Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - International Conference on Alzheimer’s Disease (ICAD 2009)

Vienna, Austria / July 11-16, 2009

Presently, the two classes of drugs available for AD treatment: cholinesterase inhibitors (ChEIs) including donepezil, tacrine, rivastigmine and galantamine, and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine have provided much insight into disease management. Studies have demonstrated that early intitiation of treatment provides significant benefits.

Early Treatment Initiation: An IMPACT Survey

Clinical studies have shown that treating patients with early-stage Alzheimer’s disease ( AD) yields statistically significant and clinically meaningful improvement in cognition and global function and may delay loss of functional abilities and need for long-term care. The rationale for treating patients who are cognitively impaired but do not have dementia is reinforced by evidence from epidemiologic studies and histopathology.

According to the Web-based IMPACT (IMportant Perspectives on Alzheimer’s Care and Treatment) survey, a majority of physicians in France, Germany, Italy, Spain and the UK agree that early treatment of AD can delay its progression. It also found that 55% of physicians believed that AD patients should continue treatment for as long as they are physically able. The European survey was conducted between April and May 2009. Presenting survey results, Prof. Lutz Fröhlich, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany, noted that about 70% of physicians reported they typically initiate treatment within one month of diagnosis, including up to 60% who said they start treatment immediately. This is in accordance with recommendations of current guidelines issued by the European Federation of Neurological Societies (Waldemar et al. Eur J Neurol 2007;14:e1-e26).

Prof. Fröhlich agreed by noting a study by Winblad et al. whereby delaying therapy reduced the beneficial effects of treatment (Dement Geriatr Cogn Disord 2006;21:353-63). The study investigated AD progression in patients with possible or probable AD given three years’ continuous therapy with the cholinesterase inhibitor (ChEI) donepezil compared with patients given placebo for one year followed by two years on donepezil. Patients who received three years of active therapy tended to have less global deterioration according to the Gottfries, Bråne and Steen (GBS) scale, compared with those who delayed treatment. Also statistically significant differences were seen in cognitive function (Mini Mental State Examination [MMSE]) and cognitive and functional abilities (Global Deterioration Scale [GDS]) between the two groups (Figure 1).

Figure 1.

Continuous Therapy vs. Treatment Interruption

Besides early treatment, the importance of continuous treatment of AD in order to delay cognitive and functional decline was demonstrated by Doody et al. in a phase III open-label, extension trial of patients with mild or moderate AD who took donepezil 10 mg/day for 24 weeks followed by a six-week placebo washout period. Interruption of therapy resulted in the loss of treatment-associated benefits and decrease in cognitive function scores to below original baseline values (Arch Neurol 2001;58:427-33). Although scores improved again after treatment was restarted, cognitive function scores remained below origina
ure 2).

Figure 2.

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Cost savings associated with early diagnosis and treatment of AD were revealed by research scientist Denis Getsios, BA, Center for Health Economics, Epidemiology and Science Policy, United Bioscience Corporation, Bethesda, Maryland. Mr. Getsios presented the results of an analysis using data from eight placebo-controlled trials with donepezil and a seven-year follow-up registry.

Based on 10-year follow-up of simulated individuals in the UK, the results demonstrated reduced healthcare costs and costs of caregiver time associated with early screening and pharmacologic treatment. The researchers calculated that patients screened and treated with donepezil had an average of almost five months less with MMSE scores <10, and over three months longer living in the community. According to Mr. Getsios, earlier diagnosis and treatment has tremendous implications in terms of patient quality of life and the costs over four to five years are primarily offset by reduced institutionalization.

Novel Targets

While the ChEIs and NMDA agents are effective at delaying disease progression, there is limited duration of response with variable benefit on cognition, function and behaviour. With the better understanding of the mechanisms involved in AD, longer-term therapeutic approaches with the goal of preventing cell injury, death or synapse loss or restoration of lost neuronal function are needed. Among the promising current strategies are the development of compounds specifically aimed at blocking the action of neurotoxic beta-amyloid proteins or by mitochondrial stabilization.

In AD neurons, almost all aspects of mitochondrial function, including ATP production, metabolism, reactive oxygen species (ROS) generation, calcium homeostasis and apoptosis are altered and thus targeting mitochondria has emerged as a potential therapy for the disease.

In preclinical studies, an investigational drug previously known as dimebon, renamed latrepirdine, was shown to promote neurite outgrowth and preserve mitochondrial function after brain cells were challenged with amyloid beta (Aß). It has been suggested that this may contribute to its mechanism of action and the clinical benefits seen with the drug in AD patients.

A 26-week, double-blind, placebo-controlled trial with a 26-week extension phase (one year treatment) of oral latrepirdine administered as 20 mg t.i.d. demonstrated benefit on all five outcome measures assessing cognition and memory, function and behaviour in patients with mild to moderate AD (Doody et al. Lancet 2008;372:207-15).

Combination Therapy

According to Dr. Pierre Tariot, Director, Memory Disorders Center, Banner Alzheimer’s Institute, and Research Professor of Psychiatry, University of Arizona College of Medicine, Phoenix, latrepirdine might potentially be used in combination with ChEIs to enhance treatment efficacy in AD. “Every patient is uniquely affected by AD and management is often complex,” he remarked, adding “Combination therapy may be needed to maximize clinical benefit.”

Dr. Tariot, presented the results of a phase I study of 24 patients with mild-to-moderate AD patients who had been stable on donepezil 10 mg/day for at least 60 days and tolerating it well. Patients were randomized to receive latrepirdine t.i.d. or placebo (2:1) for two or four weeks depending on dose-titration scheme.

