GE Healthcare Announces Phase I Results With Amyloid Imaging Agent GE-067
GE Healthcare, a unit of the General Electric Company (NYSE:GE), announced positive results from a Phase I clinical trial of GE-067, a [18F]-labeled PET diagnostic imaging agent being developed by the company to assist in the detection of brain beta-amyloid. The results, presented today at the International Conference on Alzheimer's Disease, Chicago, USA by the Principal Investigator, Professor Rik Vandenberghe, of the University of Leuven, Belgium, show significantly greater brain uptake of GE-067 in Alzheimer's Disease patients compared with healthy volunteers1. The two hour half-life of the [18F] labeled ligand offers the potential for greater clinical accessibility compared with the research compound [11C] PIB.
Currently, post-mortem diagnosis of Alzheimer's disease (AD) is the "gold standard" of disease confirmation, which offers no possibilities to patients and... their carers while they are alive. A key focus of AD research is to identify in vivo imaging agents that could potentially assist in the diagnosis of the disease while the patient is alive. The ability to demonstrate whether a patient does or does not have amyloid pathology might not only be used to support a clinician's diagnosis, but could in the future be used to aid treatment decisions if any of the amyloid targeted therapies now in development are successfully approved. [11C] PIB is now the most recognised and widely used research tool for imaging amyloid. A recent study2 from the Pittsburgh group of Klunk and Mathis has demonstrated that the in-vivo image seen with a PIB PET scan mirrors the distribution and intensity of amyloid pathology identified at subsequent autopsy. However, the [11C] labeled form of PIB has a short half-life (20-minutes) which hampers its potential as a routine clinical diagnostic agent. GE Healthcare has pioneered the synthesis of a PIB derivative labeled with [18F] in order to help overcome this significant barrier to potential clinical use. The [18F] form of the ligand, with a much longer half-life of 110 minutes, may offer greater clinical utility and wider accessibility to hospitals.
The Phase I study (presented using the chemical number [18F] AH1100690) consisted of 22 subjects who were injected with the agent GE-067. Initially 6 healthy volunteers had whole body scans to determine the radiation dose. A further 8 healthy and 8 probable AD) subjects had cranial scans with significant amounts of uptake being observed in the probable AD brains compared to the healthy volunteers. These initial results suggest that GE-067 could be used to detect amyloid pathology in vivo and potentially contribute towards future diagnostic and treatment algorithms, subject to performance of confirmatory studies.
Don Black, Head of R&D, Medical Diagnostics at GE Healthcare said: "We were excited to see the results from this Phase I study with GE-067 and as a result have initiated a larger study with manufacturing and scanning centres across Europe. We also plan to extend our studies to the United States of America."
Commenting on the results, Rik Vandenberghe, Principal Investigator of the trial and Professor of Neurology at the University of Leuven, Belgium said "The results of this Phase I trial are a very encouraging step forward in our quest to develop a clinically useful diagnostic imaging agent to assist in the early diagnosis of Alzheimer's Disease and directly demonstrate in vivo the presence of abnormal quantities of beta amyloid in an individual's brain. With latest estimates of the incidence of Alzheimer's Disease predicted to quadruple to 106 million by 20503 and with the potential development of amyloid - lowering therapies, there is a critical need for an effective diagnostic product to directly and reliably demonstrate the presence of amyloid deposits as early as possible during the course of the disease and ultimately improve the lives of patients and caregivers."
The PIB series of compounds are licensed by GE Healthcare from The University of Pittsburgh. In 2008, the inventors of PIB, William E. Klunk, MD, PhD, and Chester A. Mathis, PhD, from the University of Pittsburgh, were awarded the prestigious American Academy of Neurology Potamkin Prize for their significant contribution to the imaging of amyloid.
About Alzheimer Disease
Alzheimer's disease is the most common cause of dementia and a leading cause of death worldwide. Latest estimates put the global prevalence at 26.6 million and forecast that by 2050 the prevalence will quadruple, to leave 1 in 85 people worldwide living with the disease3.
References:
1. Phase I study of the 18F-labelled benzothiazole derivative [18F]AH110690 as a biomarker of AD-related brain amyloidosis Rik Vandenberghe1 et al,. Poster Presentation, International Conference on Alzheimer's Disease 2008.
2. Post-mortem correlates of in vivo PIB-PET amyloid imaging in a typical case of Alzheimer's disease Ikonomovic, M.D. et al. Brain 2008 Jun; 131(Pt 6):1630-45.
3. Forecasting the global burden of Alzheimer's disease. R. Brookmeyer, et al. Alzheimer's and Dementia 2007 ,Volume 3 ,Issue 3 ,Pages 186 - 191
About GE Healthcare
GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. Our expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceutical manufacturing technologies is helping clinicians around the world re-imagine new ways to predict, diagnose, inform, treat and monitor disease, so patients can live their lives to the fullest.
GE Healthcare's broad range of products and services enable healthcare providers to better diagnose and treat cancer, heart disease, neurological diseases and other conditions earlier. Our vision for the future is to enable a new "early health" model of care focused on earlier diagnosis, pre-symptomatic disease detection and disease prevention. Headquartered in the United Kingdom, GE Healthcare is a $17 billion unit of General Electric Company (NYSE: GE). Worldwide, GE Healthcare employs more than 46,000 people committed to serving healthcare professionals and their patients in more than 100 countries.
GE Healthcare
Read More..
Currently, post-mortem diagnosis of Alzheimer's disease (AD) is the "gold standard" of disease confirmation, which offers no possibilities to patients and... their carers while they are alive. A key focus of AD research is to identify in vivo imaging agents that could potentially assist in the diagnosis of the disease while the patient is alive. The ability to demonstrate whether a patient does or does not have amyloid pathology might not only be used to support a clinician's diagnosis, but could in the future be used to aid treatment decisions if any of the amyloid targeted therapies now in development are successfully approved. [11C] PIB is now the most recognised and widely used research tool for imaging amyloid. A recent study2 from the Pittsburgh group of Klunk and Mathis has demonstrated that the in-vivo image seen with a PIB PET scan mirrors the distribution and intensity of amyloid pathology identified at subsequent autopsy. However, the [11C] labeled form of PIB has a short half-life (20-minutes) which hampers its potential as a routine clinical diagnostic agent. GE Healthcare has pioneered the synthesis of a PIB derivative labeled with [18F] in order to help overcome this significant barrier to potential clinical use. The [18F] form of the ligand, with a much longer half-life of 110 minutes, may offer greater clinical utility and wider accessibility to hospitals.
The Phase I study (presented using the chemical number [18F] AH1100690) consisted of 22 subjects who were injected with the agent GE-067. Initially 6 healthy volunteers had whole body scans to determine the radiation dose. A further 8 healthy and 8 probable AD) subjects had cranial scans with significant amounts of uptake being observed in the probable AD brains compared to the healthy volunteers. These initial results suggest that GE-067 could be used to detect amyloid pathology in vivo and potentially contribute towards future diagnostic and treatment algorithms, subject to performance of confirmatory studies.
Don Black, Head of R&D, Medical Diagnostics at GE Healthcare said: "We were excited to see the results from this Phase I study with GE-067 and as a result have initiated a larger study with manufacturing and scanning centres across Europe. We also plan to extend our studies to the United States of America."
Commenting on the results, Rik Vandenberghe, Principal Investigator of the trial and Professor of Neurology at the University of Leuven, Belgium said "The results of this Phase I trial are a very encouraging step forward in our quest to develop a clinically useful diagnostic imaging agent to assist in the early diagnosis of Alzheimer's Disease and directly demonstrate in vivo the presence of abnormal quantities of beta amyloid in an individual's brain. With latest estimates of the incidence of Alzheimer's Disease predicted to quadruple to 106 million by 20503 and with the potential development of amyloid - lowering therapies, there is a critical need for an effective diagnostic product to directly and reliably demonstrate the presence of amyloid deposits as early as possible during the course of the disease and ultimately improve the lives of patients and caregivers."
The PIB series of compounds are licensed by GE Healthcare from The University of Pittsburgh. In 2008, the inventors of PIB, William E. Klunk, MD, PhD, and Chester A. Mathis, PhD, from the University of Pittsburgh, were awarded the prestigious American Academy of Neurology Potamkin Prize for their significant contribution to the imaging of amyloid.
About Alzheimer Disease
Alzheimer's disease is the most common cause of dementia and a leading cause of death worldwide. Latest estimates put the global prevalence at 26.6 million and forecast that by 2050 the prevalence will quadruple, to leave 1 in 85 people worldwide living with the disease3.
References:
1. Phase I study of the 18F-labelled benzothiazole derivative [18F]AH110690 as a biomarker of AD-related brain amyloidosis Rik Vandenberghe1 et al,. Poster Presentation, International Conference on Alzheimer's Disease 2008.
2. Post-mortem correlates of in vivo PIB-PET amyloid imaging in a typical case of Alzheimer's disease Ikonomovic, M.D. et al. Brain 2008 Jun; 131(Pt 6):1630-45.
3. Forecasting the global burden of Alzheimer's disease. R. Brookmeyer, et al. Alzheimer's and Dementia 2007 ,Volume 3 ,Issue 3 ,Pages 186 - 191
About GE Healthcare
GE Healthcare provides transformational medical technologies and services that are shaping a new age of patient care. Our expertise in medical imaging and information technologies, medical diagnostics, patient monitoring systems, performance improvement, drug discovery, and biopharmaceutical manufacturing technologies is helping clinicians around the world re-imagine new ways to predict, diagnose, inform, treat and monitor disease, so patients can live their lives to the fullest.
GE Healthcare's broad range of products and services enable healthcare providers to better diagnose and treat cancer, heart disease, neurological diseases and other conditions earlier. Our vision for the future is to enable a new "early health" model of care focused on earlier diagnosis, pre-symptomatic disease detection and disease prevention. Headquartered in the United Kingdom, GE Healthcare is a $17 billion unit of General Electric Company (NYSE: GE). Worldwide, GE Healthcare employs more than 46,000 people committed to serving healthcare professionals and their patients in more than 100 countries.
GE Healthcare
Anavex Presents Neuroprotective Effects Of Anavex 1-41 At The International Conference On Alzheimer's Disease 2008
ANAVEX Life Sciences Corp. (OTCBB: AVXL), a biopharmaceutical company engaged in the discovery and development of novel therapeutics to treat Central Nervous System (CNS) diseases and cancer, presented data from the company's novel compound, ANAVEX 1-41, targeting Alzheimer's disease, at the International Conference on Alzheimer's Disease (ICAD) 2008, Chicago, USA, July 26 to 31, 2008. The compound has a synergistic neuroprotective and anti-apoptotic effect in Alzheimer's disease in animal models using amyloid (beta) 25-35 peptide.
"We are pleased by our continued progress in the development of ANAVEX 1-41, and are excited to be presenting data regarding its potent neuroprotective and... anti-apoptotic properties at such low doses at ICAD," said Dr. Vamvakides, Chief Scientific Officer of ANAVEX. "Based on our pre-clinical studies to date, we continue to believe that ANAVEX 1-41 may offer disease-modifying options that reverse memory and learning deficits and protect nerve cells from death."
The Anavex Life Sciences presentation is entitled: "Neuroprotective effects of activators/agonists of the sigma-1 chaperone protein against amyloid toxicity in a mouse mode". The authors are: Tanguy Maurice (1), Vanessa Villard (1), Johann Meaner (1), Emetine Keller (1), Fanny Malaria (1), Alexandre Vamvakides (2) 1. Inserm U. 710, EPHE, Univ. Montpellier II, Montpellier, France 2. Anavex Life Sciences, Pallini, Greece.
Neuroprotection was attained in the ANAVEX 1-41 compound at very low doses (0,1mg/kg) in mice. At the same doses there was synergy between Sigma-1 receptors and Muscarinic receptors, amplifying the anti-amnesic potential effects, as well as the anti-apoptotic and the anti-oxidative stress potential.
Neuroprotection is the most important component necessary to attain long-term benefits in neurodegenerative diseases. In Alzheimer's disease, neuroprotection is about shielding the neuronal cells in the brain from degeneration or death. Therefore, ANAVEX's potent neuroprotective compound may offer disease-modifying treatment and not merely symptomatic relief from Alzheimer's disease. Moreover, the compound does not target pathologoanatomic hallmarks, such as amyloid-plaques, whose role has turned out to be controversial, since approaches to inhibit them have failed to provide compelling benefit.
Anavex's approach is based on the exploitation of the multiple modulation properties of Sigma-1 receptors, which are as of yet unexploited by the existing drugs in the market. Sigma-1 receptors are proteins that regulate the activity of other different proteins (like IP3 receptors or ER stress sensors) and also of sodium and calcium channels. Moreover, through their modulatory role, Sigma-1 receptors are able to regulate cellular apoptotic processes.
Unlike the challenge of pro-amyloid and anti-amyloid theories of AD, Anavex Life Sciences' SIGMACEPTOR(TM) Discovery Platform sigma-1 activator molecules target neuronal intracellular structures with the goal of preventing neurodegenerative action of disturbed biochemical pathways and channels.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (http://www.anavex.com) is an emerging biopharmaceutical company engaged in the discovery and development of novel drug targets for the treatment of cancer and neurological diseases such as Alzheimer's, epilepsy and depression. The company's proprietary SIGMACEPTOR(TM) Discovery Platform involves the rational design of drug compounds that fulfill specific criteria based on unmet market needs and new scientific advances. Selected drug candidates demonstrate high, non-exclusive affinity for sigma receptors, which are involved in the modulation of multiple cellular biochemical signaling pathways.
ANAVEX's SIGMACEPTOR(TM)-N program involves the development of novel and original drug candidates that target neurological and neurodegenerative diseases (Alzheimer's disease, epilepsy, depression, pain). The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for anti-amnesic, neuroprotective, anti-apoptotic, anti-oxidative, anti-inflammatory, anti-convulsive, anti-depressant and anxiolytic properties. The company believes that oxidative stress, not amyloid-beta, is the cause of Alzheimer's. ANAVEX 1-41 uses sigma receptors, a unique class of receptor molecules, to guard against oxidative stress and repair cells compromised by its effects. So far, through the advanced pre-clinical phase of development, the compound has performed extremely well in well-recognized animal models of Alzheimer's disease, underscoring the promise of this alternative approach to the disease.
ANAVEX SIGMACEPTOR(TM)-C program involves the development of novel and original drug candidates targeting cancer. The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for selective pro-apoptotic, anti-metastatic and low toxicity properties in various types of solid cancers such as colon, prostate, breast and lung. ANAVEX 7-1037 has already demonstrated its ability to significantly delay the growth of cancerous tumors in patient-derived xenografts during advanced pre-clinical studies.
Forward-Looking Statements
Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks and uncertainties inherent in drug discovery and development, which include, without limitation, the potential failure of development candidates to advance through preclinical studies or demonstrate safety and efficacy in clinical testing and the ability to file an IND or commence clinical studies. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
Anavex Life Sciences Corp
Read More..
"We are pleased by our continued progress in the development of ANAVEX 1-41, and are excited to be presenting data regarding its potent neuroprotective and... anti-apoptotic properties at such low doses at ICAD," said Dr. Vamvakides, Chief Scientific Officer of ANAVEX. "Based on our pre-clinical studies to date, we continue to believe that ANAVEX 1-41 may offer disease-modifying options that reverse memory and learning deficits and protect nerve cells from death."
The Anavex Life Sciences presentation is entitled: "Neuroprotective effects of activators/agonists of the sigma-1 chaperone protein against amyloid toxicity in a mouse mode". The authors are: Tanguy Maurice (1), Vanessa Villard (1), Johann Meaner (1), Emetine Keller (1), Fanny Malaria (1), Alexandre Vamvakides (2) 1. Inserm U. 710, EPHE, Univ. Montpellier II, Montpellier, France 2. Anavex Life Sciences, Pallini, Greece.
Neuroprotection was attained in the ANAVEX 1-41 compound at very low doses (0,1mg/kg) in mice. At the same doses there was synergy between Sigma-1 receptors and Muscarinic receptors, amplifying the anti-amnesic potential effects, as well as the anti-apoptotic and the anti-oxidative stress potential.
