Vol. 1, No. 6 / June 2002

Psychotropic Drug Update
Medications for dementia:
New drugs, mechanisms are coming for Alzheimer’s disease

• GABA receptor agonists • Monoamine oxidase inhibitors • COX-2 inhibitors • Antioxidants • Statins • Nootropics • Nerve growth factor • Beta amyloid antagonists • NMDA antagonists • Somatostatin agonist

Associate Professor Department of Psychiatry University of Cincinnati College of Medicine Cincinnati, Ohio

The aging of America has placed the search for new and better treatments for Alzheimer’s disease (AD) on the front burner. Roughly 4 million people in the United States suffer from AD, and that number is expected to more than triple by the year 2050.¹ An estimated 3% of the U.S. population ages 65 to 74 have AD, and almost 50% of persons 85 and older are suspected of having the illness.² Aside from its ravages on patients and the stress it imposes on their families, AD is straining our nation’s healthcare system and social services, and is costing society tens of billions of dollars annually (Box 1).

Four agents approved by the Food and Drug Administration for AD treatment—donepezil, galantamine, rivastigmine, and tacrine—all have been proven safe and effective for treatment of mild-to-moderate Alzheimer’s dementia. There is no evidence, however, that any of these compounds halt the underlying dementing process.

But there is hope. Some 55 compounds are in the clinical pipeline for AD treatment. In addition to treating dementia, many of these agents may also either interfere with the disease’s onset and progress or improve cognitive function. While some of these agents are in phase I trials (i.e., 7 to 10 years away from reaching the market), others in phase III trials are within 2 to 3 years of market entry.

Let’s look at these agents by class and phase of development and what the evidence says about their ability to help patients battle Alzheimer’s dementia.

GABA receptor agonists

Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter found in the brain, has multiple receptor subtypes that affect both anxiety and sleep disorders. Stimulation of certain GABA receptors also impedes memory, and laboratory studies with GABA antagonists have shown increases in memory and learning.³

A decrease in GABA is believed to contribute to AD development. Decreased GABA deficits have also been discovered during autopsies in the brains of AD patients.⁴ Thus, researchers are investigating compounds that modulate the GABA system.⁵

NGD-97-1, Neurogen Corporation’s GABA receptor agonist, is licensed to Pfizer Inc. for AD treatment. The compound is being tested in a phase II study comparing three dosages of the drug to a marketed AD medication and a placebo in 200 AD patients. A previous phase I safety and efficacy study showed that the drug was well tolerated across a range of dosages in both young and elderly volunteers.⁶

Monoamine oxidase inhibitors

Monoamine oxidase-B inhibitors (MAOIs), classically known for their use in treating Parkinson’s disease and depression, have been proven effective and safe in delaying the progression of AD.

MAOIs are believed to act through their antioxidant properties⁷ and possibly through other mechanisms. It also has been reported that Alzheimer’s patients have increased platelet MAO-B levels, and this may reflect elevated MAO-B levels in the brain. By inhibiting the MAO-B enzyme, these agents may prevent degradation of dopamine and norepinephrine and thus boost neuronal transmission.

Examples of MAOIs in development for AD include rasagiline, SL-251188, and selegiline.⁸ Rasagiline, owned by Teva Pharmaceuticals, is in development for both AD and Parkinson’s disease. A phase II safety study in AD patients conducted in Israel has been completed, and the drug is being considered as an add-on to existing AD treatments.⁹ Sanofi-Synthelabo’s compound, SL-251188, is in phase I trials for both AD and smoking cessation.¹⁰

More than 27 clinical trials of selegiline have been conducted in AD. A recent meta-analysis of selegiline versus placebo showed some short-term cognitive benefits, but the level of response did not reach clinical importance or statistical significance.¹¹

COX-2 inhibitors

Patients from rheumatology clinics who take high doses of anti-inflammatory drugs appear to be at lower relative risk of developing AD.¹² Indeed, inflammation may speed AD progression by enhancing amyloid deposition in the brain and possibly by increasing neuronal death. Cyclooxgenase-2 (COX-2) is expressed in response to inflammatory stimuli and is involved in the production of prostaglandins that mediate pain and contribute to inflammation. COX-2 is found in high levels in areas of the brain related to memory, and these levels correlate with beta amyloid plaque deposition. COX-2 inhibition thus holds much promise in AD treatment.

