- Plus, Taking Antidementia Drugs Extends Lifespan Three Years in

Alzheimer's -



    CHICAGO, July 30 /EMWNews/ -- 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.