Roche announced that the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned Roche will continue with its ongoing Phase III EMILIA registration study. Roche will continue to work with the FDA and expects a global regulatory submission of T-DM1 mid 2012.
The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2 positive breast cancer, who had received on average seven prior medicines, including two HER2 targeted agents.
Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices), for whom a medicine’s early safety and efficacy data are reasonably likely to predict clinical benefit. Following the pre-submission meeting with the FDA in March 2010, Roche concluded it was appropriate to submit a BLA for accelerated approval. In their review of the BLA, FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population.
“We firmly believe in the potential of T-DM1 as a novel HER2 targeted option and remain fully committed to its ongoing development,” said Hal Barron, M.D., Head of Global Development and Chief Medical Officer for Roche.
Roche will submit the data from the amended Phase III randomized EMILIA study to support a global regulatory submission in mid 2012. The EMILIA study compares T-DM1 to lapatinib in combination with capecitabine in people with advanced HER2 positive breast cancer whose disease has worsened after receiving initial treatment.
T-DM1 is an antibody-drug conjugate (ADC), also known as an armed antibody, being studied for advanced HER2 positive breast cancer. T-DM1 attaches trastuzumab and the chemotherapy DM1 together using a stable linker, which is designed to keep T-DM1 in one piece until it reaches specific cancer cells. The antibody (trastuzumab) binds to the HER2 positive cancer cells, and is thought to block out-of-control signals that make the cancer grow while also calling on the body’s immune system to attack the cells. Then, once T-DM1 is absorbed into those cancer cells, it is designed to destroy them by releasing the DM1. Genentech licenses technology for T-DM1 under an agreement with ImmunoGen, Inc.
About studies with T-DM1 and other HER2 targeted agents
The FDA submission was based on a Phase II study known as TDM4374g, a single-arm, multi-center trial designed to assess single-agent T-DM1 in 110 women with HER2 positive advanced breast cancer whose disease had worsened after receiving at least two prior HER2 targeted treatments (Herceptin and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane and capecitabine. The primary endpoint of the study was objective response rate (a complete or partial tumor shrinkage of at least 30 percent, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility.
Results from the study were presented at the 2009 San Antonio Breast Cancer Symposium and demonstrated that T-DM1 shrank tumors in 33 percent of women with advanced HER2 positive breast cancer that had worsened following treatment with an average of seven prior medicines for metastatic disease. In the study, most side effects were mild (Grade 1-2) and similar to those observed in previous clinical trials of T-DM1. The most common adverse events of any grade were fatigue (62 percent) and nausea (37 percent). The most common severe adverse events (Grade 3 or higher) were a low level of platelets in the blood (7 percent), fatigue (5 percent) and cellulitis (4 percent). No severe cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with liver failure. The safety results were consistent with data from earlier studies, including a proof-of-concept Phase II study (TDM4258g), which also was included in the submission to the FDA.
Several other Phase II and III trials of T-DM1, and other HER2 targeted medicines are ongoing:
* Preliminary results from a randomized Phase II study (TDM4450g) comparing T-DM1 to Herceptin (trastuzumab) in combination with docetaxel chemotherapy in people who have not been previously treated for their advanced HER2 positive breast cancer have been accepted for presentation at the European Society of Medical Oncology (ESMO) congress in Milan (Italy) in October.
* An ongoing Phase III study, MARIANNE, will compare both T-DM1 alone and T-DM1 in combination with pertuzumab to Herceptin in combination with a taxane chemotherapy in people with advanced HER2 positive breast cancer who have not been previously treated for advanced disease.
* CLEOPATRA is the pivotal registration trial with pertuzumab in combination with Herceptin and docetaxel in first-line HER2 positive metastatic breast cancer. Filing timelines remain unchanged; Roche expects a global regulatory filing of pertuzumab based on the CLEOPATRA study at the end of 2011.
Pertuzumab is a new type of targeted anti-tumor agent called a HER2 dimerisation inhibitor (HDI), which inhibits the pairing (or dimerisation) of the HER2 protein with other HER-family receptors. This pairing is responsible for initiating intracellular HER signaling. HER-signaling pathways are believed to play an important role in the growth and survival of several different cancer types. The modes of action of Herceptin and pertuzumab are believed to be synergistic. Herceptin also binds to HER2, but in a different place.
