Alzheimer’s Disease Therapies

By | April 15, 2015

Current Therapies for Alzheimer’s Disease

Because there is currently no cure for Alzheimer’s disease (), the primary goal of treatment remains the relief of cognitive, functional, and behavioral symptoms associated with the disease. Hence, current therapies aim to improve the quality of life for both Alzheimer’s disease patients and the caregivers who often must cope with the significant burden of this disease. Acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and natural antioxidants are used to ameliorate cognitive and functional symptoms of the disease, while antipsychotics and antidepressants target behavioral symptoms. Therapies aim to maintain the functioning of neurons, but none prevents or reverses the deposition of amyloid plaques and neurofibrillary tangles. Patients are typically classified using the Mini-Mental State Examination (MMSE) scale, which has scores ranging from 0 to 30, where lower scores indicate higher cognitive disturbance. Patients are classified as having mild, moderate, or severe Alzheimer’s disease, and drugs are approved specifically for these severity classes in the major pharmaceutical markets.

Table Current Therapies Used for Alzheimer’s Disease lists therapies frequently prescribed to treat Alzheimer’s disease in the major pharmaceutical markets; some of these agents are used off-label. Various factors influence the choice of agent, including general attitudes toward dementia and the efficacy of current therapies, the availability and reimbursement of different therapies, and a therapy’s ability to treat the different symptoms of Alzheimer’s disease. Table Key End Points in Landmark Trials for the Treatment of Mild to Moderate Alzheimer’s Disease compares the relative safety and efficacy of acetylcholinesterase inhibitors and NMDA receptor antagonists in Alzheimer’s disease. Table Emerging Therapies in Development for Alzheimer’s Disease lists key clinical trial end points used in determining efficacy in the treatment of mild to moderate Alzheimer’s disease.

TABLE Current Therapies Used for Alzheimer’s Disease

Agent Company/Brand Daily Dose Availability
Acetylcholinesterase inhibitors
Donepezil Eisai/Pfizer’s Aricept 5-10 mg qd US, France, Germany, Italy, Spain, UK, Japan
Rivastigmine Novartis’s Exelon/Prometax 3-6 mg bid US, France, Germany, Italy, Spain, UK
Galantamine Shire/Janssen’s Reminyl a 4-12 mg bid US, France, Germany, Italy, Spain, UK
N-methyl-D-aspartate receptor antagonists
Memantine Merz’s Axura/Akatinol, Lundbeck’s Ebixa, Forest Laboratories’ Namenda 10 mg bid US, France, Germany, Italy, Spain, UK
Natural antioxidants
Vitamin E Generics 500-1, 000 mg bid US, France, Germany, Italy, Spain, UK, Japan
Ginkgo biloba Pharmaton’s Ginkoba, generics 40-80 mg tid US, France, Germany, Spain
Antipsychotics
Risperidone Janssen’s Risperdal 0.5-2.0 mg qd US, France, Germany, Italy, Spain, UK, Japan
Antidepressants
Citalopram Lundbeck’s Cipramil, Forest Laboratories’ Celexa, generics 20 mg qd US, France, Germany, Italy, Spain, UK

aBecause of medication errors from confusion of the brand name Reminyl with Aventis’s Amaryl (glimepiride), Janssen plans to change the brand name of its galantamine products; a new name is expected to be announced in the first half of 2005.

bid = Twice daily;

qd = Once daily;

qid = Four times daily;

tid = Three times daily.

TABLE Key End Points in Landmark Trials for the Treatment of Mild to Moderate Alzheimer’s Disease

Goal Key Primary End Points Key Secondary End Points
Effect on cognition Mean treatment-placebo difference in ADAS-cog change scores at study end Mean change from baseline on the standardized Mini Mental State Exam for treated and placebo patients
■ Cumulative percentages of patients from treatment or placebo groups having attained at least a certain ADAS-cog score at study end
Effect on behavior ■ Mean treatment-placebo differences in CIBIC-plus scores at study end ■ Least squares mean change from baseline of the Neuropsychiatric Inventory (NPI) total score at study end
■ Neuropsychiatric Inventory (NPI) total score at study end
Effect on function ■ Median time to clinically evident functional decline of treated versus placebo, as assessed by the Alzheimer’s disease Functional Assessment and Change Scale (Alzheimer’s disease-FACS), MMSE, and Clinical Dementia Rating Scale (CDR) ■ Differences in mean change from baseline for treated patients and placebo, for instrumental ADLs, and basici ADLs on the Alzheimer’s disease Functional Assessment and Change Scale (Alzheimer’s disease-FACS)
■ Bristol Activities of Daily Living Scale (BADLS) ■ MMSE total scores
■ CDR scale
■ Disability Assessment for Dementia (DAD) ■ Progressive deterioration scale
■ Alzheimer’s disease Cooperative Study ADLs inventory (ADCS/ADL)
Overall clinical effect ■ Mean treatment-placebo differences in CIBIC-plus ratings at study end ■ Clinical Dementia Rating scale, sum of the boxes scale (CDR-SB) total scores
■ Least squares mean change in the Gottfries-Brane-Steen total score at study end (measuring intellectual impairment, activities of daily living, emotional reaction/function, and behavior) ■ Global Deterioration Scale (GDS)