Neuroprotection is the most important component necessary to attain long-term benefits in neurodegenerative diseases. In Alzheimer's disease, neuroprotection is about shielding the neuronal cells in the brain from degeneration or death. Therefore, ANAVEX's potent neuroprotective compound may offer disease-modifying treatment and not merely symptomatic relief from Alzheimer's disease. Moreover, the compound does not target pathologoanatomic hallmarks, such as amyloid-plaques, whose role has turned out to be controversial, since approaches to inhibit them have failed to provide compelling benefit.
Anavex's approach is based on the exploitation of the multiple modulation properties of Sigma-1 receptors, which are as of yet unexploited by the existing drugs in the market. Sigma-1 receptors are proteins that regulate the activity of other different proteins (like IP3 receptors or ER stress sensors) and also of sodium and calcium channels. Moreover, through their modulatory role, Sigma-1 receptors are able to regulate cellular apoptotic processes.
Unlike the challenge of pro-amyloid and anti-amyloid theories of AD, Anavex Life Sciences' SIGMACEPTOR(TM) Discovery Platform sigma-1 activator molecules target neuronal intracellular structures with the goal of preventing neurodegenerative action of disturbed biochemical pathways and channels.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (http://www.anavex.com) is an emerging biopharmaceutical company engaged in the discovery and development of novel drug targets for the treatment of cancer and neurological diseases such as Alzheimer's, epilepsy and depression. The company's proprietary SIGMACEPTOR(TM) Discovery Platform involves the rational design of drug compounds that fulfill specific criteria based on unmet market needs and new scientific advances. Selected drug candidates demonstrate high, non-exclusive affinity for sigma receptors, which are involved in the modulation of multiple cellular biochemical signaling pathways.
ANAVEX's SIGMACEPTOR(TM)-N program involves the development of novel and original drug candidates that target neurological and neurodegenerative diseases (Alzheimer's disease, epilepsy, depression, pain). The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for anti-amnesic, neuroprotective, anti-apoptotic, anti-oxidative, anti-inflammatory, anti-convulsive, anti-depressant and anxiolytic properties. The company believes that oxidative stress, not amyloid-beta, is the cause of Alzheimer's. ANAVEX 1-41 uses sigma receptors, a unique class of receptor molecules, to guard against oxidative stress and repair cells compromised by its effects. So far, through the advanced pre-clinical phase of development, the compound has performed extremely well in well-recognized animal models of Alzheimer's disease, underscoring the promise of this alternative approach to the disease.
ANAVEX SIGMACEPTOR(TM)-C program involves the development of novel and original drug candidates targeting cancer. The company's lead drug candidates exhibit high, non-exclusive affinity for sigma receptors with strong evidence for selective pro-apoptotic, anti-metastatic and low toxicity properties in various types of solid cancers such as colon, prostate, breast and lung. ANAVEX 7-1037 has already demonstrated its ability to significantly delay the growth of cancerous tumors in patient-derived xenografts during advanced pre-clinical studies.
Forward-Looking Statements
Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks and uncertainties inherent in drug discovery and development, which include, without limitation, the potential failure of development candidates to advance through preclinical studies or demonstrate safety and efficacy in clinical testing and the ability to file an IND or commence clinical studies. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof.
Anavex Life Sciences Corp
First Ever Study On Alzheimer's Disease Treatment In Hispanics Presented At Major Medical Meeting
Eisai Inc. and Pfizer Inc (NYSE: PFE) announced results from a new open-label study that showed Hispanics with mild to moderate Alzheimer's disease (AD) experienced significant improvement in cognition compared to baseline after 12 weeks of treatment with ARICEPT. This is the first clinical trial looking at an AD prescription medication exclusively in Hispanics, and is important given the high risk of AD among this large population. These results are consistent with pivotal ARICEPT studies in the general population and also in studies specific to African Americans, as seen in the 2006 Treatment of Alzheimer's in African American Patients (TAAAP) study. The Evaluating ARICEPT Treatment in Hispanics (EARTH) study was presented at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease and Related Disorders (ICAD).
"We know the Hispanic community is in need of increased education on the benefits of diagnosing and treating AD early," said Dr. Oscar Lopez, professor, department of neurology, University of Pittsburgh, and the first author of the... EARTH poster presented at ICAD. "This news should serve as a call to action for Hispanic families to watch for early signs of AD among their loved ones and speak with a doctor as soon as possible if symptoms are suspected."
This multi-center open-label clinical trial enrolled 106 Hispanic men and women from across the U.S. Patients were at least 50 years of age and had a diagnosis of mild to moderate AD. In order to most accurately measure the efficacy of ARICEPT in Hispanics, unique measurement tools with little language bias were specifically selected for use in the EARTH study. For instance, the Fuld Object Memory Evaluation (FOME) assessment reduces dependence on spoken English, and it has been proven effective in detecting cognitive impairment and in the diagnosis of AD in Spanish-speaking individuals. The Symbol Digit Modality Test (SDMT) is also extremely sensitive for detecting dementia and has minimal cultural bias. A third, commonly used measurement included the Mini-Mental State Examination (MMSE).
The MMSE score, which measures cognitive function, significantly improved from baseline (p<0.0001) with a treatment effect that was similar to that seen in the pivotal studies for ARICEPT. The FOME, which assesses learning and memory through common object recognition, also showed significant improvement with ARICEPT (p=0.0042) in terms of retrieval scores. The FOME storage scores did not show statistically significant improvement from baseline. The SDMT measures speed of mental processing, attention and concentration functions, and also showed significant improvement from baseline (p<0.0001). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). A numeric improvement in NPI total score was observed but did not reach statistical significance; however, the NPI Caregiver Distress scale (NPI-D) total score significantly improved (p=0.0500).
The most common adverse events greater than or equal to five percent were insomnia (9.5 percent), dizziness (7.6 percent), diarrhea (5.7 percent) and nausea (5.7 percent).
"All too often, Hispanics dismiss the symptoms of AD as signs of normal aging and wait years before consulting a doctor," said Yanira Cruz, who has a doctorate in public health and is president and CEO of the National Hispanic Council on Aging (NHCOA), a national organization dedicated to improving the quality of life for Hispanic communities. "This study reminds us of the value of treating AD to slow symptoms of the disease, and I encourage primary care physicians with Hispanic patients to start screening for signs of dementia at a younger age, potentially at 55 or 60 years."
Dr. Cruz urges more attention to diagnosis and treatment of AD among Hispanics and advises family members suspecting AD symptoms in a loved one to visit http://www.losamigosdesumemoria.com to learn more about the disease and complete an online memory screener.
The EARTH study represents Eisai and Pfizer's leadership in understanding the benefits of ARICEPT in multiple populations. The TAAAP study, published in the Journal of the National Medical Association in 2006, found that African Americans with mild to moderate AD and treated with ARICEPT experienced significant improvement in cognition and function. ARICEPT has now been studied in two underserved populations, both with higher prevalence and incidence of AD than the general population.
Alzheimer's Disease in the Hispanic Community
-- There are an estimated 200,000 Hispanics living in the U.S. with AD today, and by 2050, it is estimated that approximately 1.3 million Hispanic Americans will have the disease.
-- Due to language differences and cultural barriers, Hispanics typically wait to see a doctor until they are in a later stage of the disease -- usually three years after symptoms emerge.
-- Many Hispanics living with AD remain undiagnosed and untreated (approximately 40 percent).
-- Hispanics start showing AD symptoms nearly seven years earlier than non-Hispanics.
-- Reasons for increased AD risk in the Hispanic community include the growing senior population (age is the number one risk for disease), higher rates of diabetes and hypertension (known risk factors), and familial risk (genetics and heredity).
-- Hispanic participation in AD clinical trials remains historically low. Information About ARICEPT Treatment in Alzheimer's Disease
ARICEPT is the only AD treatment to be approved in the U.S. for mild, moderate and severe dementia of the Alzheimer's type. While there is no cure for AD, ARICEPT can help slow the progression of symptoms. Extensive data derived from clinical studies with thousands of patients have demonstrated that ARICEPT helps cognition and function.
ARICEPT is an acetylcholinesterase inhibitor and is believed to work by inhibiting the breakdown of acetylcholine, thereby increasing available levels of this chemical in the brain. There is an established association between the loss of acetylcholine, a brain chemical involved in memory and thinking, and AD.
In a progressively degenerative disease such as Alzheimer's, improvement, stabilization or a less-than-expected decline over time is considered a positive response to treatment. These types of responses have been observed in patients treated with ARICEPT in clinical trials for AD. Individual responses to treatment vary, and some patients may not respond.
ARICEPT is well tolerated, but may not be for everyone. People at risk for stomach ulcers or who take certain other medicines should tell their doctors because serious stomach problems, such as bleeding, may get worse. Some people who take ARICEPT may experience fainting. Some people may have nausea, vomiting, diarrhea, bruising, or not sleep well. Some people may have muscle cramps or loss of appetite or may feel tired. In studies these were usually mild and temporary.
About Eisai Inc.
Eisai Inc. is a U.S. pharmaceutical subsidiary of Eisai Co., Ltd., a research-based human health care (hhc) company that discovers, develops and markets products throughout the world. Eisai focuses its efforts in three therapeutic areas: neurology, gastrointestinal disorders and oncology/critical care. Established in 1995 and ranked among the top-20 U.S. pharmaceutical companies (based on retail sales), Eisai Inc. began marketing its first product in the United States in 1997 and has rapidly grown to become an integrated pharmaceutical business with fiscal year 2007 (year ended March 31, 2008) sales of approximately $3 billion, including the results of the acquisition of MGI PHARMA, Inc.
Eisai Inc. employs approximately 1,500 people at its headquarters in Woodcliff Lake, NJ, at its state-of-the-art pharmaceutical production and formulation research and development facility in Research Triangle Park, NC, and in the field. For more information about Eisai, please visit http://www.eisai.com.
About Pfizer Inc
Founded in 1849, Pfizer is the world's largest research-based pharmaceutical company. Pfizer is taking new approaches to advancing better health as it discovers, develops, manufactures and delivers quality, safe and effective prescription medicines to treat and help prevent disease for both people and animals. Pfizer also partners with healthcare providers, governments and local communities around the world to expand access to medicines and to provide better quality health care and health system support. At Pfizer, more than 85,000 colleagues in more than 90 countries work every day to help people stay happier and healthier longer and to reduce the human and economic burden of disease worldwide. For more information visit http://www.pfizer.com.
Pfizer Inc
Read More..
"We know the Hispanic community is in need of increased education on the benefits of diagnosing and treating AD early," said Dr. Oscar Lopez, professor, department of neurology, University of Pittsburgh, and the first author of the... EARTH poster presented at ICAD. "This news should serve as a call to action for Hispanic families to watch for early signs of AD among their loved ones and speak with a doctor as soon as possible if symptoms are suspected."
This multi-center open-label clinical trial enrolled 106 Hispanic men and women from across the U.S. Patients were at least 50 years of age and had a diagnosis of mild to moderate AD. In order to most accurately measure the efficacy of ARICEPT in Hispanics, unique measurement tools with little language bias were specifically selected for use in the EARTH study. For instance, the Fuld Object Memory Evaluation (FOME) assessment reduces dependence on spoken English, and it has been proven effective in detecting cognitive impairment and in the diagnosis of AD in Spanish-speaking individuals. The Symbol Digit Modality Test (SDMT) is also extremely sensitive for detecting dementia and has minimal cultural bias. A third, commonly used measurement included the Mini-Mental State Examination (MMSE).
The MMSE score, which measures cognitive function, significantly improved from baseline (p<0.0001) with a treatment effect that was similar to that seen in the pivotal studies for ARICEPT. The FOME, which assesses learning and memory through common object recognition, also showed significant improvement with ARICEPT (p=0.0042) in terms of retrieval scores. The FOME storage scores did not show statistically significant improvement from baseline. The SDMT measures speed of mental processing, attention and concentration functions, and also showed significant improvement from baseline (p<0.0001). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). A numeric improvement in NPI total score was observed but did not reach statistical significance; however, the NPI Caregiver Distress scale (NPI-D) total score significantly improved (p=0.0500).
The most common adverse events greater than or equal to five percent were insomnia (9.5 percent), dizziness (7.6 percent), diarrhea (5.7 percent) and nausea (5.7 percent).
"All too often, Hispanics dismiss the symptoms of AD as signs of normal aging and wait years before consulting a doctor," said Yanira Cruz, who has a doctorate in public health and is president and CEO of the National Hispanic Council on Aging (NHCOA), a national organization dedicated to improving the quality of life for Hispanic communities. "This study reminds us of the value of treating AD to slow symptoms of the disease, and I encourage primary care physicians with Hispanic patients to start screening for signs of dementia at a younger age, potentially at 55 or 60 years."
Dr. Cruz urges more attention to diagnosis and treatment of AD among Hispanics and advises family members suspecting AD symptoms in a loved one to visit http://www.losamigosdesumemoria.com to learn more about the disease and complete an online memory screener.
The EARTH study represents Eisai and Pfizer's leadership in understanding the benefits of ARICEPT in multiple populations. The TAAAP study, published in the Journal of the National Medical Association in 2006, found that African Americans with mild to moderate AD and treated with ARICEPT experienced significant improvement in cognition and function. ARICEPT has now been studied in two underserved populations, both with higher prevalence and incidence of AD than the general population.
Alzheimer's Disease in the Hispanic Community
-- There are an estimated 200,000 Hispanics living in the U.S. with AD today, and by 2050, it is estimated that approximately 1.3 million Hispanic Americans will have the disease.
-- Due to language differences and cultural barriers, Hispanics typically wait to see a doctor until they are in a later stage of the disease -- usually three years after symptoms emerge.
-- Many Hispanics living with AD remain undiagnosed and untreated (approximately 40 percent).
-- Hispanics start showing AD symptoms nearly seven years earlier than non-Hispanics.
-- Reasons for increased AD risk in the Hispanic community include the growing senior population (age is the number one risk for disease), higher rates of diabetes and hypertension (known risk factors), and familial risk (genetics and heredity).
-- Hispanic participation in AD clinical trials remains historically low. Information About ARICEPT Treatment in Alzheimer's Disease
ARICEPT is the only AD treatment to be approved in the U.S. for mild, moderate and severe dementia of the Alzheimer's type. While there is no cure for AD, ARICEPT can help slow the progression of symptoms. Extensive data derived from clinical studies with thousands of patients have demonstrated that ARICEPT helps cognition and function.
ARICEPT is an acetylcholinesterase inhibitor and is believed to work by inhibiting the breakdown of acetylcholine, thereby increasing available levels of this chemical in the brain. There is an established association between the loss of acetylcholine, a brain chemical involved in memory and thinking, and AD.
In a progressively degenerative disease such as Alzheimer's, improvement, stabilization or a less-than-expected decline over time is considered a positive response to treatment. These types of responses have been observed in patients treated with ARICEPT in clinical trials for AD. Individual responses to treatment vary, and some patients may not respond.
ARICEPT is well tolerated, but may not be for everyone. People at risk for stomach ulcers or who take certain other medicines should tell their doctors because serious stomach problems, such as bleeding, may get worse. Some people who take ARICEPT may experience fainting. Some people may have nausea, vomiting, diarrhea, bruising, or not sleep well. Some people may have muscle cramps or loss of appetite or may feel tired. In studies these were usually mild and temporary.
About Eisai Inc.
Eisai Inc. is a U.S. pharmaceutical subsidiary of Eisai Co., Ltd., a research-based human health care (hhc) company that discovers, develops and markets products throughout the world. Eisai focuses its efforts in three therapeutic areas: neurology, gastrointestinal disorders and oncology/critical care. Established in 1995 and ranked among the top-20 U.S. pharmaceutical companies (based on retail sales), Eisai Inc. began marketing its first product in the United States in 1997 and has rapidly grown to become an integrated pharmaceutical business with fiscal year 2007 (year ended March 31, 2008) sales of approximately $3 billion, including the results of the acquisition of MGI PHARMA, Inc.
Eisai Inc. employs approximately 1,500 people at its headquarters in Woodcliff Lake, NJ, at its state-of-the-art pharmaceutical production and formulation research and development facility in Research Triangle Park, NC, and in the field. For more information about Eisai, please visit http://www.eisai.com.