Herceptin is a humanized antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of Herceptin is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumor. Herceptin has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2 positive breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, Herceptin has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2 positive breast cancer. Herceptin is marketed in the United States by Genentech, in Japan by Chugai and internationally by Roche. Since 1998, Herceptin has been used to treat more than 740,000 patients with HER2 positive breast cancer worldwide.
Friday, September 3, 2010
Roche announces Operational Excellence initiative
Roche announced the launch of a Group-wide Operational Excellence initiative. In view of mounting pressures to curb healthcare costs – especially in the United States and Europe – together with recent developments in late-stage projects in the Roche pipeline, this initiative aims to adapt cost structures and accelerate productivity improvements Group-wide.
Severin Schwan, CEO of Roche, commented: “We have launched this initiative from a position of strength. By contrast with many of our competitors, we are only marginally affected by patent expiries. Furthermore, despite the recent setbacks, we have one of the strongest R&D product pipelines in the industry. We will focus our resources towards investments that will drive innovation and ensure the company’s long-term success, while at the same time protecting our profitability so as to safeguard our financial flexibility. Roche also confirms its full-year outlook for 2010.”
With tightening healthcare budgets, Roche expects that payers will increasingly allocate resources to treatments and diagnostic tools providing the highest medical value for patients. Therefore, Operational Excellence is not simply a cost-reduction effort but is above all about pro-actively setting the right priorities to ensure a successful future.
Over the months ahead, all parts of the organisation will review and analyse their respective structures and processes. Detailed decisions on the measures that will be taken and the potential impact on staffing levels will be announced before the end of the year. The Operational Excellence initiative is scheduled for implementation during 2011 and 2012.
Severin Schwan, CEO of Roche, commented: “We have launched this initiative from a position of strength. By contrast with many of our competitors, we are only marginally affected by patent expiries. Furthermore, despite the recent setbacks, we have one of the strongest R&D product pipelines in the industry. We will focus our resources towards investments that will drive innovation and ensure the company’s long-term success, while at the same time protecting our profitability so as to safeguard our financial flexibility. Roche also confirms its full-year outlook for 2010.”
With tightening healthcare budgets, Roche expects that payers will increasingly allocate resources to treatments and diagnostic tools providing the highest medical value for patients. Therefore, Operational Excellence is not simply a cost-reduction effort but is above all about pro-actively setting the right priorities to ensure a successful future.
Over the months ahead, all parts of the organisation will review and analyse their respective structures and processes. Detailed decisions on the measures that will be taken and the potential impact on staffing levels will be announced before the end of the year. The Operational Excellence initiative is scheduled for implementation during 2011 and 2012.
European Commission Issues Positive Decision for Approval of Seroquel XR
AstraZeneca announced that the European Commission (EC) has issued a positive decision for the approval of once-daily SEROQUEL XR (quetiapine fumarate) Extended Release Tablets as an add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had sub-optimal response to antidepressant monotherapy.
This decision follows a positive recommendation by the Committee for Medicinal Products for Human Use (CHMP) in April of this year.
AstraZeneca will now move forward in obtaining local approvals. This is a 30 day process in the 17 member states that took part in the original Mutual Recognition Procedure. For other member states timelines will vary.
Within this application, the product information for SEROQUEL XR has been updated with respect to several individual safety topics such as: suicidality, weight gain, hyperglycaemia, extrapyramidal symptoms, akathisia, somnolence, orthostatic hypotension, and dizziness. Guidance is also provided on safe administration of SEROQUEL XR, including consideration of the safety profile with respect to the individual patient's diagnosis and the dose being administered. Implementation of this updated product information will occur upon obtaining local approval.
About SEROQUEL XR
To date, SEROQUEL XR has been approved in 72 countries for schizophrenia, 57 countries for bipolar mania, 49 countries for bipolar depression, 33 countries for bipolar maintenance, 6 countries for MDD, with US receiving approval of SEROQUEL XR for the adjunctive treatment of MDD in December 2009, and 3 countries for Generalised Anxiety Disorder (GAD).
This decision follows a positive recommendation by the Committee for Medicinal Products for Human Use (CHMP) in April of this year.
