This process is necessary because atrophied testicles produce reduced levels of natural testosterone, this situation should be rectified prior to post-cycle Clomid therapy.
HCG administration post-cycle is common practice among bodybuilders in the belief that it will aid the natural testosterone recovery, but this theory is unfounded and also counterproductive. The rapid rise in both testosterone, and thus estrogen due to aromatisation, from the administration of HCG causes further inhibition of the HPTA (Hypothalamic/Pituitary/Testicular Axis - feedback loop discussed above); this actually worsens the recovery situation. HCG does not restore the natural testosterone production.
The typically observed dosing of 2000 to 5000IU every 4 to 5 days causes such an increase in estrogen levels via aromatisation of the natural testosterone that this has been responsible for many cases of gynecomastia.
From the above discussion it is clear that HCG is best used during a cycle, either to:
1) Avoid testicular atrophy, or
2) Rectify the problem of an existing testicular atrophy.
Doses of HCG
Smaller doses, more frequently during a cycle will give best overall results with least unwanted side effects. Somewhere between 500iu and 1000iu per day would be best over about a two-week period. These doses are sufficient to avoid/rectify testicular atrophy without increasing estrogen levels too dramatically and risking gynecomastia. This dosing schedule also avoids the risk of permanently down-regulating the LH receptors in the testes.
Presentation and Administration of HCG
Synthetic HCG is often known as Pregnyl (generic name) and is available in 2500iu and 5000iu (not ideal for the above doses!). Administration of the compound is either by intra-muscular or subcutaneous injection. It comes as a powder which needs to be mixed with the sterile water. The powder is temperature-sensitive prior to mixing and should not be exposed to direct heat. After mixing, it should be kept refrigerated and used within a few weeks - though there are sterility issues which need to be considered after mixing.
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