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Alzheimer's, Dementia & Mental Health
Alzheimer’s
Experts Focus on Report of Anti-Amyloid Drug Clinical Trial
Four trials on different approaches offer some
encouragement
 June 11, 2007 – Although no one has found a magic
bullet, there was some encouragement about possible Alzheimer’s
therapies from reports on four clinical trials presented today at the
2nd Alzheimer’s Association International Conference on Prevention of
Dementia in Washington, D.C. Much of the attention was on the results of
the first Phase III trial of an anti-amyloid treatment using
tramiprosate (Alzhemed, Neurochem).
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These reports
included data from:
• The
first Phase III trial of an anti-amyloid therapy in Alzheimer’s,
tramiprosate (Alzhemed, Neurochem).
• A
six-month extension of a Phase II trial in mild to moderate
Alzheimer’s of an oral drug with a novel mechanism of action
(Dimebon, Medivation).
• A 4½
year follow-up data on participants from the first major
Alzheimer’s immunotherapy trial (AN1792, Elan and Wyeth)
•
72-week safety and tolerability results from a diabetes drug
being investigated in Alzheimer’s (rosiglitazone,
GlaxoSmithKline). |
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While currently approved treatment options offer
some relief of symptoms for perhaps a year or two, they do not change
the course of the disease. It is widely believed that Alzheimer’s is
associated with the accumulation of a brain protein known as amyloid ß (Aß)
which, in its soluble form, is toxic to brain cells.
“Amyloid as a cause for Alzheimer’s and a primary
target for therapies and preventions must be thoroughly tested,” said
William Thies, Ph.D., Alzheimer’s Association vice president for Medical
and Scientific Relations.
“We need an answer to this question so that we can
then sharpen our focus on attacking amyloid and creating better
treatments, or change the focus to other areas if the theory is wrong.”
Very few drugs make it through the process from
initial identification through approval for marketing, or even to Phase
III clinical trials. According to the Pharmaceutical Research and
Manufacturers of America, economists estimate that it takes an average
of 12 to 15 years to discover and develop a new medicine and, on
average, it costs as much as $800 million.
On average, only five of every 10,000 compounds
investigated are tested in clinical trials. Of those five, only one is
ever approved for patient use. Plus, there are a variety of logistical
challenges unique to conducting trials in people with Alzheimer’s.
“We’re very pleased to see several compounds in
Phase III clinical trials now for Alzheimer’s disease that represent a
variety of treatment strategies,” said Sam Gandy, M.D., Ph.D., chair of
the Alzheimer’s Association’s Medical & Scientific Advisory Council.
“The odds are quite good that we’ll have more effective new treatments
for Alzheimer’s in the near future.”
18-month
phase III trial of tramiprosate (Alzhemed)
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Alzheimer's, Dementia & Mental Health |
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Tramiprosate (Alzhemed, Neurochem) is an anti-amyloid
compound in Phase III Alzheimer’s clinical trials. Tramiprosate is a
small, orally-administered investigational product candidate that is
known as an amyloid ß antagonist. It is believed to act by binding to
the soluble Aß protein, thereby interfering with the complex cascade of
events associated with amyloid deposition and the toxic effects of Aß in
the brain.
At the Alzheimer’s Association Prevention
Conference, lead author Paul Aisen, M.D., Professor of Neurology and
Medicine, and Director of the Memory Disorders Program at the Georgetown
University Medical Center, Washington D.C., presented an update from the
Phase III study, which was designed to assess the safety, efficacy and
disease modifying effect of tramiprosate (Alzhemed) in patients with
mild-to-moderate Alzheimer’s.
A total of 1,052 patients were enrolled in the
multi-center, randomized, double-blind, placebo controlled study in the
U.S. and Canada. All patients were on stable doses of
acetylcholinesterase inhibitors, with or without memantine. Patients
were randomized to receive tramiprosate (Alzhemed) 100 mg, 150 mg, or
placebo twice a day for 18 months. Safety and efficacy assessments were
conducted at three-month intervals in all patients.
Primary measures included the Alzheimer’s Disease
Assessment Scale, cognitive subscale (ADAS-cog), and Clinical Dementia
Rating-Sum of Boxes (CDR-SB) to assess clinical efficacy, and volumetric
MRI to assess disease modification effect on brain volume over the
course of the study. Secondary efficacy measures included the
Mini-mental Status Examination (MMSE), Clinician’s Interview Based
Impression of Change, plus Caregiver Interview (CIBIC-plus),
Neuropsychiatric Inventory (NPI) and Disability Assessment for Dementia
(DAD).