AstraZeneca will now move forward in obtaining local approvals. This is a 30 day process in the 17 member states that took part in the original Mutual Recognition Procedure. For other member states timelines will vary.
Within this application, the product information for SEROQUEL XR has been updated with respect to several individual safety topics such as: suicidality, weight gain, hyperglycaemia, extrapyramidal symptoms, akathisia, somnolence, orthostatic hypotension, and dizziness. Guidance is also provided on safe administration of SEROQUEL XR, including consideration of the safety profile with respect to the individual patient's diagnosis and the dose being administered. Implementation of this updated product information will occur upon obtaining local approval.
About SEROQUEL XR
To date, SEROQUEL XR has been approved in 72 countries for schizophrenia, 57 countries for bipolar mania, 49 countries for bipolar depression, 33 countries for bipolar maintenance, 6 countries for MDD, with US receiving approval of SEROQUEL XR for the adjunctive treatment of MDD in December 2009, and 3 countries for Generalised Anxiety Disorder (GAD).
Wednesday, September 1, 2010
"Cholera Outbreak in Afghanistan Under Control," Says UN
The cholera outbreak that started earlier this month in central Afghanistan is now under control, the United Nations and its partners reported today, stressing that early detection and collaboration among key actors were key to averting a public health crisis.
The World Health Organization (WHO) and the Ministry of Public Health (MoPH) initiated a response immediately after the outbreak began on 9 August in the Nowa district of Ghazni province.
"Early detection of diseases is tantamount to saving lives," said Peter Graaff, WHO's Representative in Afghanistan.
"Thanks to a strong disease surveillance system and close collaboration between the MoPH, UN agencies and health NGOs [non-governmental organizations] we were quickly able to limit the magnitude of the outbreak and save lives."
Afghanistan's disease early warning system (DEWS) is now operational in all 34 provinces, and includes more than 300 surveillance officers, who help to detect and respond to disease outbreaks within 48 hours.
"In 2009 alone, we were able to rapidly respond to and control 35 cholera outbreaks and treated 1,721 reported cases across 15 provinces," said WHO epidemiologist Rashida Bano.
Cholera is an acute intestinal infection picked up through contaminated food or water. It can result in diarrhoea that can lead to severe dehydration and even death without prompt treatment.
WHO donated life-saving supplies, including cholera kits and other emergency medical supplies in the wake of the outbreak earlier this month, which affected at least 130 people.
Mr. Graaff noted that one of the challenges with regard to cholera control in Afghanistan is the insecurity in parts of the country which make it difficult to carry out timely investigations and responses.
Due to security concerns involving health ministry and UN staff, WHO said that three local NGO staff members were trained in outbreak investigation, including sample collection and treatment.
WHO added that diarrhoeal diseases are endemic to Afghanistan and there is a seasonal increase from July to September. Most of the vulnerability to waterborne diseases comes from contaminated water sources, as only 23 per cent of Afghans have access to safe drinking water.
Source: United Nations
The World Health Organization (WHO) and the Ministry of Public Health (MoPH) initiated a response immediately after the outbreak began on 9 August in the Nowa district of Ghazni province.
"Early detection of diseases is tantamount to saving lives," said Peter Graaff, WHO's Representative in Afghanistan.
"Thanks to a strong disease surveillance system and close collaboration between the MoPH, UN agencies and health NGOs [non-governmental organizations] we were quickly able to limit the magnitude of the outbreak and save lives."
Afghanistan's disease early warning system (DEWS) is now operational in all 34 provinces, and includes more than 300 surveillance officers, who help to detect and respond to disease outbreaks within 48 hours.
"In 2009 alone, we were able to rapidly respond to and control 35 cholera outbreaks and treated 1,721 reported cases across 15 provinces," said WHO epidemiologist Rashida Bano.
Cholera is an acute intestinal infection picked up through contaminated food or water. It can result in diarrhoea that can lead to severe dehydration and even death without prompt treatment.
WHO donated life-saving supplies, including cholera kits and other emergency medical supplies in the wake of the outbreak earlier this month, which affected at least 130 people.
Mr. Graaff noted that one of the challenges with regard to cholera control in Afghanistan is the insecurity in parts of the country which make it difficult to carry out timely investigations and responses.