About Pfizer Inc
Founded in 1849, Pfizer is the world's largest research-based pharmaceutical company. Pfizer is taking new approaches to advancing better health as it discovers, develops, manufactures and delivers quality, safe and effective prescription medicines to treat and help prevent disease for both people and animals. Pfizer also partners with healthcare providers, governments and local communities around the world to expand access to medicines and to provide better quality health care and health system support. At Pfizer, more than 85,000 colleagues in more than 90 countries work every day to help people stay happier and healthier longer and to reduce the human and economic burden of disease worldwide. For more information visit http://www.pfizer.com.
Pfizer Inc
Diverse Approaches To Alzheimer's Therapies Continue To Show Progress At ICAD
Results from clinical trials of three potential Alzheimer's therapies raise hope for new and better treatments of the disease, according to data reported today at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) in Chicago.
A related study showed that taking antidementia drugs appears to have a positive impact on extending lifespan in those with Alzheimer's.
These reports included:
Eighteen-month data from... an open-label extension of a pivotal trial of Dimebon (Medivation) in mild to moderate Alzheimer's.
-- Nine-month data from an interim analysis of the first U.S. Phase II trial of intravenous immunoglobulin, or IVIg (Baxter), in Alzheimer's.
-- Results of a Phase II study of a monoclonal antibody (LY2062430, Lilly) in mild to moderate Alzheimer's.
-- Research suggesting that persistent antidementia drug use increases survival in people with Alzheimer's.
"Therapies targeting amyloid in Alzheimer's disease must continue to be thoroughly tested," said William Thies, PhD, Alzheimer's Association vice president for Medical and Scientific Relations. "At the same time, we know that Alzheimer's is a complex disease and that better treatments and preventions will likely also be complex, so we must investigate every promising drug target looking eventually towards the possibility of a multi-strategy approach."
18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer's
In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behavior in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.
One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.
Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.
Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.
"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."
"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.
First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer's
IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.
Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Weill Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.
Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.
In the total group, the researchers found statistically significant differences favoring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favoring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favored IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.
When the results for each dose were analyzed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.
Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioral disturbances in placebo-treated patients than those who received IVIg.
"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect. Additional studies may be required."
Phase II Immunotherapy Trial with LY2062430 in Mild to Moderate Alzheimer's
Previous research has shown that antibodies that bind to beta amyloid can be given intravenously. By binding to beta amyloid and increasing the rate of its removal from the body, these antibody infusions may slow the progression of Alzheimer's.
Eric Siemers, MD, Medical Director of the Alzheimer's Disease Research Team at Eli Lilly and Company, and colleagues conducted a Phase II trial of a monoclonal antibody, known as LY2062430, that binds to the mid-domain of beta amyloid.
Fifty-two (52) people with mild to moderate Alzheimer's and 16 volunteer subjects were studied. Alzheimer's patients received 12 weekly infusions of placebo or antibody (100 mg every 4 weeks, 100 mg once per week, 400 mg every 4 weeks or 400 mg once per week). Volunteers received a single 100 mg dose of antibody. Safety assessments included brain imaging using magnetic resonance imaging (MRI) and examination of cerebrospinal fluid (CSF, a fluid normally present around the brain and spinal cord). In an optional sub-study, 24 Alzheimer's patients and 13 volunteers underwent a type of brain imaging known as SPECT using a tracer (known as IMPY) that measures the amount of amyloid plaque present in the brain. Measures of symptom severity were obtained in all AD patients using the Alzheimer's Disease Assessment Scale - Cognition (ADAS-cog).
The researchers found that following administration of the antibody, the amount of beta amyloid in blood increased substantially after the antibody bound to the beta amyloid protein. A small amount of the antibody enters the CSF, and in the Alzheimer's patients beta amyloid also increased in CSF, similarly bound to the antibody. For patients treated with 400 mg of the antibody, the amount of the type of beta amyloid primarily found in plaque (known as AB1-42) that appeared in the blood correlated with the amount of amyloid plaque in the brains based on IMPY scans (r=0.65, p=0.02). According to Siemers, this finding suggests that some of the beta amyloid protein present in plaque moves to blood after treatment with the antibody.
Certain other types of beta amyloid thought to be primarily or exclusively found in amyloid plaque are also increased in blood and CSF of study participants. The antibody produced no change in cognitive scores or in the total amount of amyloid plaque based on IMPY scans. Siemers said that this was expected in a study of this duration.
According to the researchers, brain imaging using MRI and CSF safety assessments showed no evidence of inflammation, bleeding or other side effects throughout the trial. No side effects were identified that appeared to be related to antibody treatment.
"We saw an increase in amyloid beta, which is thought to be bound to LY2062430, in both the blood and cerebrospinal fluid of study participants," Siemers said. "Additionally, after treatment we found a correlation between beta amyloid in blood and the amount of amyloid plaque in brain as determined by IMPY imaging, as well as an increase in blood and CSF in certain types of beta amyloid found in plaques. These biomarker data suggest that amyloid plaques in the brain may begin to 'dissolve' after 12 weeks of treatment with this antibody. We're now planning a Phase III clinical trial of this drug to be started in 2009."
Antidementia Drugs Contribute to Longer Life in People with Alzheimer's
Survival (life span) in people with Alzheimer's is recognized to be shorter than what is expected in cognitively normal seniors and is recognized to be influenced by several factors including age, disease severity, general debility, and gender. Approved antidementia drugs have been shown help with the symptoms of Alzheimer's but their influence on life span is not known.
At ICAD 2008, Susan Rountree, MD, of the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston, Texas, reported on a study of the persistent use of antidementia drugs and their influence on survival.
The researchers followed 641 people diagnosed with Alzheimer's at an academic medical clinic between 1989 and 2005. These individuals had been on drug therapy over the course of their Alzheimer's for variable amounts of time and the majority had used one or more of the commercially available antidementia drugs (donepezil, galantamine, rivastigmine, tacrine, or memantine).
Total years on medication was divided by the total years of disease symptoms to determine a persistency score for each individual. Participants were divided into four groups (1st, 2nd, 3rd, 4th quartiles) ranging from the lowest to highest persistency scores and the researchers compared life span among the groups after adjustment for a variety of factors generally recognized to influence survival. The 1st quartile took drug less than 33 percent of the time, 2nd quartile = 34-55 percent of the time, 3rd quartile = 56-70 percent of the time, and the 4th quartile = 71-99 percent of the time.
Over the entire course of the study, 12 percent of participants never took any antidementia drugs. Fifty-three (53) percent of the participants died.
The researchers found an inverse and statistically significant relationship between the overall risk of death and the persistency of drug use. Those in the lowest persistency group (1st quartile) were 2.4 times more likely to die than those in the highest persistency group (4th quartile). Those with intermediate drug exposure had increased risk of death of 2.2 times (2nd quartile) and 1.5 times (3rd quartile) compared to the most persistent users. More persistent therapy was associated with a longer median survival time; the median survival between the lowest quartile group and the most persistent users was 3.12 years.
"In our study, people with Alzheimer's who took antidementia drugs more persistently lived longer than those who took the medications for shorter time intervals," Rountree said. "In an earlier study involving this group, we reported that persistency of treatment was also associated with long term cognitive and functional benefits. Persistent drug therapy appears to help Alzheimer's patients live longer and the mechanism may be related to overall improvement of cognition and function resulting from current symptomatic therapies."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Jeffrey Cummings. "18-Month data from an open-label extension of a one-year controlled trial of dimebon in patient with mild-to-moderate Alzheimer's disease." (Funder: Medivation)
-- Diamanto Tsakanikas. - "Effects of uninterrupted intravenous immunoglobulin treatment of Alzheimer's disease for 9 months." (Funder: Baxter International)
-- Eric R. Siemers. - "Safety, tolerability and biomarker effects of an Abeta monoclonal antibody administered to patients with Alzheimer's disease." (Funder: Eli Lilly and Company)
-- Susan Rountree. - "Persistent Antidementia Drug Treatment and Survival in an Alzheimer's Disease Cohort." (Funders: Forest Research Institute and The Cynthia and George Mitchell Foundation)
All materials to be presented at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of date/time in advance.
Alzheimer's Association
Read More..
A related study showed that taking antidementia drugs appears to have a positive impact on extending lifespan in those with Alzheimer's.
These reports included:
Eighteen-month data from... an open-label extension of a pivotal trial of Dimebon (Medivation) in mild to moderate Alzheimer's.
-- Nine-month data from an interim analysis of the first U.S. Phase II trial of intravenous immunoglobulin, or IVIg (Baxter), in Alzheimer's.
-- Results of a Phase II study of a monoclonal antibody (LY2062430, Lilly) in mild to moderate Alzheimer's.
-- Research suggesting that persistent antidementia drug use increases survival in people with Alzheimer's.
"Therapies targeting amyloid in Alzheimer's disease must continue to be thoroughly tested," said William Thies, PhD, Alzheimer's Association vice president for Medical and Scientific Relations. "At the same time, we know that Alzheimer's is a complex disease and that better treatments and preventions will likely also be complex, so we must investigate every promising drug target looking eventually towards the possibility of a multi-strategy approach."
18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer's
In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behavior in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.
One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.
Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.
Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.
"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."
"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.
First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer's
IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.
Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Weill Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.
Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.
In the total group, the researchers found statistically significant differences favoring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favoring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favored IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.
When the results for each dose were analyzed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.
Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioral disturbances in placebo-treated patients than those who received IVIg.
"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect. Additional studies may be required."
Phase II Immunotherapy Trial with LY2062430 in Mild to Moderate Alzheimer's
Previous research has shown that antibodies that bind to beta amyloid can be given intravenously. By binding to beta amyloid and increasing the rate of its removal from the body, these antibody infusions may slow the progression of Alzheimer's.
Eric Siemers, MD, Medical Director of the Alzheimer's Disease Research Team at Eli Lilly and Company, and colleagues conducted a Phase II trial of a monoclonal antibody, known as LY2062430, that binds to the mid-domain of beta amyloid.
Fifty-two (52) people with mild to moderate Alzheimer's and 16 volunteer subjects were studied. Alzheimer's patients received 12 weekly infusions of placebo or antibody (100 mg every 4 weeks, 100 mg once per week, 400 mg every 4 weeks or 400 mg once per week). Volunteers received a single 100 mg dose of antibody. Safety assessments included brain imaging using magnetic resonance imaging (MRI) and examination of cerebrospinal fluid (CSF, a fluid normally present around the brain and spinal cord). In an optional sub-study, 24 Alzheimer's patients and 13 volunteers underwent a type of brain imaging known as SPECT using a tracer (known as IMPY) that measures the amount of amyloid plaque present in the brain. Measures of symptom severity were obtained in all AD patients using the Alzheimer's Disease Assessment Scale - Cognition (ADAS-cog).
The researchers found that following administration of the antibody, the amount of beta amyloid in blood increased substantially after the antibody bound to the beta amyloid protein. A small amount of the antibody enters the CSF, and in the Alzheimer's patients beta amyloid also increased in CSF, similarly bound to the antibody. For patients treated with 400 mg of the antibody, the amount of the type of beta amyloid primarily found in plaque (known as AB1-42) that appeared in the blood correlated with the amount of amyloid plaque in the brains based on IMPY scans (r=0.65, p=0.02). According to Siemers, this finding suggests that some of the beta amyloid protein present in plaque moves to blood after treatment with the antibody.
Certain other types of beta amyloid thought to be primarily or exclusively found in amyloid plaque are also increased in blood and CSF of study participants. The antibody produced no change in cognitive scores or in the total amount of amyloid plaque based on IMPY scans. Siemers said that this was expected in a study of this duration.
According to the researchers, brain imaging using MRI and CSF safety assessments showed no evidence of inflammation, bleeding or other side effects throughout the trial. No side effects were identified that appeared to be related to antibody treatment.
"We saw an increase in amyloid beta, which is thought to be bound to LY2062430, in both the blood and cerebrospinal fluid of study participants," Siemers said. "Additionally, after treatment we found a correlation between beta amyloid in blood and the amount of amyloid plaque in brain as determined by IMPY imaging, as well as an increase in blood and CSF in certain types of beta amyloid found in plaques. These biomarker data suggest that amyloid plaques in the brain may begin to 'dissolve' after 12 weeks of treatment with this antibody. We're now planning a Phase III clinical trial of this drug to be started in 2009."
Antidementia Drugs Contribute to Longer Life in People with Alzheimer's
Survival (life span) in people with Alzheimer's is recognized to be shorter than what is expected in cognitively normal seniors and is recognized to be influenced by several factors including age, disease severity, general debility, and gender. Approved antidementia drugs have been shown help with the symptoms of Alzheimer's but their influence on life span is not known.
At ICAD 2008, Susan Rountree, MD, of the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston, Texas, reported on a study of the persistent use of antidementia drugs and their influence on survival.
The researchers followed 641 people diagnosed with Alzheimer's at an academic medical clinic between 1989 and 2005. These individuals had been on drug therapy over the course of their Alzheimer's for variable amounts of time and the majority had used one or more of the commercially available antidementia drugs (donepezil, galantamine, rivastigmine, tacrine, or memantine).
Total years on medication was divided by the total years of disease symptoms to determine a persistency score for each individual. Participants were divided into four groups (1st, 2nd, 3rd, 4th quartiles) ranging from the lowest to highest persistency scores and the researchers compared life span among the groups after adjustment for a variety of factors generally recognized to influence survival. The 1st quartile took drug less than 33 percent of the time, 2nd quartile = 34-55 percent of the time, 3rd quartile = 56-70 percent of the time, and the 4th quartile = 71-99 percent of the time.
Over the entire course of the study, 12 percent of participants never took any antidementia drugs. Fifty-three (53) percent of the participants died.
The researchers found an inverse and statistically significant relationship between the overall risk of death and the persistency of drug use. Those in the lowest persistency group (1st quartile) were 2.4 times more likely to die than those in the highest persistency group (4th quartile). Those with intermediate drug exposure had increased risk of death of 2.2 times (2nd quartile) and 1.5 times (3rd quartile) compared to the most persistent users. More persistent therapy was associated with a longer median survival time; the median survival between the lowest quartile group and the most persistent users was 3.12 years.
"In our study, people with Alzheimer's who took antidementia drugs more persistently lived longer than those who took the medications for shorter time intervals," Rountree said. "In an earlier study involving this group, we reported that persistency of treatment was also associated with long term cognitive and functional benefits. Persistent drug therapy appears to help Alzheimer's patients live longer and the mechanism may be related to overall improvement of cognition and function resulting from current symptomatic therapies."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Jeffrey Cummings. "18-Month data from an open-label extension of a one-year controlled trial of dimebon in patient with mild-to-moderate Alzheimer's disease." (Funder: Medivation)
-- Diamanto Tsakanikas. - "Effects of uninterrupted intravenous immunoglobulin treatment of Alzheimer's disease for 9 months." (Funder: Baxter International)
-- Eric R. Siemers. - "Safety, tolerability and biomarker effects of an Abeta monoclonal antibody administered to patients with Alzheimer's disease." (Funder: Eli Lilly and Company)
-- Susan Rountree. - "Persistent Antidementia Drug Treatment and Survival in an Alzheimer's Disease Cohort." (Funders: Forest Research Institute and The Cynthia and George Mitchell Foundation)
All materials to be presented at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of date/time in advance.
Alzheimer's Association
Diverse Approaches To Alzheimer's Therapies Continue To Show Progress At ICAD
Results from clinical trials of three potential Alzheimer's therapies raise hope for new and better treatments of the disease, according to data reported today at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) in Chicago.
A related study showed that taking antidementia drugs appears to have a positive impact on extending lifespan in those with Alzheimer's.
These reports included:
Eighteen-month data from... an open-label extension of a pivotal trial of Dimebon (Medivation) in mild to moderate Alzheimer's.
-- Nine-month data from an interim analysis of the first U.S. Phase II trial of intravenous immunoglobulin, or IVIg (Baxter), in Alzheimer's.
-- Results of a Phase II study of a monoclonal antibody (LY2062430, Lilly) in mild to moderate Alzheimer's.