Examples of COX-2 inhibitors in development for AD treatment include Merck’s compound rofecoxib in phase II and Pharmacia’s celecoxib in phase III.¹³ Rofecoxib is being examined in separate studies for its ability to both delay AD onset and retard its progression. Celecoxib was chosen by the National Institute on Aging (NIA) as part of the Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT). The large multi-center trial, which started early in 2001, is evaluating celecoxib’s effect on preventing the onset of AD.¹⁴

Antioxidants

There is extensive evidence that oxidative damage caused by free radicals in the brain may contribute to AD development. Free radicals are reactive oxygen-containing compounds that may attack and damage neuronal cell membranes. The brain is particularly sensitive to this type of insult because of its high fatty acid content, high oxygen use, and low antioxidant levels. The use of antioxidants, such as vitamin E, has been proposed to slow the progress of AD.

Sano⁷ conducted a placebo-controlled, randomized, multi-center trial of 341 patients with moderate AD. Patients were treated across 2 years with vitamin E, selegiline, a combination of both, or a placebo. The patients were evaluated according to whether they died, were institutionalized, suffered a decrease in their daily activities, or lapsed into severe dementia. Results indicated that treatment with selegiline or vitamin E slowed the disease’s progression.

Another compound, CPI-1189, an oral antioxidant produced by Centaur Pharmaceuticals, is being developed for the treatment of both AD- and AIDS-related dementia. The compound is in phase II trials for dementia.¹⁵

Statins

Researchers have hypothesized that the cholesterol-lowering HMG CoA reductase inhibitors (“statins”) may have a prophylactic effect on AD. Two recent clinical reports describe an association between statin therapy and a 70% reduction in AD occurrence. The role of statins in reducing the risk of AD has not yet been evaluated in a double-blind, placebo-controlled trial.

A number of laboratory findings, however, suggest that these agents have potentially neuroprotective properties, including antioxidant, anti-inflammatory, and antiplatelet effects. Experiments in cell culture and in vivo demonstrate that treatment with statins reduces production of beta-amyloid peptide, the main component of amyloid plaques.

Lovastatin SGOT, Andrx Corporation’s extendedrelease oral formulation of lovastatin, is in phase II trials for AD.¹⁶

Nootropics

The word nootropics is derived from Greek and translates as “acting on the mind,” Pfizer’s pramiracetam and GlaxoSmithKline’s oxiracetam are examples of this drug class and both are classified functionally as acetylcholine (ACH) agonists. These agents are approved in a number of European countries but are still in phase III trials in the United States.¹⁷ Few well-controlled, prospective clinical trials have been performed for most drugs in this group, however.¹⁸

Nerve growth factor

Nerve growth factor (NGF) is essential to the development and maintenance of peripheral and central neurons in the brain. Reduced levels of NGF may be among the causes of the increased neuronal loss found in Alzheimer’s patients. The development of compounds that either mimic or stimulate the production of NGF has drawn much attention of late.

Leteprinim potassium (Neotrofin), developed by NeoTherapeutics Inc., is the first of these compounds to reach an advanced stage of development. Originally examined through the orphan drug program for Huntington’s disease and spinal cord injury, the agent is in phase III trials in the United States. A pivotal double-blind, placebo-controlled trial is under way in 521 patients. ¹⁹ All patients have been receiving the drug for up to 6 months. A preliminary analysis of the study showed improvement in clinical global ratings, but the drug showed no significant benefit over a placebo at the predetermined 12-week endpoints required by the Food and Drug Administration. The company intends to partner with a co-developer before future AD studies are initiated.²⁰

Another method of treating AD involves transplanting genetically modified cells that secrete NGF directly into affected areas of the brain. Results from a Ceregene Inc. phase I clinical trial for Alzheimer’s gene therapy, which began enrolling patients in 2000, are scheduled for release at the end of this year.²¹

Xaliproden hydrochloride (SR-57746A), SanofiSynthelabo’s compound, is being developed for AD and amyotrophic lateral sclerosis. It acts as both an NGF agonist and a 5 hydroxytryptamine 1A agonist. The agent is in phase IIB trials for AD in the United States.²²

Beta amyloid antagonists

AN-1792, an Alzheimer’s vaccine, is being developed jointly by Elan Corp. and Wyeth Pharmaceuticals. This beta amyloid protein antagonist would elicit an immune response to the amyloid plaque of AD. Theoretically, antibodies from the response would bind with the plaque and thereby eliminate it.