Alzheimer’s Therapy: Acetylcholinesterase Inhibitors

Alzheimer’s Therapy: N-Methyl-D-Aspartate Receptor Antagonists

Alzheimer’s Therapy: Natural Antioxidants

Alzheimer’s Therapy: Antipsychotics

Alzheimer’s Therapy: Antidepressants

Emerging Therapies for Alzheimer’s Disease

In recent years, there have been few breakthroughs in the understanding of Alzheimer’s disease () pathogenesis, and research in this field is proceeding along several different paths. Drug developers are taking one of two major approaches to address the disease. The first focuses on the symptomatic treatment of the disease — that is, drugs that enhance the function of viable neurons but have not been shown in clinical use to repair degenerated neurons or permanently alter the course of Alzheimer’s disease. The second approach is a disease-modifying strategy that attempts to halt the neurodegeneration associated with the underlying causes of the disease — foremost, the accumulation of amyloid plaques in the brain. One major symptomatic approach focuses on relieving cognitive symptoms in Alzheimer’s disease patients by enhancing the function of the chohnergic system or other neurotransmitters. Although some acetylcholinesterase inhibitors () have proved successful in this area, many other research programs are ongoing. Even when acetylcholinesterase inhibitors have proved safe and efficacious in clinical trials, they have the potential of providing only symptomatic relief.

Other primary research strategies for Alzheimer’s disease center on disease modification and prevention by targeting specific steps in the neurodegenerative cascade. In keeping with the amyloid cascade hypothesis (), a major focus of these strategies is on clearing or inhibiting the formation of insoluble beta-amyloid (Aβ) peptides. Immunotherapies (e.g., vaccines) and Aβ inhibitors (e.g., β-secretase inhibitors, aggregation inhibitors) are examples of therapies that attempt to use these approaches. Importantly, although preclinical results suggest that the clearing of amyloid plaques restores cognitive function, an unequivocal clinical demonstration of this hypothesis is still lacking, so it remains unclear whether therapies targeting amyloid plaques will be successful in treating Alzheimer’s disease. In fact, some researchers believe plaque formation is a natural neuroprotective response of the brain to injury (), so that its removal would prove detrimental. In preclinical models, however, Aβ clearance is associated with cognitive improvement; preliminary data from Aβ vaccine trials suggest that patients who received the vaccine showed some cognitive stabilization and were later found at autopsy to have reduced amyloid plaque levels ().

Few companies are targeting the tau protein, which aggregates into intracellular neurofibrillary tangles (). AstraZeneca is developing AZD-1080, an inhibitor of NFT aggregation; the drug is in preclinical testing. Sirenade Pharmaceuticals and Neuropharma are developing kinase inhibitors that aim to prevent the inappropriate phosphorylation of tau, which leads to NFT formation. These drugs remain in preclinical studies.

In recent years, retrospective clinical analysis of epidemiological studies suggests that several existing pharmacological agents, such as estrogens and statins, may decrease the incidence of Alzheimer’s disease and play a neuroprotective role (). However, the Women’s Health Initiative Memory Study (WHIMS), which examined whether postmenopausal estrogen supplementation (estrogen plus progestin) reduces the risk of dementia and/or mild cognitive impairment (MCI) in healthy women aged 65 or older, showed that estrogen plus progestin therapy increases older women’s risk for dementia (). Therefore, estrogen strategies will not launch for the treatment of Alzheimer’s disease.

An extensive review of clinical trials failed to provide sufficient evidence to recommend statins for reducing the risk of Alzheimer’s disease, but there is a growing body of biological, epidemiological, and limited nonrandomized clinical evidence showing that lowering serum cholesterol may retard Alzheimer’s disease pathogenesis (). Clinical studies to determine the potential benefit of statin therapy in Alzheimer’s disease are in the early stages.