The Phase III clinical trial for Alzhemed has
generated an unprecedented amount and complexity of data. The company
discovered there were significant and unexpected differences in the data
between the study’s many sites, making it very difficult to determine
the total outcome of the trial. Therefore, the company is working to
account for the site differences, so it can analyze the data to
determine the total results.
“At this time, we don’t have the results for the
Alzhemed Phase III clinical trial,” said Gandy. “However, we have
learned important lessons about how to do these types of very complex,
long-term, large-scale Alzheimer’s trials, which in itself is very
important because there are now so many promising Alzheimer’s therapies
in the pipeline.”
12-Month
Phase II Trial Results for Dimebon
Dimebon (Medivation) is an oral medication that has
been shown to inhibit brain cell death in preclinical models relevant to
Alzheimer's and Huntington's diseases. Dimebon appears to block a new
target that involves mitochondrial pores, which are believed to play a
role in the cell death that is associated with neurodegenerative
diseases and the aging process.
In an already reported six-month study, 183
patients in Russia with mild to moderate Alzheimer’s were randomized to
receive Dimebon 20 mg orally three times a day or placebo for six months
and then offered blinded continuation of the study for an additional six
months. Other anti-dementia drugs were not allowed. ADAS-cog (primary
endpoint), CIBIC-plus, MMSE, NPI, and activities of daily living (ADL)
were assessed at baseline and at weeks 12, 26, 39 and 52.
Patients improved significantly compared to
baseline and compared to placebo at six months on all five outcome
measures. Dimebon was well tolerated in the study.
At the Prevention Conference, Rachelle Doody, M.D.,
Ph.D., Effie Marie Cain Chair in Alzheimer’s Disease Research and
Professor of Neurology at Baylor College of Medicine, reported 12-month
results that included the blinded, six-month extension of this trial in
which patients continued treatment in their original group.
4½ year
follow-up on Alzheimer’s immunotherapy with AN1792
Immunotherapy for Alzheimer’s has shown great
promise, though the first major clinical trial using an active
immunotherapeutic approach with a compound called AN1792 (a synthetic
form of the amyloid ß protein) (Elan and Wyeth) was halted due to brain
inflammation in about six percent of participants.
After treatment was discontinued, researchers
continued to follow the participants from that trial.
In data presented at the 2007 Alzheimer’s
Association Prevention Conference, Michael Grundman, M.D., M.P.H.,
Senior Director of Clinical Development in the Alzheimer’s Disease
Program at Elan Pharmaceuticals, Inc., and colleagues found that four
and a half years after being immunized with AN1792, patients who
developed antibodies to the amyloid ß protein continued to show
detectable amyloid ß antibodies and less decline in activities of daily
living (ADL) compared to placebo treated patients. 159 patient/caregiver
pairs participated in this follow-up study (30 placebo; 129 AN1792). Of
the 129 AN1792 treated patients, 25 were classified as antibody
responders.
Antibody responders showed significantly slower
decline on the Disability Assessment for Dementia (DAD) compared to
placebo patients.
The DAD is an ADL scale developed for patients with
Alzheimer’s that is administered to the patient’s caregiver through an
interview. This scale assesses a patient’s ability to initiate, plan and
perform activities related to hygiene, dressing, continence, eating and
meal preparation, telephoning, going on an outing, finance and
correspondence, medications, leisure and housework.
Antibody responders also showed a significant
favorable difference compared to placebo patients on a dependence scale
that measures disease impact on patients and caregivers.
According to the researchers, antibody responders
also showed less decline on a memory test than those who received
placebo. Brain volume changes were similar in antibody responders and
placebo patients beyond the first year of follow-up, and no additional
cases of encephalitis were observed.
“The favorable results on Activities of Daily
Living among the antibody responders in this study support the
hypothesis that amyloid ß immunotherapy may have long-term benefits for
patients with mild to moderate Alzheimer’s and their caregivers,”
Grundman said.