-- Research suggesting that persistent antidementia drug use increases survival in people with Alzheimer's.
"Therapies targeting amyloid in Alzheimer's disease must continue to be thoroughly tested," said William Thies, PhD, Alzheimer's Association vice president for Medical and Scientific Relations. "At the same time, we know that Alzheimer's is a complex disease and that better treatments and preventions will likely also be complex, so we must investigate every promising drug target looking eventually towards the possibility of a multi-strategy approach."
18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer's
In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behavior in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.
One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.
Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.
Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.
"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."
"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.
First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer's
IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.
Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Weill Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.
Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.
In the total group, the researchers found statistically significant differences favoring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favoring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favored IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.
When the results for each dose were analyzed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.
Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioral disturbances in placebo-treated patients than those who received IVIg.
"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect. Additional studies may be required."
Phase II Immunotherapy Trial with LY2062430 in Mild to Moderate Alzheimer's
Previous research has shown that antibodies that bind to beta amyloid can be given intravenously. By binding to beta amyloid and increasing the rate of its removal from the body, these antibody infusions may slow the progression of Alzheimer's.
Eric Siemers, MD, Medical Director of the Alzheimer's Disease Research Team at Eli Lilly and Company, and colleagues conducted a Phase II trial of a monoclonal antibody, known as LY2062430, that binds to the mid-domain of beta amyloid.
Fifty-two (52) people with mild to moderate Alzheimer's and 16 volunteer subjects were studied. Alzheimer's patients received 12 weekly infusions of placebo or antibody (100 mg every 4 weeks, 100 mg once per week, 400 mg every 4 weeks or 400 mg once per week). Volunteers received a single 100 mg dose of antibody. Safety assessments included brain imaging using magnetic resonance imaging (MRI) and examination of cerebrospinal fluid (CSF, a fluid normally present around the brain and spinal cord). In an optional sub-study, 24 Alzheimer's patients and 13 volunteers underwent a type of brain imaging known as SPECT using a tracer (known as IMPY) that measures the amount of amyloid plaque present in the brain. Measures of symptom severity were obtained in all AD patients using the Alzheimer's Disease Assessment Scale - Cognition (ADAS-cog).
The researchers found that following administration of the antibody, the amount of beta amyloid in blood increased substantially after the antibody bound to the beta amyloid protein. A small amount of the antibody enters the CSF, and in the Alzheimer's patients beta amyloid also increased in CSF, similarly bound to the antibody. For patients treated with 400 mg of the antibody, the amount of the type of beta amyloid primarily found in plaque (known as AB1-42) that appeared in the blood correlated with the amount of amyloid plaque in the brains based on IMPY scans (r=0.65, p=0.02). According to Siemers, this finding suggests that some of the beta amyloid protein present in plaque moves to blood after treatment with the antibody.
Certain other types of beta amyloid thought to be primarily or exclusively found in amyloid plaque are also increased in blood and CSF of study participants. The antibody produced no change in cognitive scores or in the total amount of amyloid plaque based on IMPY scans. Siemers said that this was expected in a study of this duration.
According to the researchers, brain imaging using MRI and CSF safety assessments showed no evidence of inflammation, bleeding or other side effects throughout the trial. No side effects were identified that appeared to be related to antibody treatment.
"We saw an increase in amyloid beta, which is thought to be bound to LY2062430, in both the blood and cerebrospinal fluid of study participants," Siemers said. "Additionally, after treatment we found a correlation between beta amyloid in blood and the amount of amyloid plaque in brain as determined by IMPY imaging, as well as an increase in blood and CSF in certain types of beta amyloid found in plaques. These biomarker data suggest that amyloid plaques in the brain may begin to 'dissolve' after 12 weeks of treatment with this antibody. We're now planning a Phase III clinical trial of this drug to be started in 2009."
Antidementia Drugs Contribute to Longer Life in People with Alzheimer's
Survival (life span) in people with Alzheimer's is recognized to be shorter than what is expected in cognitively normal seniors and is recognized to be influenced by several factors including age, disease severity, general debility, and gender. Approved antidementia drugs have been shown help with the symptoms of Alzheimer's but their influence on life span is not known.
At ICAD 2008, Susan Rountree, MD, of the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston, Texas, reported on a study of the persistent use of antidementia drugs and their influence on survival.
The researchers followed 641 people diagnosed with Alzheimer's at an academic medical clinic between 1989 and 2005. These individuals had been on drug therapy over the course of their Alzheimer's for variable amounts of time and the majority had used one or more of the commercially available antidementia drugs (donepezil, galantamine, rivastigmine, tacrine, or memantine).
Total years on medication was divided by the total years of disease symptoms to determine a persistency score for each individual. Participants were divided into four groups (1st, 2nd, 3rd, 4th quartiles) ranging from the lowest to highest persistency scores and the researchers compared life span among the groups after adjustment for a variety of factors generally recognized to influence survival. The 1st quartile took drug less than 33 percent of the time, 2nd quartile = 34-55 percent of the time, 3rd quartile = 56-70 percent of the time, and the 4th quartile = 71-99 percent of the time.
Over the entire course of the study, 12 percent of participants never took any antidementia drugs. Fifty-three (53) percent of the participants died.
The researchers found an inverse and statistically significant relationship between the overall risk of death and the persistency of drug use. Those in the lowest persistency group (1st quartile) were 2.4 times more likely to die than those in the highest persistency group (4th quartile). Those with intermediate drug exposure had increased risk of death of 2.2 times (2nd quartile) and 1.5 times (3rd quartile) compared to the most persistent users. More persistent therapy was associated with a longer median survival time; the median survival between the lowest quartile group and the most persistent users was 3.12 years.
"In our study, people with Alzheimer's who took antidementia drugs more persistently lived longer than those who took the medications for shorter time intervals," Rountree said. "In an earlier study involving this group, we reported that persistency of treatment was also associated with long term cognitive and functional benefits. Persistent drug therapy appears to help Alzheimer's patients live longer and the mechanism may be related to overall improvement of cognition and function resulting from current symptomatic therapies."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Jeffrey Cummings. "18-Month data from an open-label extension of a one-year controlled trial of dimebon in patient with mild-to-moderate Alzheimer's disease." (Funder: Medivation)
-- Diamanto Tsakanikas. - "Effects of uninterrupted intravenous immunoglobulin treatment of Alzheimer's disease for 9 months." (Funder: Baxter International)
-- Eric R. Siemers. - "Safety, tolerability and biomarker effects of an Abeta monoclonal antibody administered to patients with Alzheimer's disease." (Funder: Eli Lilly and Company)
-- Susan Rountree. - "Persistent Antidementia Drug Treatment and Survival in an Alzheimer's Disease Cohort." (Funders: Forest Research Institute and The Cynthia and George Mitchell Foundation)
All materials to be presented at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of date/time in advance.
Alzheimer's Association
Read More..
A related study showed that taking antidementia drugs appears to have a positive impact on extending lifespan in those with Alzheimer's.
These reports included:
Eighteen-month data from... an open-label extension of a pivotal trial of Dimebon (Medivation) in mild to moderate Alzheimer's.
-- Nine-month data from an interim analysis of the first U.S. Phase II trial of intravenous immunoglobulin, or IVIg (Baxter), in Alzheimer's.
-- Results of a Phase II study of a monoclonal antibody (LY2062430, Lilly) in mild to moderate Alzheimer's.
-- Research suggesting that persistent antidementia drug use increases survival in people with Alzheimer's.
"Therapies targeting amyloid in Alzheimer's disease must continue to be thoroughly tested," said William Thies, PhD, Alzheimer's Association vice president for Medical and Scientific Relations. "At the same time, we know that Alzheimer's is a complex disease and that better treatments and preventions will likely also be complex, so we must investigate every promising drug target looking eventually towards the possibility of a multi-strategy approach."
18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer's
In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behavior in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.
One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.
Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.
Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.
"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."
"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.
First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer's
IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.
Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Weill Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.
Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.
In the total group, the researchers found statistically significant differences favoring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favoring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favored IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.
When the results for each dose were analyzed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.
Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioral disturbances in placebo-treated patients than those who received IVIg.
"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect. Additional studies may be required."
Phase II Immunotherapy Trial with LY2062430 in Mild to Moderate Alzheimer's
Previous research has shown that antibodies that bind to beta amyloid can be given intravenously. By binding to beta amyloid and increasing the rate of its removal from the body, these antibody infusions may slow the progression of Alzheimer's.
Eric Siemers, MD, Medical Director of the Alzheimer's Disease Research Team at Eli Lilly and Company, and colleagues conducted a Phase II trial of a monoclonal antibody, known as LY2062430, that binds to the mid-domain of beta amyloid.
Fifty-two (52) people with mild to moderate Alzheimer's and 16 volunteer subjects were studied. Alzheimer's patients received 12 weekly infusions of placebo or antibody (100 mg every 4 weeks, 100 mg once per week, 400 mg every 4 weeks or 400 mg once per week). Volunteers received a single 100 mg dose of antibody. Safety assessments included brain imaging using magnetic resonance imaging (MRI) and examination of cerebrospinal fluid (CSF, a fluid normally present around the brain and spinal cord). In an optional sub-study, 24 Alzheimer's patients and 13 volunteers underwent a type of brain imaging known as SPECT using a tracer (known as IMPY) that measures the amount of amyloid plaque present in the brain. Measures of symptom severity were obtained in all AD patients using the Alzheimer's Disease Assessment Scale - Cognition (ADAS-cog).
The researchers found that following administration of the antibody, the amount of beta amyloid in blood increased substantially after the antibody bound to the beta amyloid protein. A small amount of the antibody enters the CSF, and in the Alzheimer's patients beta amyloid also increased in CSF, similarly bound to the antibody. For patients treated with 400 mg of the antibody, the amount of the type of beta amyloid primarily found in plaque (known as AB1-42) that appeared in the blood correlated with the amount of amyloid plaque in the brains based on IMPY scans (r=0.65, p=0.02). According to Siemers, this finding suggests that some of the beta amyloid protein present in plaque moves to blood after treatment with the antibody.
Certain other types of beta amyloid thought to be primarily or exclusively found in amyloid plaque are also increased in blood and CSF of study participants. The antibody produced no change in cognitive scores or in the total amount of amyloid plaque based on IMPY scans. Siemers said that this was expected in a study of this duration.
According to the researchers, brain imaging using MRI and CSF safety assessments showed no evidence of inflammation, bleeding or other side effects throughout the trial. No side effects were identified that appeared to be related to antibody treatment.
"We saw an increase in amyloid beta, which is thought to be bound to LY2062430, in both the blood and cerebrospinal fluid of study participants," Siemers said. "Additionally, after treatment we found a correlation between beta amyloid in blood and the amount of amyloid plaque in brain as determined by IMPY imaging, as well as an increase in blood and CSF in certain types of beta amyloid found in plaques. These biomarker data suggest that amyloid plaques in the brain may begin to 'dissolve' after 12 weeks of treatment with this antibody. We're now planning a Phase III clinical trial of this drug to be started in 2009."
Antidementia Drugs Contribute to Longer Life in People with Alzheimer's
Survival (life span) in people with Alzheimer's is recognized to be shorter than what is expected in cognitively normal seniors and is recognized to be influenced by several factors including age, disease severity, general debility, and gender. Approved antidementia drugs have been shown help with the symptoms of Alzheimer's but their influence on life span is not known.
At ICAD 2008, Susan Rountree, MD, of the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston, Texas, reported on a study of the persistent use of antidementia drugs and their influence on survival.
The researchers followed 641 people diagnosed with Alzheimer's at an academic medical clinic between 1989 and 2005. These individuals had been on drug therapy over the course of their Alzheimer's for variable amounts of time and the majority had used one or more of the commercially available antidementia drugs (donepezil, galantamine, rivastigmine, tacrine, or memantine).
Total years on medication was divided by the total years of disease symptoms to determine a persistency score for each individual. Participants were divided into four groups (1st, 2nd, 3rd, 4th quartiles) ranging from the lowest to highest persistency scores and the researchers compared life span among the groups after adjustment for a variety of factors generally recognized to influence survival. The 1st quartile took drug less than 33 percent of the time, 2nd quartile = 34-55 percent of the time, 3rd quartile = 56-70 percent of the time, and the 4th quartile = 71-99 percent of the time.
Over the entire course of the study, 12 percent of participants never took any antidementia drugs. Fifty-three (53) percent of the participants died.
The researchers found an inverse and statistically significant relationship between the overall risk of death and the persistency of drug use. Those in the lowest persistency group (1st quartile) were 2.4 times more likely to die than those in the highest persistency group (4th quartile). Those with intermediate drug exposure had increased risk of death of 2.2 times (2nd quartile) and 1.5 times (3rd quartile) compared to the most persistent users. More persistent therapy was associated with a longer median survival time; the median survival between the lowest quartile group and the most persistent users was 3.12 years.
"In our study, people with Alzheimer's who took antidementia drugs more persistently lived longer than those who took the medications for shorter time intervals," Rountree said. "In an earlier study involving this group, we reported that persistency of treatment was also associated with long term cognitive and functional benefits. Persistent drug therapy appears to help Alzheimer's patients live longer and the mechanism may be related to overall improvement of cognition and function resulting from current symptomatic therapies."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Jeffrey Cummings. "18-Month data from an open-label extension of a one-year controlled trial of dimebon in patient with mild-to-moderate Alzheimer's disease." (Funder: Medivation)
-- Diamanto Tsakanikas. - "Effects of uninterrupted intravenous immunoglobulin treatment of Alzheimer's disease for 9 months." (Funder: Baxter International)
-- Eric R. Siemers. - "Safety, tolerability and biomarker effects of an Abeta monoclonal antibody administered to patients with Alzheimer's disease." (Funder: Eli Lilly and Company)
-- Susan Rountree. - "Persistent Antidementia Drug Treatment and Survival in an Alzheimer's Disease Cohort." (Funders: Forest Research Institute and The Cynthia and George Mitchell Foundation)
All materials to be presented at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of date/time in advance.
Alzheimer's Association
Lifestyle Factors Contribute To Lowering And Raising Risk Of Alzheimer's Disease
A new study suggests that those who are unmarried or not living with a partner in midlife could have an increased risk of developing Alzheimer's disease, according to research reported today at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008), in Chicago.
Additional research on Alzheimer risk factors presented at ICAD 2008 indicates that people who ruminate, or repeatedly think about their problems, may be... less likely to develop the disease, while people with metabolic syndrome (a combination of cardiovascular health related symptoms) are at higher risk. Finally, a large meta-analysis of nine European risk factor surveys confirmed a well recognized group of Alzheimer risk factors, including memory complaint, severe head trauma, diabetes, stroke and low education.
"We may not be able to do anything about aging, genetics or family history, but research shows us that there are lifestyle decisions we all can make to keep our brains healthier as we age, and that also may lower our risk of developing Alzheimer's disease," said William Thies, PhD, vice president for Medical & Scientific Relations at the Alzheimer's Association.
Unmarried Life: Paving the Way for Dementia?
Research suggests that maintaining regular social interaction can contribute to maintaining brain health as we age and possibly decrease one's risk of developing Alzheimer's. When people are married they are able to have close interaction on a regular basis. This may reduce the occurrence of dementia.
Krister Hakansson, BA, of Karolinska Institutet, KI Alzheimer Research Center, Stockholm, Sweden and Vaxjo University, School of Social Sciences, Vaxjo, Sweden, conducted a first-of-its-kind evaluation of whether midlife marital status is related to late-life cognitive function. The study examined 1,449 individuals from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study in midlife and then again in 1998, an average of 21 years later.
At re-examination, 139 persons were diagnosed with some form of cognitive impairment: 82 with mild cognitive impairment (MCI) and 48 with Alzheimer's. Persons in the study who were living with a partner in midlife were significantly less likely to show cognitive impairment compared to all other categories (single, separated, divorced or widowed). Those in the study who were married or lived with a significant other in midlife had a 50% lower risk of having dementia in late-life compared to those who lived alone, even after adjustments for education, BMI, cholesterol, blood pressure, occupation, physical activity, smoking habits, depression, ApoE status, age at follow-up and gender.