Due to security concerns involving health ministry and UN staff, WHO said that three local NGO staff members were trained in outbreak investigation, including sample collection and treatment.
WHO added that diarrhoeal diseases are endemic to Afghanistan and there is a seasonal increase from July to September. Most of the vulnerability to waterborne diseases comes from contaminated water sources, as only 23 per cent of Afghans have access to safe drinking water.
Source: United Nations
Proper Treatment of Migrants in Saudi Arabia a Must Says UN
The reported deaths of five Ethiopian migrants in a deportation facility in Saudi Arabia has refocused attention on the way asylum-seekers are treated, with the United Nations refugees agency recalling its appeal last month for the kingdom's authorities to stop sending people back strife-torn to Somalia.
"These two cases were not necessarily linked, but certainly, the five deaths in detention were deplorable," Adrian Edwards, spokesperson of the UN High Commissioner for Refugees (UNHCR) told reporters in Geneva.
Asked if an investigation will be carried out with regard to the alleged deaths of the five Ethiopians earlier this week, Mr. Edwards said he believed that the "competent authorities" were looking into the matter.
He said UNHCR had no access to any detention or deportation facilities in Saudi Arabia, adding that the agency was exploring the possibility of being allowed to screen the people in those centres to ensure that those being deported were not in the category of people in need of international protection.
In its statement on 30 July, UNHCR said that in June alone, more than 1,000 Somalis were deported from Saudi Arabia, according to reports from Mogadishu, Somalia's capital. A similar number of Somalis were returned to their country in July.
Monitoring reports indicated that most deportees said they fled Somalia due to conflict, indiscriminate violence and human rights abuses, with most coming from southern and central Somalia, which includes Mogadishu.
UNCHR considers such deportations to be incompatible with agency's guidelines on international protection needs of Somali refugees and asylum-seekers. A majority of those being sent back from Saudi Arabia are women.
In its July statement, UNHCR said that many of the people who had been sent back to Somalia from Saudi Arabia had probably come through Yemen, where most of them were immediately recognized as refugees.
Source: United Nations
"These two cases were not necessarily linked, but certainly, the five deaths in detention were deplorable," Adrian Edwards, spokesperson of the UN High Commissioner for Refugees (UNHCR) told reporters in Geneva.
Asked if an investigation will be carried out with regard to the alleged deaths of the five Ethiopians earlier this week, Mr. Edwards said he believed that the "competent authorities" were looking into the matter.
He said UNHCR had no access to any detention or deportation facilities in Saudi Arabia, adding that the agency was exploring the possibility of being allowed to screen the people in those centres to ensure that those being deported were not in the category of people in need of international protection.
In its statement on 30 July, UNHCR said that in June alone, more than 1,000 Somalis were deported from Saudi Arabia, according to reports from Mogadishu, Somalia's capital. A similar number of Somalis were returned to their country in July.
Monitoring reports indicated that most deportees said they fled Somalia due to conflict, indiscriminate violence and human rights abuses, with most coming from southern and central Somalia, which includes Mogadishu.
UNCHR considers such deportations to be incompatible with agency's guidelines on international protection needs of Somali refugees and asylum-seekers. A majority of those being sent back from Saudi Arabia are women.
In its July statement, UNHCR said that many of the people who had been sent back to Somalia from Saudi Arabia had probably come through Yemen, where most of them were immediately recognized as refugees.
Source: United Nations
Bristol-Myers Squibb and Pfizer Inc Evaluate Unmet Need in Patients with Atrial Fibrillation
Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer (NYSE: PFE) report that preliminary results from the Phase 3 AVERROES clinical trial of the investigational drug apixaban compared with acetylsalicylic acid (ASA, or aspirin) in patients with atrial fibrillation expected to be or demonstrated to be unsuitable for warfarin therapy will be presented at the European Society of Cardiology Congress 2010. The results will be presented during the "Hot Line" session on August 31, 2010, in Stockholm, Sweden.