72-week
safety and tolerability results with Rosiglitazone XR
Rosiglitazone is used to treat type 2 diabetes. It
lowers blood sugar by helping cells use insulin more efficiently to
remove excess sugar from the blood. It has been suggested that
rosiglitazone also may influence inflammation and other brain cell
processes that may be related to the development of Alzheimer's.
However, a recently published meta-analysis
reported that rosiglitazone use in diabetes was linked to increased risk
of myocardial infarction and death from cardiovascular causes.
Scientists at GlaxoSmithKline studied Alzheimer’s
patients treated with rosiglitazone XR, an extended-release form of the
drug, to evaluate its tolerability and safety during 12 months of
treatment. This study was a follow-up, open-label, extension study to a
randomized, controlled trial that suggested rosiglitazone may be
effective in some patients depending upon their APOE genotype – APOE
e4-negative subjects showed improvement, whereas e4-positive subjects
showed either no improvement or a decline.
Three hundred thirty-seven (337) patients with
mild-to-moderate Alzheimer’s were enrolled in the study; 82 percent
completed it. Seven percent withdrew due to adverse events (AEs).
Forty-eight (48) percent of subjects experienced =1 AE, most commonly
peripheral oedema, which is accumulation of fluid, usually in the legs
or sacral region (6 percent), and nasopharyngitis, which is inflammation
of the nasal passages and upper part of the pharynx (5 percent). 9
percent experienced =1 severe adverse event (SAE); each SAE except
fractures (2 percent) occurred in = 1 percent of subjects.
Few subjects exhibited clinically significant
changes in heart rate (<1 percent), or clinically significant abnormal
ECG readings (2 percent) during the study. Changes in insulin
sensitivity and glycemic control measures were within expected ranges
and typical of an older population with a low level of insulin
resistance.
“Rosiglitazone XR appeared to be generally well
tolerated in subjects with Alzheimer’s for up to 72 weeks,” said Michael
Gold, M.S., M.D., Global Clinical Vice President, Neurology, at
GlaxoSmithKline. “Rosiglitazone use in Alzheimer’s appears to have a
safety profile comparable to that established in type 2 diabetes.”
Recent reports have raised concerns about increased
risk of heart attack and death from cardiovascular causes during use of
rosiglitazone in diabetes. The issue continues to be investigated in
ongoing studies and data analyses.
“There is value in continuing to study
rosiglitazone in Alzheimer’s. We need to attack the disease through
multiple mechanisms, and the only way we can learn with certainty about
issues of safety and efficacy in Alzheimer’s is through clinical
trials,” Thies said. “There are risks involved in clinical studies, and
we do need to ensure that all risks are thoroughly described and
explained to study participants and family members. That’s why we have
informed consent, and why the process is so important.”
Large-scale clinical trials are underway to
investigate the effectiveness of rosiglitazone as a potential new
treatment for Alzheimer’s.
Rosiglitazone is not currently approved for
treatment of Alzheimer’s.
About the
Alzheimer’s Association Prevention Conference
The Alzheimer’s Association International
Conference on Prevention of Dementia is the world's only
multidisciplinary forum to convene professionals from the fields of
bench research, drug discovery, medicine, care and public policy. More
than 1,000 dementia experts from around the world will gather to present
and discuss the latest detection, treatment and prevention research, and
address how together we can prevent Alzheimer's from becoming a global
health crisis. The 2007 Alzheimer’s Association Prevention Conference
will be held June 9-12 at the Marriott Wardman Park Hotel in Washington,
D.C.
About the
Alzheimer’s Association
The Alzheimer’s Association is the leading
voluntary health organization in Alzheimer’s care, support and research.
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
www.alz.org.
References:
• Paul Aisen – A Phase III Study of the Efficacy,
Safety and Disease Modification Effect of Tramiprosate in Mild-to
Moderate Alzheimer’s Disease, (Funder: Neurochem)
• Rachelle S. Doody – Results of a One-Year, Randomized,
Placebo-Controlled Trial of Dimebon for the Treatment of Mild to
Moderate Alzheimer’s Disease. (Funder: Medivation)
• Michael Grundman (first author, Leon Thal (deceased)) – Long Term
Follow Up of Patients Immunized with AN1972(QS-21): Reduced Functional
Decline in Antibody Responders. (Funder: Elan)
• David Hosford – Long-Term Safety and Tolerability of Rosiglitazone XR
in Alzheimer’s Disease. (Funder: GlaxoSmithKline)
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