A Variety of New Methods May Improve Drug Discovery and Clinical Studies in
Alzheimer's
WASHINGTON, June 10 /PRNewswire-USNewswire/ -- Alzheimer's clinical
trials that include home visits could result in shorter recruitment periods
and increased patient retention rates, and may save considerable time and
expense, according to research reported today at the 2nd Alzheimer's
Association International Conference on Prevention of Dementia in
Washington, DC.
Clinical trials are essential to testing the safety and benefit of
promising new treatments for Alzheimer's and other diseases. Slow
recruitment and loss of participants during the trial slows the progress of
developing new treatments. It also increases the costs of research.
Clinical trials for Alzheimer's face special challenges. They recruit
not just the person with the disease but also at least one other person
close to them, commonly called a caregiver, who has to accompany them on
study visits. The patients often have functional and behavioral problems
that make it difficult to get them ready for a study visit. The caregivers
often have their own health problems and job demands that present
challenges to study participation. In some cases, caregivers face the added
burden of making a decision regarding treatment that may expose their loved
one to risk.
"Other than lack of sufficient funding, recruiting and retaining
clinical study volunteers is now the single greatest impediment to
developing better treatment and prevention strategies for Alzheimer's,"
said William Thies, PhD, vice president for Medical and Scientific
Relations at the Alzheimer's Association. The Alzheimer's Association
recently implemented a Clinical Studies Initiative to elevate awareness and
support of Alzheimer's clinical research among physicians and the public.
With the expected rapid escalation in the number of people with
Alzheimer's in the near future, and the accompanying financial, societal
and personal catastrophes, scientists in government, academia and industry
are working to improve drug discovery and the clinical trials that are used
to test drug therapies. This includes improving the earliest stage of drug
discovery on the "front end" so that development is more efficient and the
compounds are more likely to be effective, plus understanding better and
improving the recruitment and retention of participants into Alzheimer's
clinical studies.
Home Visits Improve Willingness to Participate in Alzheimer's Clinical
Trials
Jason Karlawish, PhD, associate professor of medicine and associate
director of the PENN Memory Center, and his colleagues at the University of
Pennsylvania recently completed a study addressing the challenges of
recruiting and retaining study participants for Alzheimer's clinical
trials. They tested whether redesigned clinical trials might improve
caregivers' willingness to participate in Alzheimer's trials by analyzing
the value of four possible alterations in the study.
The researchers interviewed 108 caregivers of community dwelling
persons with Alzheimer's who were followed at the PENN Memory Center. The
caregivers were asked questions about their willingness to participate in
hypothetical studies which differed according to four variables: location
of study visits, method of transportation to study visits, chance of
receiving a drug or placebo, and level of risk of the study drug.
Participants were asked to rank their willingness to participate in each
varying study on a seven-point scale.
The scientists found that 17 percent of participants were willing to
participate in a high risk Alzheimer's disease redesigned clinical trial
with no amenities. When home visits were added, the willingness to
participate increased to 27 percent. Low risk, home visits, and a higher
chance of the active treatment increased the willingness to participate to
60 percent. The additional willingness generated by reducing travel
inconvenience offset negative study features, such as taking a high-risk
drug. Home visits also made caregivers of sicker patients more willing to
participate in studies.
"Altering studies to include home visits could result in shorter
recruitment periods and increased patient retention rates," Karlawish said.
"The amount of time we save through these alterations could offset the
added costs of the home visits, and, in fact, we may save considerable time
and expense if the participants don't have to come in to the clinic so
often."
Improving Drug Discovery at the Earliest Stages
Over the past three decades, a problem has emerged in new drug
discovery and development in which an increasing investment in research by
industry and government is not proportionally reflected in successful new
therapies. As such, a potential crisis is emerging, especially for diseases
such as Alzheimer's, which is projected to reach epidemic proportions in
the near future.
The United States Food and Drug Administration (FDA) and National
Institutes of Health (NIH) have made requests that academia and industry
address the emerging crisis across multiple diseases by exploring
strategies to improve efficiency and innovation in the drug discovery and
development process.
D.M. Watterson, Ph.D., Co-Director of the Center for Drug Discovery and
Chemical Biology, John G. Searle Endowed Chair in Molecular Biology and
Biochemistry, and Professor of Molecular Pharmacology and Biological
Chemistry in the Feinberg School of Medicine at Northwestern University in
Chicago, and colleagues from the Center for Drug Discovery and Chemical
Biology (CDDCB) in Chicago, IL, met with their colleagues in industry and
at government agencies to identify how they could respond to the need for a
more effective process. Together, they developed "smart chemistry"
integrated with "smart biology" approaches to drug discovery that have a
potential for making the process more efficient, facilitate innovation, and
identify novel compounds that might alter disease progression.
The "smart chemistry" approach uses the information found in chemical
and pharmacological databases to identify common strengths of molecules,
defined by their physical properties, that turn out to be good drugs. The
chemists mine these databases and propose testable hypotheses about what
common themes among the physical properties of small molecules with
different structures make them more drug-like. The identification of common
themes aids in the design of new molecules.
"The 'smart chemistry' approach to discovery allows a better fit
between biology and chemistry at both the virtual molecule design phase and
in the assembly line phase of synthetic production and testing," Watterson
said. "This makes possible a more rapid and less costly response to
biomedical needs as well as the generation of new molecules that are
candidate compounds for development into new drugs."