Atrial fibrillation (AF) is the most common serious chronic arrhythmia, affecting about 4.5 million people in Europe and 2.2 million people in the United States.(1) Patients with AF are at five times greater risk for stroke compared with the general population.(2) Fifteen percent of all strokes are attributable to AF, and one quarter of all strokes in persons older than 80 years are attributable to AF.(1)
In addition to treatments for heart rate and rhythm, treatment guidelines recommend that AF patients at moderate to high risk of stroke receive anticoagulation therapy with a vitamin K antagonist (VKA), such as warfarin.(1) However, surveys of practice patterns in developed countries demonstrate that 40 percent to 50 percent of patients with AF who are at moderate or high risk for stroke do not receive VKA.(1) The most common reason for not treating AF patients with a VKA appears to be concern about bleeding.(1) Difficulties managing and maintaining therapeutic warfarin dosing, as well as the use of other prescription drugs that interfere with warfarin therapy are additional concerns.(1) Currently, guidelines for the management of patients with AF recommend the use of aspirin for those who cannot take oral anticoagulants.(3)
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an investigational oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.
Atrial fibrillation (AF) is the most common serious chronic arrhythmia, affecting about 4.5 million people in Europe and 2.2 million people in the United States.(1) Patients with AF are at five times greater risk for stroke compared with the general population.(2) Fifteen percent of all strokes are attributable to AF, and one quarter of all strokes in persons older than 80 years are attributable to AF.(1)
In addition to treatments for heart rate and rhythm, treatment guidelines recommend that AF patients at moderate to high risk of stroke receive anticoagulation therapy with a vitamin K antagonist (VKA), such as warfarin.(1) However, surveys of practice patterns in developed countries demonstrate that 40 percent to 50 percent of patients with AF who are at moderate or high risk for stroke do not receive VKA.(1) The most common reason for not treating AF patients with a VKA appears to be concern about bleeding.(1) Difficulties managing and maintaining therapeutic warfarin dosing, as well as the use of other prescription drugs that interfere with warfarin therapy are additional concerns.(1) Currently, guidelines for the management of patients with AF recommend the use of aspirin for those who cannot take oral anticoagulants.(3)
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an investigational oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.
A new era for patients with atrial fibrillation - Dabigatran etexilate at the forefront
The European Society of Cardiology (ESC) issued revised practice guidelines for the management of atrial fibrillation (AF), including guidance on the role of a novel oral treatment, dabigatran etexilate, for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). At the same time, Boehringer Ingelheim confirms that the U.S. Food and Drug Administration (FDA) granted a priority review designation for Boehringer Ingelheim's novel oral direct thrombin inhibitor dabigatran etexilate for the prevention of stroke in AF. A priority review designation is given to new drugs that are expected to offer major advances in treatment, or provide a treatment where no adequate therapy exists. An FDA advisory committee will meet on Monday, September 20th, to review and discuss dabigatran etexilate data.
In addition to the US, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive a marketing authorization for dabigatran etexilate in first countries by end of 2010 or beginning of 2011.
RE-LY® study
All applications, including the FDA New Drug Application (NDA) are based on the results of the pivotal Phase III RE-LY® study (Randomized Evaluation of Long-term anticoagulant therapY), published in the New England Journal of Medicine in August 2009, comparing the efficacy and safety of two doses of dabigatran etexilate with warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with atrial fibrillation.(1)
Results from RE-LY ®, the largest AF study completed to date, showed that in patients with AF, dabigatran etexilate 150mg b.i.d. significantly reduced the risk of stroke and systemic embolism by 34% compared to warfarin, with comparable rates of major bleeding. Dabigatran etexilate 110mg b.i.d. demonstrated similar reductions in stroke and systemic embolism while delivering a reduction in major bleeding rates compared to warfarin. Additionally, both doses showed a significant reduction in haemorrhagic stroke and a significant reduction in life threatening, intracranial and total bleeding compared to warfarin.(1)
Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim said, "Boehringer Ingelheim has a long term commitment to the treatment and prevention of stroke. The decision by the US FDA to grant a priority designation review is an important step in making dabigatran etexilate available for patients with atrial fibrillation to prevent them from strokes."
New practice guidelines on atrial fibrillation
Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK and a member of the Task Force writing group for the new ESC Guidelines for the management of atrial fibrillation commented, "The updated guidelines reflect the high need for novel treatments in the prevention of atrial-fibrillation related stroke. Both the personal and economic burden of AF-related stroke is high. Consideration of new prevention therapies will improve the overall standard of care."