The researcher observed that there were differences between groups of people who had been living alone for different reasons. The all-life singles had a doubled risk, whereas the ones who stayed divorced from midlife onwards had a tripled risk. The most dramatic risk increase was found for those widowed before midlife and who stayed widowed. Compared to those married at midlife and still so at late-life, they had more than a six-fold risk of developing Alzheimer's.
"Living in a couple relationship is normally one of the most intense forms of social and intellectual stimulation. If social and cognitive challenges can protect against dementia, so should living in a couple relation," said Hakansson. "This study points to the beneficial effects of a married life, consistent with the general hypothesis of social stimulation as a protective factor against dementia."
Tendency for Rumination in Midlife May Decrease Risk for Dementia Decades Later
According to Ramit Ravona-Springer, MD, of Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel and colleagues, "rumination" refers to the disposition for repetitive thinking over one's problems.
Tendency for rumination when confronting difficulties in family and work settings was assessed in about 9,000 participants in the IIHD study, a longitudinal investigation of the incidence and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Tendency for rumination was assessed as 1=always forget, 2=tend to forget, 3=tend to ruminate, 4=usually ruminate.
Dementia was assessed three decades later in 1,890 participants among 2,604 survivors of the original cohort. Mean age of the participants was 82 at the time of final assessment. 308 were diagnosed as demented, 175 as having mild cognitive impairment, and 1,407 had no cognitive impairment.
The prevalence rates of dementia (adjusted for age, area of birth, and socioeconomic status) were 21% for those who always forget difficulties in familial settings, 18% for those who tend to forget, 14% for those who tend to ruminate over difficulties, and 14% for those who usually ruminate. When rumination in response to difficulties at work was assessed, prevalence rates of dementia were 24% for those who always forget difficulties, 19% for those who tend to forget, 15% for those who tend to ruminate over difficulties, and 15% for those who usually ruminate.
A total score for rumination in both family and work settings was calculated, and subjects were divided into four groups according to this score. Relative to the group with the lowest total rumination score, dementia prevalence was 30 to 40 percent less in groups with higher scores.
"Your personality traits, specifically your psychological and cognitive style when confronting distress, may be associated with your risk for dementia," said Ravona-Springer. "However, exactly how this works still needs to be determined."
Metabolic Syndrome May Lead to Cognitive Decline
Metabolic syndrome (Met.S) is a group of heart disease risk factors that includes abdominal obesity, elevated blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. Those who have Met.S are at higher risk for developing diabetes, hypertension, and stroke, all of which increase the risk of developing dementia, including Alzheimer's disease.
Matheus Roriz-Cruz, MD, PhD, Federal University of Rio Grande do Sul State, Brazil and colleagues studied the effects of Met.S on the development of cognitive impairment in people who have not had a stroke. Researchers evaluated 422 healthy elderly men and women over age 60 in Brazil and used a battery of scales to assess cognition, depression, planning and activities of daily living. Met.S was present in 39.3% of participants.
Data from the study revealed that all neurofunctional scores were significantly lower for those with Met.S, and the difference increased with age. Older people with Met.S had an almost 35% higher level of cognitive compromise when compared to those without Met.S.
"Met.S was independently associated with lower cognitive, planning, neuromotor and functional scores, and with more depressive symptoms," said Roriz-Cruz. "The results from this study reinforce the importance of maintaining good physical health in order to reduce one's risk of experiencing cognitive decline, and possibly developing Alzheimer's disease."
Risk Factors for Progression to Dementia in General Population
In the general population, many risk factors and predictors for dementia have been identified. However, a combination of risk factors may give a more accurate prediction for dementia than each individual risk factor.
Sylvaine Artero, of INSERM, Montpellier, France; Pieter Jelle Visser, of the University of Maastricht, The Netherlands; and colleagues analyzed a pooled database constructed from nine European surveys of dementia risk factors, including a total of 16,261 participants over age 55 without dementia. Potential risk factors were evaluated at baseline and incident dementia was assessed over a follow up period of up to 15 years. Risk factors included cardiovascular disorders, endocrine disorders, depression, head trauma, intoxicants (including alcohol, smoking and drugs), physical and intellectual activities, performance in activities of daily living, Apolipoprotein E genotype, cognitive complaint, and cognitive test performance.
In total, 1,530 subjects (9%) progressed towards dementia. In order, the most predictive variables were: impairment in executive function (planning), memory problems (as measured on tests), subjective complaints about memory/cognitive failure, Apolipoprotein E (ApoE) genotype, use of psychotropic medication, severe head trauma, diabetes, stroke, and problems with language. In addition, problems with activities of daily living, smoking, no drinking, no use of hypertensive drugs, low education, and female gender all independently predicted dementia at follow-up.
"Cases of dementia in the general population can be best identified by a combination of socio-demographic, clinical and cognitive factors," said Artero. "Developing a better understanding of the factors that increase risk for Alzheimer's will help us to create more effective methods to prevent people from developing the disease."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Krister Hakansson - "Unmarried life: Paving the way for dementia?" (Funders: Gun and Bertil Stohne Foundation)
-- Ramit Ravona-Springer - "Tendency for rumination as a psychological cognitive style in midlife is associated with decreased risk for dementia three decades later." (Funders: Israel Science Foundation, Israel Academy of Sciences and Humanities)
-- Matheus Roriz-Cruz - "Metabolic syndrome, successful and pathological neuroaging in a stroke-free elderly population." (Funders: Ministries of Education, Brazil and Japan)
-- Sylvaine Artero, Pieter Jelle Visser - "Risk factors for progression to dementia in general population: the Descripa study (European pooled data base)." (Funder: European Commission, 5th framework programme (QLK-6-CT-2002-02455))
Alzheimer's Association
Read More..
Additional research on Alzheimer risk factors presented at ICAD 2008 indicates that people who ruminate, or repeatedly think about their problems, may be... less likely to develop the disease, while people with metabolic syndrome (a combination of cardiovascular health related symptoms) are at higher risk. Finally, a large meta-analysis of nine European risk factor surveys confirmed a well recognized group of Alzheimer risk factors, including memory complaint, severe head trauma, diabetes, stroke and low education.
"We may not be able to do anything about aging, genetics or family history, but research shows us that there are lifestyle decisions we all can make to keep our brains healthier as we age, and that also may lower our risk of developing Alzheimer's disease," said William Thies, PhD, vice president for Medical & Scientific Relations at the Alzheimer's Association.
Unmarried Life: Paving the Way for Dementia?
Research suggests that maintaining regular social interaction can contribute to maintaining brain health as we age and possibly decrease one's risk of developing Alzheimer's. When people are married they are able to have close interaction on a regular basis. This may reduce the occurrence of dementia.
Krister Hakansson, BA, of Karolinska Institutet, KI Alzheimer Research Center, Stockholm, Sweden and Vaxjo University, School of Social Sciences, Vaxjo, Sweden, conducted a first-of-its-kind evaluation of whether midlife marital status is related to late-life cognitive function. The study examined 1,449 individuals from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study in midlife and then again in 1998, an average of 21 years later.
At re-examination, 139 persons were diagnosed with some form of cognitive impairment: 82 with mild cognitive impairment (MCI) and 48 with Alzheimer's. Persons in the study who were living with a partner in midlife were significantly less likely to show cognitive impairment compared to all other categories (single, separated, divorced or widowed). Those in the study who were married or lived with a significant other in midlife had a 50% lower risk of having dementia in late-life compared to those who lived alone, even after adjustments for education, BMI, cholesterol, blood pressure, occupation, physical activity, smoking habits, depression, ApoE status, age at follow-up and gender.
The researcher observed that there were differences between groups of people who had been living alone for different reasons. The all-life singles had a doubled risk, whereas the ones who stayed divorced from midlife onwards had a tripled risk. The most dramatic risk increase was found for those widowed before midlife and who stayed widowed. Compared to those married at midlife and still so at late-life, they had more than a six-fold risk of developing Alzheimer's.
"Living in a couple relationship is normally one of the most intense forms of social and intellectual stimulation. If social and cognitive challenges can protect against dementia, so should living in a couple relation," said Hakansson. "This study points to the beneficial effects of a married life, consistent with the general hypothesis of social stimulation as a protective factor against dementia."
Tendency for Rumination in Midlife May Decrease Risk for Dementia Decades Later
According to Ramit Ravona-Springer, MD, of Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel and colleagues, "rumination" refers to the disposition for repetitive thinking over one's problems.
Tendency for rumination when confronting difficulties in family and work settings was assessed in about 9,000 participants in the IIHD study, a longitudinal investigation of the incidence and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Tendency for rumination was assessed as 1=always forget, 2=tend to forget, 3=tend to ruminate, 4=usually ruminate.
Dementia was assessed three decades later in 1,890 participants among 2,604 survivors of the original cohort. Mean age of the participants was 82 at the time of final assessment. 308 were diagnosed as demented, 175 as having mild cognitive impairment, and 1,407 had no cognitive impairment.
The prevalence rates of dementia (adjusted for age, area of birth, and socioeconomic status) were 21% for those who always forget difficulties in familial settings, 18% for those who tend to forget, 14% for those who tend to ruminate over difficulties, and 14% for those who usually ruminate. When rumination in response to difficulties at work was assessed, prevalence rates of dementia were 24% for those who always forget difficulties, 19% for those who tend to forget, 15% for those who tend to ruminate over difficulties, and 15% for those who usually ruminate.
A total score for rumination in both family and work settings was calculated, and subjects were divided into four groups according to this score. Relative to the group with the lowest total rumination score, dementia prevalence was 30 to 40 percent less in groups with higher scores.
"Your personality traits, specifically your psychological and cognitive style when confronting distress, may be associated with your risk for dementia," said Ravona-Springer. "However, exactly how this works still needs to be determined."
Metabolic Syndrome May Lead to Cognitive Decline
Metabolic syndrome (Met.S) is a group of heart disease risk factors that includes abdominal obesity, elevated blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. Those who have Met.S are at higher risk for developing diabetes, hypertension, and stroke, all of which increase the risk of developing dementia, including Alzheimer's disease.
Matheus Roriz-Cruz, MD, PhD, Federal University of Rio Grande do Sul State, Brazil and colleagues studied the effects of Met.S on the development of cognitive impairment in people who have not had a stroke. Researchers evaluated 422 healthy elderly men and women over age 60 in Brazil and used a battery of scales to assess cognition, depression, planning and activities of daily living. Met.S was present in 39.3% of participants.
Data from the study revealed that all neurofunctional scores were significantly lower for those with Met.S, and the difference increased with age. Older people with Met.S had an almost 35% higher level of cognitive compromise when compared to those without Met.S.
"Met.S was independently associated with lower cognitive, planning, neuromotor and functional scores, and with more depressive symptoms," said Roriz-Cruz. "The results from this study reinforce the importance of maintaining good physical health in order to reduce one's risk of experiencing cognitive decline, and possibly developing Alzheimer's disease."
Risk Factors for Progression to Dementia in General Population
In the general population, many risk factors and predictors for dementia have been identified. However, a combination of risk factors may give a more accurate prediction for dementia than each individual risk factor.
Sylvaine Artero, of INSERM, Montpellier, France; Pieter Jelle Visser, of the University of Maastricht, The Netherlands; and colleagues analyzed a pooled database constructed from nine European surveys of dementia risk factors, including a total of 16,261 participants over age 55 without dementia. Potential risk factors were evaluated at baseline and incident dementia was assessed over a follow up period of up to 15 years. Risk factors included cardiovascular disorders, endocrine disorders, depression, head trauma, intoxicants (including alcohol, smoking and drugs), physical and intellectual activities, performance in activities of daily living, Apolipoprotein E genotype, cognitive complaint, and cognitive test performance.
In total, 1,530 subjects (9%) progressed towards dementia. In order, the most predictive variables were: impairment in executive function (planning), memory problems (as measured on tests), subjective complaints about memory/cognitive failure, Apolipoprotein E (ApoE) genotype, use of psychotropic medication, severe head trauma, diabetes, stroke, and problems with language. In addition, problems with activities of daily living, smoking, no drinking, no use of hypertensive drugs, low education, and female gender all independently predicted dementia at follow-up.
"Cases of dementia in the general population can be best identified by a combination of socio-demographic, clinical and cognitive factors," said Artero. "Developing a better understanding of the factors that increase risk for Alzheimer's will help us to create more effective methods to prevent people from developing the disease."
About ICAD 2008
The 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2008) is the largest gathering of international leaders in Alzheimer research and care ever convened. At ICAD 2008, more than 5,000 researchers from 60 countries will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2008 will be held in Chicago at McCormick Place, Lake Side Center from July 26-31.
About the Alzheimer's Association
The Alzheimer's Association is the leading voluntary health organization in Alzheimer's research, care and support. Our mission is to eliminate Alzheimer's disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit http://www.alz.org.
-- Krister Hakansson - "Unmarried life: Paving the way for dementia?" (Funders: Gun and Bertil Stohne Foundation)
-- Ramit Ravona-Springer - "Tendency for rumination as a psychological cognitive style in midlife is associated with decreased risk for dementia three decades later." (Funders: Israel Science Foundation, Israel Academy of Sciences and Humanities)
-- Matheus Roriz-Cruz - "Metabolic syndrome, successful and pathological neuroaging in a stroke-free elderly population." (Funders: Ministries of Education, Brazil and Japan)
-- Sylvaine Artero, Pieter Jelle Visser - "Risk factors for progression to dementia in general population: the Descripa study (European pooled data base)." (Funder: European Commission, 5th framework programme (QLK-6-CT-2002-02455))
Alzheimer's Association
Memory Pharmaceuticals Presents Positive Preclinical Data For MEM 68626 At ICAD 2008
Memory Pharmaceuticals Corp. (Nasdaq: MEMY) presented preclinical data for MEM 68626, its lead 5-HT6 antagonist drug candidate, at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD) in Chicago. The results demonstrate that MEM 68626 is effective in models of cognition that are considered predictive of efficacy in Alzheimer's disease and mild cognitive impairment (MCI). In addition, the data suggests the potential for once-daily oral dosing with a favorable safety and toxicology profile.
"We are extremely pleased with the data emerging from our proprietary 5- HT6 antagonist program. MEM 68626 produces a robust effect in key models of cognition with a favorable safety and... pharmacokinetic profile, providing a strong rationale for clinical development in a cognition indication," stated Vaughn M. Kailian, President and Chief Executive Officer of Memory Pharmaceuticals. "We look forward to advancing this program into the clinic by year-end."
The results were presented in a poster titled "Characterization of serotonin 5-HT6 receptor antagonists as putative drugs for age-related mild cognitive impairment and Alzheimer's disease." The data included the following:
-- MEM 68626 significantly enhanced object recognition in young rats, demonstrating improvements in both acquisition and consolidation memory processes in a model of episodic memory.
-- In a model of spatial reference memory, MEM 68626 restored cognitive function in aged-impaired rats, and this effect was maintained with longer- term dosing.
-- The data suggests that MEM 68626 was active in the cortical and hippocampal areas of the brain, critical regions that are compromised in Alzheimer's disease and MCI.
-- Pharmacokinetic studies of MEM 68626 demonstrated that the compound achieved plasma and brain exposure levels sufficient for once-a-day dosing.
Memory Pharmaceuticals also presented a poster titled "Working Memory Deficits in rTg4510 Tau Transgenic Mice," which was selected as a "Hot Topics" presentation.
About MEM 68626
MEM 68626 is a novel, potent and selective antagonist of the 5-HT6 receptor, a validated target for the treatment of cognitive disorders. The compound has demonstrated efficacy in multiple preclinical models of cognition and obesity and has a favorable safety and toxicology profile in animal studies. MEM 68626 is the lead compound in Memory Pharmaceuticals' 5-HT6 antagonist program.