According to Watterson, the emphasis is on synthesizing compounds that
have a higher probability to be stable, non-toxic, and cause fewer adverse
effects. Minozac, a compound designed and synthesized in the Watterson
laboratory, is an example of a novel compound developed using the
integration of "smart chemistry" with "smart biology." Minozac limits
excessive production of brain proinflammatory cytokines, which are small
proteins that can cause tissue injury, and improves neurologic outcomes in
animal models of diseases such as Alzheimer's, traumatic brain injury (TBI)
and epilepsy. Minozac has been licensed to industry for clinical
development.
Collaborative studies with Linda Van Eldik, PhD, co-director of CDDCB
and a Professor of Cell and Molecular Biology at the Feinberg School of
Medicine, are exploring animal models of Alzheimer's and other brain
disorders that have brain inflammation as a key contributor to disease
progression. The ultimate goal is to develop a series of novel molecules
which would be effective against a variety of disorders where brain
inflammation and proinflammatory cytokine overproduction are involved.
Patients With Greater Comprehension of Their Situation Are Willing To
Accept More Risk
As clinical trials move forward with promising new treatments for
Alzheimer's, stakeholder perspectives can inform decisions about what risks
are acceptable for what kinds of treatment benefits. Pharmaceutical
companies, clinicians and the FDA need to understand patients' and family
members' willingness to accept risky treatments for Alzheimer's. This
information will provide important guidance on what drugs are appropriate
for Alzheimer's treatment.
"Several of the potential treatments being tested may present more than
minimal risks to patients," Karlawish said. "For example, researchers had
to stop one of the early studies of the anti-amyloid vaccination because
subjects developed encephalitis, a dangerous inflammation of the brain."
Karlawish and colleagues studied the willingness of persons with
Alzheimer's to take risk to treat their disease. The study involved
interviews with 34 community dwelling persons with very mild to moderate
Alzheimer's who were followed at the PENN Memory Center and their
caregivers. Patients were asked whether they would want to take medications
which would delay the progression of Alzheimer's by one year, under varying
levels of risk. The risks discussed were similar to those for drugs
currently being researched for the treatment of the disease, and ranged
from a 30 percent chance of pain to a 10 percent chance of death.
Caregivers were asked similar questions on behalf of their relative.
The researchers found that patients with more insight into the
symptoms, diagnosis, and prognosis of their cognitive impairment were
generally more risk tolerant. Risk-takers were also more likely to be
judged competent to make a treatment decision and more capable of thinking
through risks, benefits and purpose of an Alzheimer's medicine.
"From the patient perspective, the willingness to take a risky
Alzheimer's treatment is more driven by their awareness of their illness
and their capacity to understand, appreciate, and reason through a
treatment's purpose, benefits and risks to themselves, and not so much on
the severity of their Alzheimer's disease," Karlawish said.
Older Adults More Familiar With Alzheimer's Are More Willing To Accept
Treatment Risks
While the tremendous burden of Alzheimer's on people with the disease,
families and society is acknowledged, there is little quantitative evidence
of the level of risk individuals are willing to accept for treatment
benefits. At the Alzheimer's Association Prevention Conference, Reed
Johnson, PhD, Senior Fellow and Principal Economist at RTI Health
Solutions, and colleagues reported results from a study on how much risk
American older adults are willing to take in exchange for a disease
modifying treatment for Alzheimer's.
For the study, a nationally representative panel of 2,146 U.S. adults
60 years of age and older (avg. 70 years) completed an Internet-based
questionnaire. Respondents chose between pairs of hypothetical treatment
alternatives, including different, 7-year, Alzheimer's-progression profiles
and first year risk of death/permanent severe disability due to stroke or
encephalopathy. The maximum acceptable risk (MAR) respondents were willing
to accept in exchange for treatment benefits was calculated for various
clinical benefit levels. Results were stratified based on respondent
characteristics and familiarity with Alzheimer's.
The scientists found that respondents were willing to accept a 46.8
percent increase in the chance of death or disability in exchange for the
benefit of preventing Alzheimer's disease progression beyond the mild
state. Individual characteristics that had statistically higher MARs were
younger
versus older respondents, more educated versus less educated, and
respondents familiar with Alzheimer's versus less familiar.
"We found that older Americans are so concerned about the serious
consequences of Alzheimer's that they are willing to trade a higher risk of
other disabling illness or death in order to have access to a treatment
that could delay the progressive and lethal consequences of Alzheimer's,"
Johnson said. "This survey is the first to our knowledge that is able to
quantify this fear of Alzheimer's in a manner that could be useful to
health authorities as they plan for the increase in Alzheimer's brought on
by the aging of our population."
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, DC.
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.
-- Jason Karlawish -- Home Visits May Improve Recruitment In AD
Clinical Trials. (Funders: Marion S. Ware Alzheimer Program)
-- D. M. Watterson -- Improving The CNS Drug Discovery Process: Case
Study With An Integrative Approach Yielding Novel Potential Disease
Modifying Therapies. (Funders: National Institutes of Health, Alzheimer's
Drug Discovery Foundation)
-- Jason Karlawish -- How Much Risk Is An Alzheimer's Disease Patient
Willing To Take To Treat Their Alzheimer's Disease? (Funders: Marion S.
Ware Alzheimer Program, Paul Beeson Faculty Scholars Award)
-- F. Reed Johnson -- The Effect of Individual Characterictics on
Benefit- Risk Trade-Offs for Modifying the Progression of Alzheimer's
Disease. (Funder: Elan Pharmaceuticals, RTI International Senior
Fellowship)
SOURCE Alzheimer's Association
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Related links:
http://www.alz.org
CONTACT:
Alzheimer's Association media line,
+1-312-335-4078, media@alz.org; Prevention Conference press room,
June 9-12, +1-202-745-2108
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