Limitations of current therapy
Well-controlled vitamin K antagonist (VKA) therapy (warfarin), currently used for the prevention of stroke in atrial fibrillation, is highly effective in reducing the risk of stroke by approximately two-thirds(2), but is associated with an increased risk of bleeding as well as several limitations. Drug-drug and food interactions as well as the requirement for frequent monitoring result in only about 50% of eligible patients receiving VKA therapy(3) with fewer than half of these controlled within the therapeutic INR range.(4)
Stroke is more likely to be severe and fatal in patients with AF, and those who survive face persistent neurological deficits, persistent disability and poorer functional performance.(5,6)
According to Professor Jonas Oldgren, Associate Professor of Cardiology, Uppsala Clinical Research Centre (which furthermore was one of the coordinating centres in RE-LY®), "Dabigatran etexilate is the first treatment to significantly reduce stroke in patients with atrial fibrillation across all risk groups, when compared to well-controlled warfarin. This novel direct thrombin inhibitor could represent a very important advance in the prevention of stroke in patients with AF for both healthcare professionals and patients alike."
Dr. Oldgren referred to a sub-group analysis presented at this year's American College of Cardiology's annual congress in March, which assessed the rate of stroke and systemic embolism in patients defined as being at low, moderate or high risk of such events by the validated stroke risk stratification score, CHADS 2. The results of this analysis showed that dabigatran etexilate 150mg significantly reduced the number of strokes in patients with AF, irrespective of a patient’s risk profile. Dabigatran etexilate 110mg b.i.d. was associated with significantly lower major bleeding events and both dabigatran doses showed significantly lower intracranial bleeding rates when compared to well-controlled warfarin.(7)
RE-LY® is the largest AF study ever completed (18,113 patients) investigating dabigatran etexilate vs. well controlled warfarin. RE-LY® included patients with at least one risk factor of stroke, representative of a real-world setting. In addition, 50% of enrolled patients were naïve to previous oral anticoagulants, a population who may reflect a more realistic experience with anticoagulants, as they are more likely to represent the patient group with the highest percentages outside of the therapeutic INR range.(1,8)
Up to three million people worldwide suffer strokes related to AF each year,(9-11) which tend to be especially severe and disabling,(10) with half of people dying within one year.(12) Therefore, there is an clear medical need for an effective and safe anticoagulant, without the multiple limitations of VKA therapy.
About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) was a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.
The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).
Compared to well controlled warfarin, dabigatran etexilate showed in the trial:(1)
* Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
* Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
* Significantly lower life threatening and intracranial bleeding with both doses
* Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.
About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80.(13) A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population.(14) People with AF are at increased risk of blood clots, which raises stroke risk by five times.(15,16) Up to 3 million people worldwide suffer strokes related to AF each year. 10-12 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system.(9) AF alone is associated with a cost of up to €13.5 billion across the European Union. 15 Warfarin is the current standard of care for reducing stroke in patients with AF. It is highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting. 17 However in clinical practice, due to the well-known limitations with warfarin only 51% of diagnosed patients with AF at risk of stroke receive warfarin(3) and fewer than half of these are controlled within the narrow therapeutic range.(4)
About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) (18) targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.
Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.
Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.
About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim's clinical trial program to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:
* Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries
* Treatment of acute VTE
* Secondary prevention of VTE
* Secondary prevention of cardiac events in patients with acute coronary syndrome (ACS)
* Stroke prevention in atrial fibrillation (AF).
In addition to the US, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive a marketing authorization for dabigatran etexilate in first countries by end of 2010 or beginning of 2011.
RE-LY® study
All applications, including the FDA New Drug Application (NDA) are based on the results of the pivotal Phase III RE-LY® study (Randomized Evaluation of Long-term anticoagulant therapY), published in the New England Journal of Medicine in August 2009, comparing the efficacy and safety of two doses of dabigatran etexilate with warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with atrial fibrillation.(1)
Results from RE-LY ®, the largest AF study completed to date, showed that in patients with AF, dabigatran etexilate 150mg b.i.d. significantly reduced the risk of stroke and systemic embolism by 34% compared to warfarin, with comparable rates of major bleeding. Dabigatran etexilate 110mg b.i.d. demonstrated similar reductions in stroke and systemic embolism while delivering a reduction in major bleeding rates compared to warfarin. Additionally, both doses showed a significant reduction in haemorrhagic stroke and a significant reduction in life threatening, intracranial and total bleeding compared to warfarin.(1)
Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim said, "Boehringer Ingelheim has a long term commitment to the treatment and prevention of stroke. The decision by the US FDA to grant a priority designation review is an important step in making dabigatran etexilate available for patients with atrial fibrillation to prevent them from strokes."