About the Company
Memory Pharmaceuticals Corp., a biopharmaceutical company, is focused on developing innovative drugs for the treatment of debilitating CNS disorders, many of which exhibit significant impairment of memory and other cognitive functions, including Alzheimer's disease and schizophrenia. For additional information, please visit our website at http://www.memorypharma.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks and uncertainties. All statements, other than statements of historical facts, regarding management's expectations, beliefs, goals, plans or Memory Pharmaceuticals' prospects, future financial position, future revenues and projected costs should be considered forward-looking. Readers are cautioned that actual results may differ materially from projections or estimates due to a variety of important factors, including the outcome of clinical trials of Memory Pharmaceuticals' drug candidates and whether they demonstrate these candidates' safety and effectiveness; the risks and uncertainties associated with: obtaining additional financing to support Memory Pharmaceuticals' R&D and clinical activities and operations; obtaining regulatory approvals to conduct clinical trials and to commercialize Memory Pharmaceuticals' drug candidates; Memory Pharmaceuticals' ability to enter into and maintain collaborations with third parties for its drug development programs; Memory Pharmaceuticals' dependence on its collaborations and its license relationships; achieving milestones under Memory Pharmaceuticals' collaborations; Memory Pharmaceuticals' dependence on preclinical and clinical investigators, preclinical and clinical research organizations, manufacturers and consultants; protecting the intellectual property developed by or licensed to Memory Pharmaceuticals; and Memory Pharmaceuticals' ability to maintain listing on the Nasdaq Global Market. These and other risks are described in greater detail in Memory Pharmaceuticals' filings with the Securities and Exchange Commission. Memory Pharmaceuticals may not actually achieve the goals or plans described in its forward-looking statements, and investors should not place undue reliance on these statements. Memory Pharmaceuticals disclaims any intent or obligation to update any forward-looking statements as a result of developments occurring after the date of this press release.
Memory Pharmaceuticals Corp.
Read More..
"We are extremely pleased with the data emerging from our proprietary 5- HT6 antagonist program. MEM 68626 produces a robust effect in key models of cognition with a favorable safety and... pharmacokinetic profile, providing a strong rationale for clinical development in a cognition indication," stated Vaughn M. Kailian, President and Chief Executive Officer of Memory Pharmaceuticals. "We look forward to advancing this program into the clinic by year-end."
The results were presented in a poster titled "Characterization of serotonin 5-HT6 receptor antagonists as putative drugs for age-related mild cognitive impairment and Alzheimer's disease." The data included the following:
-- MEM 68626 significantly enhanced object recognition in young rats, demonstrating improvements in both acquisition and consolidation memory processes in a model of episodic memory.
-- In a model of spatial reference memory, MEM 68626 restored cognitive function in aged-impaired rats, and this effect was maintained with longer- term dosing.
-- The data suggests that MEM 68626 was active in the cortical and hippocampal areas of the brain, critical regions that are compromised in Alzheimer's disease and MCI.
-- Pharmacokinetic studies of MEM 68626 demonstrated that the compound achieved plasma and brain exposure levels sufficient for once-a-day dosing.
Memory Pharmaceuticals also presented a poster titled "Working Memory Deficits in rTg4510 Tau Transgenic Mice," which was selected as a "Hot Topics" presentation.
About MEM 68626
MEM 68626 is a novel, potent and selective antagonist of the 5-HT6 receptor, a validated target for the treatment of cognitive disorders. The compound has demonstrated efficacy in multiple preclinical models of cognition and obesity and has a favorable safety and toxicology profile in animal studies. MEM 68626 is the lead compound in Memory Pharmaceuticals' 5-HT6 antagonist program.
About the Company
Memory Pharmaceuticals Corp., a biopharmaceutical company, is focused on developing innovative drugs for the treatment of debilitating CNS disorders, many of which exhibit significant impairment of memory and other cognitive functions, including Alzheimer's disease and schizophrenia. For additional information, please visit our website at http://www.memorypharma.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks and uncertainties. All statements, other than statements of historical facts, regarding management's expectations, beliefs, goals, plans or Memory Pharmaceuticals' prospects, future financial position, future revenues and projected costs should be considered forward-looking. Readers are cautioned that actual results may differ materially from projections or estimates due to a variety of important factors, including the outcome of clinical trials of Memory Pharmaceuticals' drug candidates and whether they demonstrate these candidates' safety and effectiveness; the risks and uncertainties associated with: obtaining additional financing to support Memory Pharmaceuticals' R&D and clinical activities and operations; obtaining regulatory approvals to conduct clinical trials and to commercialize Memory Pharmaceuticals' drug candidates; Memory Pharmaceuticals' ability to enter into and maintain collaborations with third parties for its drug development programs; Memory Pharmaceuticals' dependence on its collaborations and its license relationships; achieving milestones under Memory Pharmaceuticals' collaborations; Memory Pharmaceuticals' dependence on preclinical and clinical investigators, preclinical and clinical research organizations, manufacturers and consultants; protecting the intellectual property developed by or licensed to Memory Pharmaceuticals; and Memory Pharmaceuticals' ability to maintain listing on the Nasdaq Global Market. These and other risks are described in greater detail in Memory Pharmaceuticals' filings with the Securities and Exchange Commission. Memory Pharmaceuticals may not actually achieve the goals or plans described in its forward-looking statements, and investors should not place undue reliance on these statements. Memory Pharmaceuticals disclaims any intent or obligation to update any forward-looking statements as a result of developments occurring after the date of this press release.
Memory Pharmaceuticals Corp.
Alzheimer's - Positive New Data On Dimebon's Long-Term Efficacy And Novel Mechanism Of Action
Medivation, Inc. (NASDAQ: MDVN) announced new data showing that its investigational drug Dimebon continues to produce broad, clinically meaningful benefits in Alzheimer's disease patients after long-term dosing, and appears to operate through a novel mechanism of action. These data were presented recently in a podium session and two poster sessions at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD) in Chicago. The presentations are highlighted below.
Dimebon Preserves All Key Functions in Alzheimer's Patients for 18 Months in Open-Label
Extension of First Pivotal Trial
New data from a six-month open-label extension of the 12-month placebo-controlled study of Dimebon in patients with mild-to-moderate Alzheimer's disease demonstrated that Dimebon continued to... improve the clinical course of the disease. After 18 months of treatment, Dimebon preserved function in patients at their original levels upon entering the trial across all key aspects of Alzheimer's disease, specifically memory and thinking, behavior, activities of daily living and overall function. These results are noteworthy as untreated Alzheimer's patients progressively deteriorate over time in these areas. Dimebon remained well tolerated throughout the 18-month treatment period.
The open-label extension data were presented in a poster session by Jeffrey Cummings, M.D., Director of the Mary S. Easton Center for Alzheimer's Disease Research at UCLA. "To my knowledge, no other approved or investigational treatment has stabilized function across all facets of Alzheimer's disease for this length of time," said Dr. Cummings. "These data suggest that Dimebon may provide long-term benefits to Alzheimer's patients and provide further support for its potential as a promising therapeutic to treat this devastating disease."
Patients originally on placebo for 12 months who were then crossed over to Dimebon in the openlabel extension phase stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they generally stabilized at a lower level of function than those treated with Dimebon for the full 18 months, suggesting a benefit of earlier treatment.
Dimebon Benefits Both Mild and Moderate Patients in 12-month Subgroup Analyses
New data from subgroup analyses by disease severity of the Dimebon double-blind placebocontrolled trial showed that Dimebon benefited both mild and moderate patients. In both mild and moderate patients, Dimebon treatment resulted in significant benefit on the study's primary endpoint, the Alzheimer's Disease Assessment Scale-cognition subscale, or ADAS-cog. The benefit in the moderate subpopulation was particularly robust, with a 9.7 point drug-placebo difference on the ADAS-cog (p<0.0001) after 12 months of treatment.
The subgroup analyses were presented in a separate poster presentation at ICAD 2008 by Rachelle Doody, M.D., Ph.D., the Effie Marie Cain Chair in Alzheimer's Disease Research at the Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine in Houston. "A nearly 10-point improvement over placebo in moderate patients on the ADAS-cog, a well-validated cognition scale in Alzheimer's disease, is unquestionably of clinical significance, especially in light of a clinical effect seen on the clinician's assessment of global function," said Dr. Doody. "If the results we saw for both the mild and moderate patients can be replicated, I believe that Dimebon will be an important advance in the treatment of Alzheimer's disease, regardless of stage."
Dimebon's Novel Mechanism of Action
In a podium presentation at ICAD 2008, Medivation presented new data on Dimebon's novel mitochondrial mechanism of action. Mitochondria generate energy for cells and play important roles in mediating cell function and survival. Mitochondrial dysfunction has been linked in the published literature to both Alzheimer's and Huntington's diseases. Preclinical data presented showed that Dimebon improves mitochondrial function in the setting of cellular stress with very high potency. For example, Dimebon treatment improved mitochondrial function and increased the number of surviving cells after treatment with a cell toxin known as ionomycin in a dose-dependent fashion. The effect of Dimebon to improve mitochondrial dysfunction has been confirmed in the independent laboratory of Maria Ankarcrona, Ph.D., Associate Professor at the Karolinska Institutet in Sweden.
"All of the approved Alzheimer's disease drugs operate by one of two mechanisms - cholinesterase inhibition or NMDA-receptor antagonism," noted Bengt Winblad, M.D., Ph.D., Head of the Karolinska Institutet's Alzheimer's Disease Research Center. "The body of preclinical and clinical data generated thus far convinces me that Dimebon is exerting its effects through a different mechanism. The data presented today support the hypothesis that Dimebon improves mitochondrial dysfunction. This is a novel mechanism that may, in part, explain the clinical benefits seen in Alzheimer's patients treated with Dimebon."
About the Pivotal Study
Dimebon's first pivotal Alzheimer's trial was a randomized, double-blind, placebo-controlled study of 183 patients with mild to moderate Alzheimer's disease. In this study, patients treated with Dimebon experienced statistically significant improvements compared to placebo in all the key aspects of the disease: memory and thinking, activities of daily living, behavior and overall function - after both six months and a full year of treatment. Dimebon's benefit over placebo continued to increase throughout the 12-month treatment period. At the end of 12 months, Dimebon-treated patients preserved their starting level of function on each measure of Alzheimer's disease. Results of the pivotal study were published in the July 19, 2008 issue of The Lancet.
Earlier this year, the U.S. Food and Drug Administration (FDA) informed Medivation that this study can be used as one of the pivotal studies required to support the approval of Dimebon to treat mildto- moderate Alzheimer's disease, as long as a significant proportion of the sites in the confirmatory Phase 3 trial are located in the United States. The Company recently began a confirmatory pivotal Phase 3 trial of Dimebon in Alzheimer's disease known as the CONNECTION study. Patients and caregivers can learn more about the study by visiting http://www.connectionstudy.com or by calling 1-877-888-6386.
About the Open-Label Extension
All patients who completed 12-months of dosing in the first pivotal trial were eligible to enroll in an open-label extension. All participants in the open-label extension received Dimebon, including patients who had previously received placebo during the prior 12 months of the trial. Because there was no placebo-control in the open-label extension, direct comparisons versus placebo cannot be made.
About Dimebon
Dimebon is an orally available small molecule that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer's and Huntington's diseases, making it a potential treatment for these and other neurodegenerative diseases. Preclinical data generated to date suggest that Dimebon operates through a novel mitochondrial mechanism of action. On July 7, 2008, Medivation announced positive safety and efficacy results from its Phase 2 trial of Dimebon for the treatment of Huntington's disease, which was conducted in collaboration with the Huntington Study Group. The study met its primary endpoint of safety and tolerability; in addition, Dimebon showed statistically significant benefit versus placebo in cognition as measured by the Mini-Mental State Examination, a secondary endpoint in the study. Huntington's disease is a progressive neurodegenerative disease characterized by the gradual development of involuntary muscle movement, progressive deterioration of cognitive processes and memory and severe behavioral disturbances. There are currently no approved drugs in the United States to treat this uniformly fatal genetic disorder.
About Medivation
Medivation, Inc. is a biopharmaceutical company focused on the rapid development of novel small molecule drugs to treat serious diseases for which there are limited treatment options. Medivation aims to transform the treatment of these diseases and offer hope to critically ill patients and their caregivers. The Company's current clinical development program includes a pivotal and confirmatory Phase 3 trial of Dimebon in Alzheimer's disease and a Phase 1-2 clinical trial of MDV3100 in patients with castration-resistant (also known as hormone-refractory) prostate cancer. Medivation recently announced that it plans to continue further development of Dimebon in patients with mild-to-moderate Huntington's disease based on the positive results seen in its Phase 2 trial. For more information, please visit us at http://www.medivation.com.
This press release contains forward-looking statements, including statements regarding future clinical development plans, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements involve risks and uncertainties that could cause actual results to differ significantly from those projected. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this release.] None of the Company's product candidates has been approved for sale, significant additional animal and human testing is required in order to seek marketing approval for any of its product candidates, and Medivation cannot assure you that marketing approval can be obtained for any of its product candidates. Furthermore, as is typically the case at this stage of the regulatory review process, the FDA has not yet performed an in-depth review of Medivation's preclinical and clinical data, so its views remain subject to change. Medivation's filings with the Securities and Exchange Commission, including its current report on Form 8-K filed on June 23, 2008, include information about additional factors that could affect the Company's financial and operating results.
medivation.com
Read More..
Dimebon Preserves All Key Functions in Alzheimer's Patients for 18 Months in Open-Label
Extension of First Pivotal Trial
New data from a six-month open-label extension of the 12-month placebo-controlled study of Dimebon in patients with mild-to-moderate Alzheimer's disease demonstrated that Dimebon continued to... improve the clinical course of the disease. After 18 months of treatment, Dimebon preserved function in patients at their original levels upon entering the trial across all key aspects of Alzheimer's disease, specifically memory and thinking, behavior, activities of daily living and overall function. These results are noteworthy as untreated Alzheimer's patients progressively deteriorate over time in these areas. Dimebon remained well tolerated throughout the 18-month treatment period.
The open-label extension data were presented in a poster session by Jeffrey Cummings, M.D., Director of the Mary S. Easton Center for Alzheimer's Disease Research at UCLA. "To my knowledge, no other approved or investigational treatment has stabilized function across all facets of Alzheimer's disease for this length of time," said Dr. Cummings. "These data suggest that Dimebon may provide long-term benefits to Alzheimer's patients and provide further support for its potential as a promising therapeutic to treat this devastating disease."
Patients originally on placebo for 12 months who were then crossed over to Dimebon in the openlabel extension phase stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they generally stabilized at a lower level of function than those treated with Dimebon for the full 18 months, suggesting a benefit of earlier treatment.
Dimebon Benefits Both Mild and Moderate Patients in 12-month Subgroup Analyses
New data from subgroup analyses by disease severity of the Dimebon double-blind placebocontrolled trial showed that Dimebon benefited both mild and moderate patients. In both mild and moderate patients, Dimebon treatment resulted in significant benefit on the study's primary endpoint, the Alzheimer's Disease Assessment Scale-cognition subscale, or ADAS-cog. The benefit in the moderate subpopulation was particularly robust, with a 9.7 point drug-placebo difference on the ADAS-cog (p<0.0001) after 12 months of treatment.
The subgroup analyses were presented in a separate poster presentation at ICAD 2008 by Rachelle Doody, M.D., Ph.D., the Effie Marie Cain Chair in Alzheimer's Disease Research at the Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine in Houston. "A nearly 10-point improvement over placebo in moderate patients on the ADAS-cog, a well-validated cognition scale in Alzheimer's disease, is unquestionably of clinical significance, especially in light of a clinical effect seen on the clinician's assessment of global function," said Dr. Doody. "If the results we saw for both the mild and moderate patients can be replicated, I believe that Dimebon will be an important advance in the treatment of Alzheimer's disease, regardless of stage."
Dimebon's Novel Mechanism of Action
In a podium presentation at ICAD 2008, Medivation presented new data on Dimebon's novel mitochondrial mechanism of action. Mitochondria generate energy for cells and play important roles in mediating cell function and survival. Mitochondrial dysfunction has been linked in the published literature to both Alzheimer's and Huntington's diseases. Preclinical data presented showed that Dimebon improves mitochondrial function in the setting of cellular stress with very high potency. For example, Dimebon treatment improved mitochondrial function and increased the number of surviving cells after treatment with a cell toxin known as ionomycin in a dose-dependent fashion. The effect of Dimebon to improve mitochondrial dysfunction has been confirmed in the independent laboratory of Maria Ankarcrona, Ph.D., Associate Professor at the Karolinska Institutet in Sweden.