Other disease-prevention strategies are under investigation based on retrospective clinical analyses suggesting that currently available traditional nonsteroidal anti-inflammatory drugs (NSAIDs) — specifically, nonselective nonsteroidal anti-inflammatory drugs such as R-flurbiprofen (Myriad Genetics’ Flurizan) — might play a role in Alzheimer’s disease prevention. Recent trials of cyclooxygenase-2 (COX-2) inhibitors, including rofecoxib (Merck’s Vioxx, which was withdrawn worldwide in October 2004) and the NSAID naproxen ([Roche’s Naprosyn], which inhibits both COX-1 and COX-2 enzymes), have failed to show benefit for Alzheimer’s disease patients and, in fact, appear to increase the risk of cardiovascular and cerebrovascular side effects, so the discussion here is limited to R-flurbiprofen.

Other avenues of research involve preventive trials, such as controlling patients’ hypertension or diabetes, both of which have been implicated by epidemiological studies in the development of Alzheimer’s disease. Brain-penetrating angiotensin-converting enzyme (ACE) inhibitors have shown a protective effect, but these agents are not in development for Alzheimer’s disease. Trials with the peroxisome proliferator-activated receptor (PPAR) agonist rosiglitazone (GlaxoSmithKline’s Avandia) are in Phase II for Alzheimer’s disease.

This section does not discuss research programs involving muscarinic and nicotinic receptors and monoamine oxidase (MAO) inhibitors because they do not appear to hold any significant promise for the treatment of Alzheimer’s disease. In addition, the future of programs such as that of Phytopharm/Yamanouchi’s neuroprotective agent PYM50028 is unclear.

Finally, gene therapy strategies that could potentially restore lost cognitive function are in early development.

Of all the different strategies under study for the treatment and prevention of Alzheimer’s disease, only a few are likely to impact treatment in the near term — namely, the Aβ aggregation inhibitor Alzhemed (NC-531) and the nonsteroidal anti-inflammatory drug (NSAID) R-flurbiprofen. The following sections discuss the spectrum of emerging therapies, and these therapeutic approaches are summarized in Table Emerging Therapies in Development for Alzheimer’s Disease

Compound Development Phase Marketing Company
Acetylcholinesterase inhibitors
Phenserine
United States IIb/III Axonyx
Europe IIb/III Axonyx
Japan
GABA receptor inverse agonists
S-8510
United States
Europe I Shionogi-GlaxoSmith Kline
Japan II Shionogi-GlaxoSmith Kline
Neurotransmitter modulators
NS-2330
United States II Boehringer Ingelheim/NeuroSearch
Europe IIb Boehringer Ingelheim/NeuroSearch
Japan I Boehringer Ingelheim/NeuroSearch
CX-717
United States II Cortex/Servier
Europe
Japan
SR-57746A (Xaliprodene)
United States
Europe III Sanofi-Aventis
Japan
SR-57667B
United States
Europe IIb Sanofi-Aventis
Japan
SL-65.0155
United States Sanofi-Aventis
Europe II Sanofi-Aventis
Japan Sanofi-Aventis
Beta-amyloid aggregation inhibitors
Alzhemed (NC-513)
United States III Neurochem
Europe ll/lll Neurochem
Japan
Anti-beta-amyloid neuroprotectants
PBT-1 (Clioquinol)(a)
United States
Europe
Japan
Beta-amyloid generation inhibitors
Beta-secretase inhibitors
United States PC Zapaq, Merck, Genetics Company
Europe PC Actelion, Elan
Japan PC Takeda
Beta-amyloid immunization
ACC-001
United States PC Elan/Wyeth
Europe
Japan
M266 (passive immunization)
United States PC Eli Lilly
Europe
Japan
Nonsteroidal anti-inflammatory drugs
R-flurbiprofen

(Flurizan,

MPC-7869/E-7869)

United States III Myriad Genetics
Europe
Japan
Phosphodiesterase inhibitors
MEM-1414
United States I Memory/Roche
Europe
Japan
Gene therapy
CERE-110 (NeuroRescue AD)
United States I Ceregene
Europe
Japan

aThis drug is in Phase II development in Australia by Prana Biotechnology.

PC = Preclinical (including discovery).

Alzheimer’s Therapy: GABA Receptor Inverse Agonists

Alzheimer’s Therapy: Neurotransmitter Modulators

Alzheimer’s Therapy: Beta-Amyloid Aggregation Inhibitors

Alzheimer’s Therapy: Beta-Amyloid Generation Inhibitors

Alzheimer’s Therapy: Beta-Amyloid Immunization

Alzheimer’s Therapy: Nonsteroidal Anti-inflammatory Drugs

Alzheimer’s Therapy: Gene Therapy