Investigations into this novel AD treatment approach recently were halted after four study participants presented with excessive CNS inflammation. Worldwide, of the approximately 360 patients who received multiple doses of AN-1792, 15 reported this adverse event. Elan and Wyeth are pursuing other immunologic approaches to Alzheimer’s treatment.²³

Two other beta amyloid protein antagonists include Praecis Pharmaceuticals’ PPI-1019, in phase I, and Proteo Tech’s PTI-00703, in phase II. PPI-1019 (Apan) is a protein compound that essentially interferes with the aggregation of beta-amyloid in the brain and may help promote its clearance. An initial phase I safety and pharmacokinetic study in normal subjects is under way, with a second study in Alzheimer’s patients scheduled to begin next year.²⁴

PTI-00703 is a beta-amyloid inhibitor derived from the cat’s claw, a woody vine found in the Peruvian rain forest. It is being tested in patients with mild-to-moderate AD.²⁵

NMDA antagonists

One of the more interesting areas of Alzheimer’s treatment research involves drugs affecting the interaction of glutamate with the NMDA (N-methyl-D-aspartate) receptor. Memantine, a medication in phase III trials in the United States, is owned by the German company Merz and has been available in Europe since 1982.

Glutamate, an excitatory neurotransmitter that activates neurons at the NMDA receptor, causes calcium to enter the cell. If glutamate is overproduced, it can overexcite a neuron, driving in too much calcium and resulting in cell death. Memantine blocks the NMDA receptor, protecting neurons from excessive glutamate stimulation. What’s more, memantine appears to have this protective effect without disturbing the normal function of glutamate. Initial phase III trials demonstrated positive effects on both cognitive decline and memory impairment.²⁶

A recent in-vitro study²⁷ examined the impact of combining memantine with each of three ACHE inhibitors (galantamine, tacrine, and donepezil) to see if ACHE inhibition would be lost. The positive results of this study prompted the current multi-center phase III trial in which patients are simultaneously taking both memantine and an ACHE inhibitor. Another phase III trial involving subjects with moderate to severe AD is also under way.

Somatostatin agonist

FK960, developed by the Japanese pharmaceutical company Fujisawa, has been shown to enhance both short- and long-term memory in numerous animal models of dementia. Laboratory studies indicate that the drug’s mechanism of action may be tied to somatostatin activation. Somatostatin, a neuropeptide found in the cerebral cortex, plays a central role in modulating cognitive processing. Fk960 appears to cause a release of somatostatin, thereby causing the positive cognitive effect.²⁸ The drug was well tolerated in normal elderly subjects in a phase I study and demonstrated predictable pharmacokinetics.²⁹ FK960 is now in phase II trials for AD both in Japan and the United States and has shown a positive effect in memory improvement.³⁰

Related resources

• Alzheimer’s Association. www.alz.org.

• Wolfson C, Wolfson DB, Asgharian M, et al. A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 2001;344(15):1111-6.

• Mudher A, Lovestone S. Alzheimer’s disease–do tauists and baptists finally shake hands? Trends Neurosci 2002;25(1):22-6.

Drug brand names

Celecoxib • Celebrex
Donepezil • Aricept
Galantamine • Reminyl
Lepteprinum potassium • Neotrofin
Lovastatin • Mevacor
Memantine • Ebixa
Rivastigmine • Exelon
Rofecoxib • Vioxx
Selegiline • Eldepryl
Tacrine • Cognex

Disclosure

The author reports that he serves as a co-investigator on clinical research projects funded by Merck & Co., Pfizer Inc., GlaxoSmithKline, Takeda, and Abbott Laboratories, but does not receive direct financial compensation from these companies, nor does he have any proprietary or financial interest in the test products.

References

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