"All of the approved Alzheimer's disease drugs operate by one of two mechanisms - cholinesterase inhibition or NMDA-receptor antagonism," noted Bengt Winblad, M.D., Ph.D., Head of the Karolinska Institutet's Alzheimer's Disease Research Center. "The body of preclinical and clinical data generated thus far convinces me that Dimebon is exerting its effects through a different mechanism. The data presented today support the hypothesis that Dimebon improves mitochondrial dysfunction. This is a novel mechanism that may, in part, explain the clinical benefits seen in Alzheimer's patients treated with Dimebon."
About the Pivotal Study
Dimebon's first pivotal Alzheimer's trial was a randomized, double-blind, placebo-controlled study of 183 patients with mild to moderate Alzheimer's disease. In this study, patients treated with Dimebon experienced statistically significant improvements compared to placebo in all the key aspects of the disease: memory and thinking, activities of daily living, behavior and overall function - after both six months and a full year of treatment. Dimebon's benefit over placebo continued to increase throughout the 12-month treatment period. At the end of 12 months, Dimebon-treated patients preserved their starting level of function on each measure of Alzheimer's disease. Results of the pivotal study were published in the July 19, 2008 issue of The Lancet.
Earlier this year, the U.S. Food and Drug Administration (FDA) informed Medivation that this study can be used as one of the pivotal studies required to support the approval of Dimebon to treat mildto- moderate Alzheimer's disease, as long as a significant proportion of the sites in the confirmatory Phase 3 trial are located in the United States. The Company recently began a confirmatory pivotal Phase 3 trial of Dimebon in Alzheimer's disease known as the CONNECTION study. Patients and caregivers can learn more about the study by visiting http://www.connectionstudy.com or by calling 1-877-888-6386.
About the Open-Label Extension
All patients who completed 12-months of dosing in the first pivotal trial were eligible to enroll in an open-label extension. All participants in the open-label extension received Dimebon, including patients who had previously received placebo during the prior 12 months of the trial. Because there was no placebo-control in the open-label extension, direct comparisons versus placebo cannot be made.
About Dimebon
Dimebon is an orally available small molecule that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer's and Huntington's diseases, making it a potential treatment for these and other neurodegenerative diseases. Preclinical data generated to date suggest that Dimebon operates through a novel mitochondrial mechanism of action. On July 7, 2008, Medivation announced positive safety and efficacy results from its Phase 2 trial of Dimebon for the treatment of Huntington's disease, which was conducted in collaboration with the Huntington Study Group. The study met its primary endpoint of safety and tolerability; in addition, Dimebon showed statistically significant benefit versus placebo in cognition as measured by the Mini-Mental State Examination, a secondary endpoint in the study. Huntington's disease is a progressive neurodegenerative disease characterized by the gradual development of involuntary muscle movement, progressive deterioration of cognitive processes and memory and severe behavioral disturbances. There are currently no approved drugs in the United States to treat this uniformly fatal genetic disorder.
About Medivation
Medivation, Inc. is a biopharmaceutical company focused on the rapid development of novel small molecule drugs to treat serious diseases for which there are limited treatment options. Medivation aims to transform the treatment of these diseases and offer hope to critically ill patients and their caregivers. The Company's current clinical development program includes a pivotal and confirmatory Phase 3 trial of Dimebon in Alzheimer's disease and a Phase 1-2 clinical trial of MDV3100 in patients with castration-resistant (also known as hormone-refractory) prostate cancer. Medivation recently announced that it plans to continue further development of Dimebon in patients with mild-to-moderate Huntington's disease based on the positive results seen in its Phase 2 trial. For more information, please visit us at http://www.medivation.com.
This press release contains forward-looking statements, including statements regarding future clinical development plans, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements involve risks and uncertainties that could cause actual results to differ significantly from those projected. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date of this release.] None of the Company's product candidates has been approved for sale, significant additional animal and human testing is required in order to seek marketing approval for any of its product candidates, and Medivation cannot assure you that marketing approval can be obtained for any of its product candidates. Furthermore, as is typically the case at this stage of the regulatory review process, the FDA has not yet performed an in-depth review of Medivation's preclinical and clinical data, so its views remain subject to change. Medivation's filings with the Securities and Exchange Commission, including its current report on Form 8-K filed on June 23, 2008, include information about additional factors that could affect the Company's financial and operating results.
medivation.com
Ongoing Phase II Study Explores Potential For Detection Of Amyloid Plaque Prior To Onset Of Alzheimer's Disease
Avid Radiopharmaceuticals presented clinical results on the development of a novel 18F-labeled PET amyloid imaging agent, 18F-AV-45, that may eventually provide a practical approach for routine brain imaging of people at risk for the development of Alzheimer's disease. At the ICAD meeting in Chicago, Avid presented results of the exploratory IND clinical studies of three novel amyloid plaque imaging agents. The study results demonstrated that 18F-AV-45 (AV-45) was the best of the compounds studied, and allowed for rapid (≤ 1 hour) imaging of amyloid plaque in Alzheimer's Disease (AD). Brain amyloid plaques are comprised of β-amyloid aggregates, one of the primary pathological markers of Alzheimer's disease and a key target for new therapeutic treatments under development.
AV-45, now in Phase II clinical studies, is the first F-18 PET amyloid imaging compound to enter multi-center clinical research studies in the U.S. for the detection of amyloid plaque in... patients with varying degrees of dementia. The use of the F-18 radiolabel on AV-45 allows for high quality PET imaging of amyloid plaque to be done for the first time in a community hospital or imaging clinic setting.
"The entire Alzheimer's community dreams of a day when Alzheimer's becomes a preventable disease. The only way to achieve this is through early detection and early treatment," said Daniel Skovronsky, M.D., Ph.D., CEO and President of Avid. "At Avid, we are working to make this vision a reality, and believe that AV-45 PET imaging may have the potential to detect amyloid plaque pathology in the brain prior to the development of dementia. With this in mind, we have embarked on a Phase II clinical study of AV-45 in people with mild cognitive impairment, a form of memory impairment that may eventually lead to Alzheimer's disease," added Skovronsky.
In this study reported at the ICAD meeting, AV-45 permitted the visualization of amyloid plaque - the major pathological component of AD - within as little as 50 minutes from administration and with 10 minutes of imaging time, resulting in minimal inconvenience or delay for the patient or the imaging center. These rapid imaging characteristics of AV-45 make it very convenient for brain PET imaging at both major academic research centers as well as in the community imaging center. In addition, stable levels of AV-45 were maintained in amyloid plaque for up to 90 minutes post injection, permitting high quality PET images to be obtained over an extended period of time.
About Avid Radiopharmaceuticals Inc.
Based in Philadelphia, PA, Avid Radiopharmaceuticals Inc. is a leader in the development of products with the potential for earlier and more effective detection, diagnosis and monitoring of brain disorders. The company is a pioneer in the development of molecular imaging agents for Alzheimer's disease that could lead to earlier diagnosis and better evaluation of drugs designed to prevent or reverse amyloid plaque build-up in the brain. Avid is currently enrolling patients in clinical studies of 18F-PET agents for imaging amyloid plaques in Alzheimer's disease and for imaging the vesicular monoamine transporter (VMAT2) in diseases involving dopaminergic degeneration such as Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB)
Source : Medical today
Read More..
AV-45, now in Phase II clinical studies, is the first F-18 PET amyloid imaging compound to enter multi-center clinical research studies in the U.S. for the detection of amyloid plaque in... patients with varying degrees of dementia. The use of the F-18 radiolabel on AV-45 allows for high quality PET imaging of amyloid plaque to be done for the first time in a community hospital or imaging clinic setting.
"The entire Alzheimer's community dreams of a day when Alzheimer's becomes a preventable disease. The only way to achieve this is through early detection and early treatment," said Daniel Skovronsky, M.D., Ph.D., CEO and President of Avid. "At Avid, we are working to make this vision a reality, and believe that AV-45 PET imaging may have the potential to detect amyloid plaque pathology in the brain prior to the development of dementia. With this in mind, we have embarked on a Phase II clinical study of AV-45 in people with mild cognitive impairment, a form of memory impairment that may eventually lead to Alzheimer's disease," added Skovronsky.
In this study reported at the ICAD meeting, AV-45 permitted the visualization of amyloid plaque - the major pathological component of AD - within as little as 50 minutes from administration and with 10 minutes of imaging time, resulting in minimal inconvenience or delay for the patient or the imaging center. These rapid imaging characteristics of AV-45 make it very convenient for brain PET imaging at both major academic research centers as well as in the community imaging center. In addition, stable levels of AV-45 were maintained in amyloid plaque for up to 90 minutes post injection, permitting high quality PET images to be obtained over an extended period of time.
About Avid Radiopharmaceuticals Inc.
Based in Philadelphia, PA, Avid Radiopharmaceuticals Inc. is a leader in the development of products with the potential for earlier and more effective detection, diagnosis and monitoring of brain disorders. The company is a pioneer in the development of molecular imaging agents for Alzheimer's disease that could lead to earlier diagnosis and better evaluation of drugs designed to prevent or reverse amyloid plaque build-up in the brain. Avid is currently enrolling patients in clinical studies of 18F-PET agents for imaging amyloid plaques in Alzheimer's disease and for imaging the vesicular monoamine transporter (VMAT2) in diseases involving dopaminergic degeneration such as Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB)
Source : Medical today
Encouraging Results From Phase 2 Clinical Trial Of Bapineuzumab At International Conference On Alzheimer's Disease
Elan Corporation, plc (NYSE: ELN) and Wyeth (NYSE: WYE) are presenting detailed results from the companies' 18-month Phase 2 study of bapineuzumab (AAB-001) in patients with mild to moderate Alzheimer's disease at the Alzheimer's Association's International Conference on Alzheimer's Disease 2008 in Chicago, Illinois. As previously announced, in the study, bapineuzumab appeared to have an acceptable safety profile and clinical activity in treating Alzheimer's disease. Potential efficacy signals were seen at a range of doses without a clear dose response. The study did not attain statistical significance on the... pre-specified efficacy endpoints in the overall study population. Post-hoc analyses showed statistically significant and clinically meaningful benefits in important subgroups.
The data will be presented by Sid Gilman, M.D., William J. Herdman Distinguished University Professor of Neurology, Director of Michigan Alzheimer's Disease Research Center, University of Michigan, and Chair of the independent safety monitoring committee for bapineuzumab.
"This study was limited in its size, design and goals," said Dr. Gilman, "but if the findings seen in these post-hoc analyses are replicated in the global Phase 3 program, it would be a validation of the amyloid hypothesis and could change how physicians approach the treatment of Alzheimer's disease."
Elan and Wyeth believe that the safety and efficacy findings from this Phase 2 trial of bapineuzumab in patients with mild-to-moderate Alzheimer's disease support the design of the ongoing global Phase 3 program and plan to incorporate learnings from this study into the Phase 3 program. The companies will continue to work diligently to develop much needed new treatment options for patients and physicians.
About the Phase 2 Clinical Trial
The double-blind, placebo-controlled multiple ascending dose trial was designed to assess the safety and tolerability of bapineuzumab in mild-to-moderate Alzheimer's disease and to explore efficacy at a range of doses. Two-hundred-thirty-four (234) patients were randomized1 to receive one of four doses of bapineuzumab (0.15 mg/kg [n=31], 0.5 mg/kg [n=33], 1.0 mg/kg [n=30] or 2.0 mg/kg [n=30]) or placebo [n=110] by intravenous infusion every 13 weeks. Findings were reported for 229 patients in a modified intent-to-treat (MITT) analysis. Patients were intended to receive up to six doses during the 18-month study.
The pre-specified primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Disability Assessment Scale for Dementia (DAD) in the 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg dose groups against their placebo cohorts. Other efficacy measures included change in concentrations of tau in cerebral spinal fluid (CSF), the Neuropsychological Test Battery (NTB), the Clinical Dementia Rating Sum of Boxes (CDR-SOB), the Mini Mental State Examination (MMSE) and brain volume as measured by MRI. Efficacy was assessed from baseline for 78 weeks.
Pre-Specified Efficacy Analysis
In the total study population, statistical significance was not obtained on the pre-specified efficacy endpoints of ADAS-cog and DAD.
Post-Hoc Efficacy Analyses
Modified Intent to Treat (MITT) included patients who received at least one infusion and one efficacy assessment. In analyzing the data, the following were taken into account: an assumption of non linearity of the data over time, ApoE4 carrier status, and baseline MMSE and test scores.
The clinical relevance of the results for patients receiving the full 18 months of therapy was analyzed in a completer analysis. The patients included in the completer analysis received six (6) infusions and a week 78 efficacy assessment.
Using these assumptions, trends in favor of bapineuzumab treated patients were observed in ADAS-cog and NTB in the total MITT population. Additional completer analyses reinforced these trends.
The study revealed important differences in the rate of vasogenic edema by carrier status and for this reason the total population was analyzed by ApoE4 carrier status2.
ApoE4 Non-Carrier Population
In the ApoE4 non-carrier patients, statistically significant differences from baseline to week 78 were observed in favor of bapineuzumab treated patients on both cognitive and functional efficacy endpoints:
- ADAS-cog treatment difference of 5.0; p=0.026
- NTB treatment difference of 0.35; p=0.006
- CDR-SB treatment difference of 1.5; p=0.040
A favorable directional change of 6.9, p>0.10 for DAD was observed.
The completer analysis for non-carrier patients was consistent with the above findings.
Additionally, in these non-carrier patients, MRI results showed significantly less brain volume reduction versus placebo, as measured by the Brain Boundary Shift Integral (BBSI), at 71 weeks3, with a treatment difference of 10.7 cc; p=0.004. Smaller increases in ventricular volume (VBSI) in bapineuzumab treated patients compared to placebo were observed, which were not statistically significant. Progression of Alzheimer's disease is generally associated with loss in brain volume and increases in ventricular volume.
ApoE4 Carrier Population
In the ApoE4 carrier patients, no statistically significant changes were observed in any of the cognitive or functional efficacy endpoints. The completer analysis for the carrier population showed favorable directional changes on cognitive and functional endpoints. The ongoing Phase 3 studies in ApoE4 carriers will help clarify these findings.
MRI findings in the carrier patients showed no significant change in brain volume between bapineuzumab treated and placebo patients, while a significant increase in ventricular volume in treated patients was observed, mean 2.5cc; p=0.037. The clinical relevance of this finding is still unclear and will continue to be evaluated.
"The clinically significant benefit seen with bapineuzumab treatment in the ApoE4 non-carrier subgroup is encouraging," said Dale Schenk, Ph.D., Executive Vice President and Chief Scientific Officer of Elan. "These results across multiple endpoints are consistent with what we have seen for beta amyloid immunotherapy from animal studies through to the patients."
"These data represent scientific validation of our decision to move rapidly into Phase 3 last year," said Gary L. Stiles, M.D., Chief Medical Officer, Wyeth. "In our Phase 3 program, we will learn much more since we will be able to study bapineuzumab in larger patient populations and better assess the results in ApoE4 carriers and non-carriers in separate trials. We are encouraged by these results and we'll achieve greater insight as we move forward."
Safety Findings
Adverse Events (AE) were observed in 95% of bapineuzumab treated patients versus 90% of placebo treated patients. AEs were generally mild to moderate and transient. With the exception of vasogenic edema, AEs did not appear to be dose related.
Adverse events seen in greater than 5% of bapineuzumab treated patients and at twice the rate of placebo treated patients were: back pain; anxiety; vomiting; vasogenic edema; hypertension; weight loss; paranoia; skin laceration; gait disturbance; and muscle spasm.
Three deaths occurred in bapineuzumab-treated patients, though these were not considered by the investigators to be treatment related. No deaths were reported in the placebo group. Other adverse events of interest occurring in less than five percent of patients treated with bapineuzumab included cataract, deep vein thrombosis, syncope, seizures and pulmonary embolism.
