Pharmaceutical companies are racing to develop new classes of drugs to stop
or reverse the course of Alzheimer's disease, but the forecast for many drug
candidates remains somewhat murky.
Alzheimer's affects an estimated 5 million people in the United States, and
the prevalence doubles for every five years beyond the age of 65, according to
the Centers for Disease Control and Prevention. As life expectancy continues
to rise and the elderly population grows faster than other age segments,
Alzheimer's looms as one of the largest public health problems. By 2050, the
worldwide prevalence of Alzheimer's is expected to quadruple.
Currently, three cholinesterase inhibitors (donepezil, rivastigmine, and
galantamine) and one NMDA (N-methyl-D-aspartic acid) glutamate receptor
antagonist (memantine) are approved by the FDA for the treatment of
Alzheimer's. These drugs slow disease progression with modest efficacy, but
none is able to stop or reverse the mental decline.
In recent years, several promising new drug candidates have been eagerly
pursued by drug companies in research and development, and several have
recently moved into phase 3 clinical trials (see table). Many molecules in the
development pipeline, particularly biologics, target the formation or
aggregation of beta amyloid, a peptide that is widely considered by scientists
to play a key role in Alzheimer's pathology, particularly in the formation of
protein plaques throughout the brain.
Selected Drug Candidates
in Development For Treating Alzheimer's Disease
One of the drug candidates in phase 3 clinical trials is bapineuzumab, a
monoclonal antibody that binds to beta amyloid and clears it from the brain.
Johnson and Johnson recently bought the bapineuzumab development program from
Elan, an Irish company, for $1.5 billion. However, doubts about bapineuzumab's
efficacy emerged after it failed to achieve the primary endpoint in a phase 2
trial. Previous clinical-trial data also raised a safety concern about
vasogenic edema, or accumulation of fluid in brain tissues, in some patients.
Nevertheless, the trial suggested that the drug may be efficacious in a subset
of patients who do not carry the apolipoprotein E4 (ApoE4) allele. The allele
increases the risk for developing Alzheimer's, but not all Alzheimer's
patients are carriers.
Eli Lilly also has an investigational monoclonal antibody known as
solanezumab, in phase 3 clinical development. The antibody neutralizes beta
Dimebon (also known as latrepirdine) is another promising candidate
currently being tested in phase 3 clinical trials. The drug is a small
molecule that was used for years in Russia as an antihistamine under the name
of dimebolin. In a phase 2 clinical trial whose results were published in the
July 19, 2008, The Lancet, patients with mild to moderate Alzheimer's
who received dimebon for 26 weeks showed statistically significant benefits in
cognitive functions compared with those who received placebo. The drug is
being developed by Medivation and Pfizer.
Surprisingly, dimebon was shown to increase the level of beta amyloid in
the brain, according to animal research studies released at the International
Conference on Alzheimer's Disease (ICAD) in July in Vienna. The finding calls
into question the pharmacological rationale and effectiveness of blocking beta
amyloid in treating Alzheimer's.
At the ICAD, Abbott announced that it had terminated the development of one
investigational drug for Alzheimer's. Two other molecules that interfere with
the beta-amyloid formation process—tarenflurbil, developed by Myriad
Pharmaceuticals, and tramiprosate, developed by Neurochem—have recently
failed clinical trials. Nevertheless, beta amyloid remains the main target for
Meanwhile, molecular targets other than beta amyloid are being explored by
small and large pharmaceutical companies in search of magic bullets against
Alzheimer's. Eli Lilly's semagacestat inhibits gamma-secretase and is in two
phase 3 trials. NIC5-15, a plant-derived substance tested by Humanetics in
phase 2 clinical development, is another gamma-secretase inhibitor with
insulin-sensitizing effects. Gamma-secretase is involved in the production of
beta amyloid, and its inhibition may decrease the production of beta
Roche is testing R3487, a molecule it acquired from Memory Pharmaceuticals,
as a treatment for both Alzheimer's and schizophrenia. The drug is a nicotinic
alpha-7 partial agonist.
Baxter Healthcare and the National Institutes of Health are cosponsoring a
phase 3 trial in Alzheimer's patients on the efficacy of an intravenous
immunoglobulin product (gammaglobulin IV) it manufactures. In a retrospective,
case-control study published in the July 21 Neurology, a history of
intravenous immunoglobulin use was associated with a lower risk of developing
Alzheimer's in four years. It has been speculated that passive immunization
with a mixture of human immunoglobulins, or antibodies, derived from human
plasma may remove beta amyloid from the body. Other vaccines targeting beta
amyloid are also being investigated by pharmaceutical companies.
An abstract of "Effect of Dimebon on Cognition, Activities of
Daily Living, Behaviour, and Global Function in Patients With Mild-to-Moderate
Alzheimer's Disease: A Randomised, Double-Blind, Placebo-Controlled
Study" is posted at<www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61074-0/abstract>.
An abstract of "IV Immunoglobulin Is Associated With a Reduced Risk of
Alzheimer Disease and Related Disorders" is posted at<www.neurology.org/cgi/content/abstract/73/3/180>.▪