New practice guidelines on atrial fibrillation
Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK and a member of the Task Force writing group for the new ESC Guidelines for the management of atrial fibrillation commented, "The updated guidelines reflect the high need for novel treatments in the prevention of atrial-fibrillation related stroke. Both the personal and economic burden of AF-related stroke is high. Consideration of new prevention therapies will improve the overall standard of care."
Limitations of current therapy
Well-controlled vitamin K antagonist (VKA) therapy (warfarin), currently used for the prevention of stroke in atrial fibrillation, is highly effective in reducing the risk of stroke by approximately two-thirds(2), but is associated with an increased risk of bleeding as well as several limitations. Drug-drug and food interactions as well as the requirement for frequent monitoring result in only about 50% of eligible patients receiving VKA therapy(3) with fewer than half of these controlled within the therapeutic INR range.(4)
Stroke is more likely to be severe and fatal in patients with AF, and those who survive face persistent neurological deficits, persistent disability and poorer functional performance.(5,6)
According to Professor Jonas Oldgren, Associate Professor of Cardiology, Uppsala Clinical Research Centre (which furthermore was one of the coordinating centres in RE-LY®), "Dabigatran etexilate is the first treatment to significantly reduce stroke in patients with atrial fibrillation across all risk groups, when compared to well-controlled warfarin. This novel direct thrombin inhibitor could represent a very important advance in the prevention of stroke in patients with AF for both healthcare professionals and patients alike."
Dr. Oldgren referred to a sub-group analysis presented at this year's American College of Cardiology's annual congress in March, which assessed the rate of stroke and systemic embolism in patients defined as being at low, moderate or high risk of such events by the validated stroke risk stratification score, CHADS 2. The results of this analysis showed that dabigatran etexilate 150mg significantly reduced the number of strokes in patients with AF, irrespective of a patient’s risk profile. Dabigatran etexilate 110mg b.i.d. was associated with significantly lower major bleeding events and both dabigatran doses showed significantly lower intracranial bleeding rates when compared to well-controlled warfarin.(7)
RE-LY® is the largest AF study ever completed (18,113 patients) investigating dabigatran etexilate vs. well controlled warfarin. RE-LY® included patients with at least one risk factor of stroke, representative of a real-world setting. In addition, 50% of enrolled patients were naïve to previous oral anticoagulants, a population who may reflect a more realistic experience with anticoagulants, as they are more likely to represent the patient group with the highest percentages outside of the therapeutic INR range.(1,8)
Up to three million people worldwide suffer strokes related to AF each year,(9-11) which tend to be especially severe and disabling,(10) with half of people dying within one year.(12) Therefore, there is an clear medical need for an effective and safe anticoagulant, without the multiple limitations of VKA therapy.
About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) was a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.
The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).
Compared to well controlled warfarin, dabigatran etexilate showed in the trial:(1)
* Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
* Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
* Significantly lower life threatening and intracranial bleeding with both doses
* Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.
About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80.(13) A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population.(14) People with AF are at increased risk of blood clots, which raises stroke risk by five times.(15,16) Up to 3 million people worldwide suffer strokes related to AF each year. 10-12 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system.(9) AF alone is associated with a cost of up to €13.5 billion across the European Union. 15 Warfarin is the current standard of care for reducing stroke in patients with AF. It is highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting. 17 However in clinical practice, due to the well-known limitations with warfarin only 51% of diagnosed patients with AF at risk of stroke receive warfarin(3) and fewer than half of these are controlled within the narrow therapeutic range.(4)
About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) (18) targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.
Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.
Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.
About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim's clinical trial program to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:
* Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgeries
* Treatment of acute VTE
* Secondary prevention of VTE
* Secondary prevention of cardiac events in patients with acute coronary syndrome (ACS)
* Stroke prevention in atrial fibrillation (AF).
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