Vasogenic Edema (VE)
Twelve (12) cases of vasogenic edema were reported, all in treated patients, and all resolved over time. Ten (10) of these cases were reported in ApoE4 carriers with 2 cases in ApoE4 non-carriers. Eight (8) of the 12 cases were reported in the highest dose group, including both cases seen in ApoE4 non-carriers. Six (6) of the 12 cases were not associated with clinical symptoms and were detected on routine MRI scan. One (1) patient was treated with steroids. Re-dosing was instituted in six (6) of the 12 patients and no recurrence of VE was observed.
Phase 3 Program Implications
The Phase 2 data reinforce the design of the ongoing Phase 3 studies by ApoE4 carrier and non-carrier populations and the selected dose groups. The companies plan to continue all four ongoing Phase 3 studies. The ApoE4 carrier dose in the Phase 3 trials was selected to seek to minimize the risk of VE observed in the Phase 2 trial. The companies intend to obtain feedback from regulatory authorities in the coming months to finalize parameters for the Phase 3 program and discuss and reach agreement on requirements for registration.
About Bapineuzumab
Bapineuzumab is the first humanized monoclonal antibody in late-stage investigation as a potential treatment for Alzheimer's disease. Bapineuzumab is designed to clear toxic beta amyloid from the brain. The beta amyloid protein is a key component of the neuritic plaques that are implicated in the pathology of Alzheimer's disease. A global, 4,100 patient Phase 3 clinical program was initiated in December 2007 and is intended to provide safety and efficacy data to support the filing and approval of licensing applications for bapineuzumab as a potential treatment for patients with mild to moderate Alzheimer's disease. To learn more about this enrollment, patients or caregivers should contact clinical sites directly. Participating clinical sites can be found by visiting http://www.icarastudy.com or, in the United States by calling 1 (888) 818-MEMORY. Study site details also can be found by visiting http://www.clinicaltrials.gov.
About Alzheimer's Disease
Alzheimer's disease is a progressive brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities, such as bathing and eating. As Alzheimer's disease progresses, individuals may also experience changes in personality and behavior, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations. As many as 5 million Americans are estimated to have Alzheimer's disease, and more than 26 million people worldwide. One in eight baby boomers, and half of all people over 85, will develop the disease.
About the Elan and Wyeth Collaboration
The Wyeth and Elan Alzheimer's Immunotherapy Program (AIP) includes investigational clinical programs for bapineuzumab. AIP is a collaboration between the two companies to research, develop and commercialize immunotherapeutic approaches that may be used to treat and possibly prevent the onset of Alzheimer's disease. AIP research focuses on the beta amyloid hypothesis, as the companies believe that enhancing the clearance of beta amyloid in the brain may provide a new treatment approach for Alzheimer's disease.
About Elan
Elan Corporation, plc is a neuroscience-based biotechnology company committed to making a difference in the lives of patients and their families by dedicating itself to bringing innovations in science to fill significant unmet medical needs that continue to exist around the world. Elan shares trade on the New York, London and Dublin Stock Exchanges. For additional information about the company, please visit http://www.elan.com.
About Wyeth
Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, infectious disease, gastrointestinal health, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products.
Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products, nutritionals and non-prescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health. For additional information about the company, please visit http://www.wyeth.com.
Safe Harbor/Forward-Looking Statements
The statements in this press release and on the related webcast regarding the companies' assessment of the Phase 2 data and its implications for the Phase 3 program and future development of bapineuzumab are forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. In particular, these statements are subject to the risk that further analyses of the Phase 2 data may lead to different (including less favorable) interpretations of the data than the analyses conducted to date and/or may identify important implications of the Phase 2 data that are not reflected in these statements. Clinical trial data are subject to differing interpretations, and regulatory agencies, medical and scientific experts and others may not share the companies' views of the Phase 2 data or its implications for the Phase 3 program and future development of bapineuzumab. In addition, further analyses of the Phase 2 data and discussion with regulatory authorities may lead to important modifications to the Phase 3 program. There can be no assurance that the clinical program for bapineuzumab will be successful in demonstrating safety and/or efficacy, that we will not encounter problems or delays in clinical development, or that bapineuzumab will ever receive regulatory approval or be successfully commercialized. Other risks and uncertainties that could cause actual results to differ materially from those expressed or implied by these forward-looking statements include those detailed from time to time in the Companies' periodic reports filed with the Securities and Exchange Commission, including Wyeth's current reports on Form 8-K, quarterly reports on Form 10-Q and annual report on Form 10-K, particularly the discussion under the caption "Item 1A, Risk Factors" in Wyeth's Annual Report on Form 10-K for the year ended December 31, 2007, which was filed with the Securities and Exchange Commission on February 29, 2008, and Elan's Reports of Foreign Issuer on Form 6-K and Annual Report on Form 20-F, particularly the discussion under the caption "Item 3D, Risk Factors" in Elan's Annual Report on Form 20-F for the year ended December 31, 2007, which was filed with the Securities and Exchange Commission on February 28, 2008. The forward-looking statements in this press release are qualified by these risk factors. We assume no obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.
1 Randomization was on an 8:7 ratio, with more patients receiving bapineuzumab versus placebo.
2 Literature estimates that 40-70 percent of Alzheimer's disease population are non-carriers of the Apolipoprotein E4 (ApoE4) allele
3 MRI results were measured through week 71
Read More..
The data will be presented by Sid Gilman, M.D., William J. Herdman Distinguished University Professor of Neurology, Director of Michigan Alzheimer's Disease Research Center, University of Michigan, and Chair of the independent safety monitoring committee for bapineuzumab.
"This study was limited in its size, design and goals," said Dr. Gilman, "but if the findings seen in these post-hoc analyses are replicated in the global Phase 3 program, it would be a validation of the amyloid hypothesis and could change how physicians approach the treatment of Alzheimer's disease."
Elan and Wyeth believe that the safety and efficacy findings from this Phase 2 trial of bapineuzumab in patients with mild-to-moderate Alzheimer's disease support the design of the ongoing global Phase 3 program and plan to incorporate learnings from this study into the Phase 3 program. The companies will continue to work diligently to develop much needed new treatment options for patients and physicians.
About the Phase 2 Clinical Trial
The double-blind, placebo-controlled multiple ascending dose trial was designed to assess the safety and tolerability of bapineuzumab in mild-to-moderate Alzheimer's disease and to explore efficacy at a range of doses. Two-hundred-thirty-four (234) patients were randomized1 to receive one of four doses of bapineuzumab (0.15 mg/kg [n=31], 0.5 mg/kg [n=33], 1.0 mg/kg [n=30] or 2.0 mg/kg [n=30]) or placebo [n=110] by intravenous infusion every 13 weeks. Findings were reported for 229 patients in a modified intent-to-treat (MITT) analysis. Patients were intended to receive up to six doses during the 18-month study.
The pre-specified primary efficacy endpoints were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Disability Assessment Scale for Dementia (DAD) in the 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg dose groups against their placebo cohorts. Other efficacy measures included change in concentrations of tau in cerebral spinal fluid (CSF), the Neuropsychological Test Battery (NTB), the Clinical Dementia Rating Sum of Boxes (CDR-SOB), the Mini Mental State Examination (MMSE) and brain volume as measured by MRI. Efficacy was assessed from baseline for 78 weeks.
Pre-Specified Efficacy Analysis
In the total study population, statistical significance was not obtained on the pre-specified efficacy endpoints of ADAS-cog and DAD.
Post-Hoc Efficacy Analyses
Modified Intent to Treat (MITT) included patients who received at least one infusion and one efficacy assessment. In analyzing the data, the following were taken into account: an assumption of non linearity of the data over time, ApoE4 carrier status, and baseline MMSE and test scores.
The clinical relevance of the results for patients receiving the full 18 months of therapy was analyzed in a completer analysis. The patients included in the completer analysis received six (6) infusions and a week 78 efficacy assessment.
Using these assumptions, trends in favor of bapineuzumab treated patients were observed in ADAS-cog and NTB in the total MITT population. Additional completer analyses reinforced these trends.
The study revealed important differences in the rate of vasogenic edema by carrier status and for this reason the total population was analyzed by ApoE4 carrier status2.
ApoE4 Non-Carrier Population
In the ApoE4 non-carrier patients, statistically significant differences from baseline to week 78 were observed in favor of bapineuzumab treated patients on both cognitive and functional efficacy endpoints:
- ADAS-cog treatment difference of 5.0; p=0.026
- NTB treatment difference of 0.35; p=0.006
- CDR-SB treatment difference of 1.5; p=0.040
A favorable directional change of 6.9, p>0.10 for DAD was observed.
The completer analysis for non-carrier patients was consistent with the above findings.
Additionally, in these non-carrier patients, MRI results showed significantly less brain volume reduction versus placebo, as measured by the Brain Boundary Shift Integral (BBSI), at 71 weeks3, with a treatment difference of 10.7 cc; p=0.004. Smaller increases in ventricular volume (VBSI) in bapineuzumab treated patients compared to placebo were observed, which were not statistically significant. Progression of Alzheimer's disease is generally associated with loss in brain volume and increases in ventricular volume.
ApoE4 Carrier Population
In the ApoE4 carrier patients, no statistically significant changes were observed in any of the cognitive or functional efficacy endpoints. The completer analysis for the carrier population showed favorable directional changes on cognitive and functional endpoints. The ongoing Phase 3 studies in ApoE4 carriers will help clarify these findings.
MRI findings in the carrier patients showed no significant change in brain volume between bapineuzumab treated and placebo patients, while a significant increase in ventricular volume in treated patients was observed, mean 2.5cc; p=0.037. The clinical relevance of this finding is still unclear and will continue to be evaluated.
"The clinically significant benefit seen with bapineuzumab treatment in the ApoE4 non-carrier subgroup is encouraging," said Dale Schenk, Ph.D., Executive Vice President and Chief Scientific Officer of Elan. "These results across multiple endpoints are consistent with what we have seen for beta amyloid immunotherapy from animal studies through to the patients."
"These data represent scientific validation of our decision to move rapidly into Phase 3 last year," said Gary L. Stiles, M.D., Chief Medical Officer, Wyeth. "In our Phase 3 program, we will learn much more since we will be able to study bapineuzumab in larger patient populations and better assess the results in ApoE4 carriers and non-carriers in separate trials. We are encouraged by these results and we'll achieve greater insight as we move forward."
Safety Findings
Adverse Events (AE) were observed in 95% of bapineuzumab treated patients versus 90% of placebo treated patients. AEs were generally mild to moderate and transient. With the exception of vasogenic edema, AEs did not appear to be dose related.
Adverse events seen in greater than 5% of bapineuzumab treated patients and at twice the rate of placebo treated patients were: back pain; anxiety; vomiting; vasogenic edema; hypertension; weight loss; paranoia; skin laceration; gait disturbance; and muscle spasm.
Three deaths occurred in bapineuzumab-treated patients, though these were not considered by the investigators to be treatment related. No deaths were reported in the placebo group. Other adverse events of interest occurring in less than five percent of patients treated with bapineuzumab included cataract, deep vein thrombosis, syncope, seizures and pulmonary embolism.
Vasogenic Edema (VE)
Twelve (12) cases of vasogenic edema were reported, all in treated patients, and all resolved over time. Ten (10) of these cases were reported in ApoE4 carriers with 2 cases in ApoE4 non-carriers. Eight (8) of the 12 cases were reported in the highest dose group, including both cases seen in ApoE4 non-carriers. Six (6) of the 12 cases were not associated with clinical symptoms and were detected on routine MRI scan. One (1) patient was treated with steroids. Re-dosing was instituted in six (6) of the 12 patients and no recurrence of VE was observed.
Phase 3 Program Implications
The Phase 2 data reinforce the design of the ongoing Phase 3 studies by ApoE4 carrier and non-carrier populations and the selected dose groups. The companies plan to continue all four ongoing Phase 3 studies. The ApoE4 carrier dose in the Phase 3 trials was selected to seek to minimize the risk of VE observed in the Phase 2 trial. The companies intend to obtain feedback from regulatory authorities in the coming months to finalize parameters for the Phase 3 program and discuss and reach agreement on requirements for registration.
About Bapineuzumab
Bapineuzumab is the first humanized monoclonal antibody in late-stage investigation as a potential treatment for Alzheimer's disease. Bapineuzumab is designed to clear toxic beta amyloid from the brain. The beta amyloid protein is a key component of the neuritic plaques that are implicated in the pathology of Alzheimer's disease. A global, 4,100 patient Phase 3 clinical program was initiated in December 2007 and is intended to provide safety and efficacy data to support the filing and approval of licensing applications for bapineuzumab as a potential treatment for patients with mild to moderate Alzheimer's disease. To learn more about this enrollment, patients or caregivers should contact clinical sites directly. Participating clinical sites can be found by visiting http://www.icarastudy.com or, in the United States by calling 1 (888) 818-MEMORY. Study site details also can be found by visiting http://www.clinicaltrials.gov.
About Alzheimer's Disease
Alzheimer's disease is a progressive brain disorder that gradually destroys a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities, such as bathing and eating. As Alzheimer's disease progresses, individuals may also experience changes in personality and behavior, such as anxiety, suspiciousness or agitation, as well as delusions or hallucinations. As many as 5 million Americans are estimated to have Alzheimer's disease, and more than 26 million people worldwide. One in eight baby boomers, and half of all people over 85, will develop the disease.
About the Elan and Wyeth Collaboration
The Wyeth and Elan Alzheimer's Immunotherapy Program (AIP) includes investigational clinical programs for bapineuzumab. AIP is a collaboration between the two companies to research, develop and commercialize immunotherapeutic approaches that may be used to treat and possibly prevent the onset of Alzheimer's disease. AIP research focuses on the beta amyloid hypothesis, as the companies believe that enhancing the clearance of beta amyloid in the brain may provide a new treatment approach for Alzheimer's disease.
About Elan
Elan Corporation, plc is a neuroscience-based biotechnology company committed to making a difference in the lives of patients and their families by dedicating itself to bringing innovations in science to fill significant unmet medical needs that continue to exist around the world. Elan shares trade on the New York, London and Dublin Stock Exchanges. For additional information about the company, please visit http://www.elan.com.
About Wyeth
Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, infectious disease, gastrointestinal health, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products.
Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products, nutritionals and non-prescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health. For additional information about the company, please visit http://www.wyeth.com.
Safe Harbor/Forward-Looking Statements
The statements in this press release and on the related webcast regarding the companies' assessment of the Phase 2 data and its implications for the Phase 3 program and future development of bapineuzumab are forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. In particular, these statements are subject to the risk that further analyses of the Phase 2 data may lead to different (including less favorable) interpretations of the data than the analyses conducted to date and/or may identify important implications of the Phase 2 data that are not reflected in these statements. Clinical trial data are subject to differing interpretations, and regulatory agencies, medical and scientific experts and others may not share the companies' views of the Phase 2 data or its implications for the Phase 3 program and future development of bapineuzumab. In addition, further analyses of the Phase 2 data and discussion with regulatory authorities may lead to important modifications to the Phase 3 program. There can be no assurance that the clinical program for bapineuzumab will be successful in demonstrating safety and/or efficacy, that we will not encounter problems or delays in clinical development, or that bapineuzumab will ever receive regulatory approval or be successfully commercialized. Other risks and uncertainties that could cause actual results to differ materially from those expressed or implied by these forward-looking statements include those detailed from time to time in the Companies' periodic reports filed with the Securities and Exchange Commission, including Wyeth's current reports on Form 8-K, quarterly reports on Form 10-Q and annual report on Form 10-K, particularly the discussion under the caption "Item 1A, Risk Factors" in Wyeth's Annual Report on Form 10-K for the year ended December 31, 2007, which was filed with the Securities and Exchange Commission on February 29, 2008, and Elan's Reports of Foreign Issuer on Form 6-K and Annual Report on Form 20-F, particularly the discussion under the caption "Item 3D, Risk Factors" in Elan's Annual Report on Form 20-F for the year ended December 31, 2007, which was filed with the Securities and Exchange Commission on February 28, 2008. The forward-looking statements in this press release are qualified by these risk factors. We assume no obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.
1 Randomization was on an 8:7 ratio, with more patients receiving bapineuzumab versus placebo.
2 Literature estimates that 40-70 percent of Alzheimer's disease population are non-carriers of the Apolipoprotein E4 (ApoE4) allele
3 MRI results were measured through week 71
Langganan:
Postingan (Atom)