In one cohort, patients on latrepirdine underwent seven day titration steps of 2.5 mg, 5.0 mg, 10 mg, 20 mg and in the second cohort, patients had a more rapid dose titration of 10 mg and 20 mg, each for seven days. The novel agent was well-tolerated and no changes were seen in the pharmacokinetics o
n both were co-administered over 28 days (Figure 3).

Figure 3.

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No serious adverse events (AEs) or deaths occurred. Overall, 13 of 15 (87%) latrepirdine- and five of nine (56%) placebo-treated patients reported an AE for any reason. All AEs in latrepirdine patients were mild in severity except two that were both assessed as unrelated to study drug. AEs reported for any reason in two or more latrepirdine patients and more frequently than in the placebo group were fatigue, abdominal distension, dizziness, fall, hyperkalemia and nightmare, all of which were mild/moderate and resolved with continued treatment. Those patients who underwent the rapid titration did not have a clinically relevant increased incidence of AEs compared with those on the gradual titration. Its pharmacokinetics were linear and time-dependent. No increase in C_max or area under the curve (AUC) was seen for either treatment.

“These phase I data are encouraging and serve as the foundation for the ongoing phase III CONCERT study, which recently started enrolment in the US and internationally,” Dr. Tariot told delegates. CONCERT is a 12-month clinical trial designed to evaluate the safety and efficacy of latrepirdine 5 mg or 20 mg t.i.d. added to ongoing treatment with donepezil in patients with mild to moderate AD.

Targeting b-amyloid

Many drug trials are aimed at reducing the neurotoxic effects of Aß peptide, the main component of amyloid plaque, which is believed to be a major factor in the cause of AD. A humanized anti-Aß peptide monoclonal antibody developed to bind and remove Aß from the brain, bapineuzumab, is currently being studied in four large phase III studies in patients with mild to moderate disease.

Pharmacokinetic data supporting the dose regimen being used in these trials were presented by Dr. Murray Raskind, Director, Alzheimer’s Disease Research Center (ADRC), University of Washington, Seattle. In a phase IIa double-blind study, 234 patients with mild to moderate AD were randomized to bapineuzumab 0.15, 0.5, 1.0 or 2.0 mg/kg once every 13 weeks for six infusions or placebo.

Serum bapineuzumab reached maximum concentrations within one hour after each infusion in most participants. At the four doses assessed, it exhibited small average volume of distribution at steady state
total body clearance (0.07 to 0.09 mL/h/kg) and long terminal half-life (20 to 33 days) (Table 1).

Table 1.

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Exposure to the drug was dose-proportional at the range observed, with minimal-to-modest accumulation per current dosing interval, and average AUC ratios between the third and first infusions ranging from 1.0 to 1.6. Plasma levels of Aß40 gradually reached maximum after approximately one day, and exposure to plasma Aß40 increased less than dose-proportionally. Concentrations in cerebrospinal fluid (CSF) increased with dose, while the average ratios of CSF to serum bapineuzumab concentrations indicated dose-independent flow from serum to CSF. No antibodies to bapineuzumab were detected in any patient, indicating a low likelihood of immunogenicity. The phase III trials are studying the novel agent at the three lowest doses. Dr. Raskind explained that the highest dosing regimen, 2.0 mg/kg, was discontinued following a review of vasogenic edema in the phase III clinical program by an independent safety monitoring committee.

Potential for Immunoglobulin

Intravenous immunoglobulin (IVIg), a human donor blood-derived product currently available for treatment of other neurological disorders, contains natural Aß antibodies. After showing significant benefit vs. placebo in assessments of cognition and decline in a phase II study (ICAD 2008, abstract 08-A-3147), IVIg is now being investigated in a multicentre phase III trial in patients with mild to moderate AD. Researcher Dr. Alfred Weber, Vienna, Austria, presented evidence that IVIg contains other antibodies that can modulate Aß transport/clearance. He and his team analyzed IVIg from 20 lots and found naturally occurring antibodies against the receptor for advanced glycation end products (RAGE), which binds Aß in the brain, and soluble low-density lipoprotein receptor-related protein (sLRP), the major Aß binding protein in plasma. They deduced that the anti-RAGE IgG could inhibit receptor-mediated transport of Aß across the blood-brain barrier into the central nervous system and that sLRP could lower the Aß burden in the brain by increasing the plasma levels and shifting the Aß equilibrium. According to Dr. Weber, this would suggest a broader mode of action of IVIg in AD beyond the effects of naturally occurring Aß antibodies.

Summary

Increasing insight into the pathophysiology of AD has provided promising new therapeutic targets that are now being tested in late-stage clinical trials. The development of agents aimed at stabilizing mitochondrial function administered in combination with ChEIs may prove to be a major advance in AD treatment. An agent which was associated with improved mitochondrial function in preclinical studies and is now in Phase III, latrepirdine has been shown to be well tolerated in combination with the ChEI, donepezil, in patients with mild to moderate AD. Another approach is to boost the ability of the immune system to remove Aß. Several biologic agents are being investigated as passive immunotherapy, avoiding the immune toxicities seen in clinical studies of vaccines against Aß. Among these agents, the humanized monoclonal antibody bapineuzumab was well tolerated in a Phase IIa study thus providing support for further development. Another potential immunotherapy is IVIg, which contains natural antibodies against Aß, but may have a broader mechanism of action in AD, according to new study data. In the absence of a cure, the main goal at present remains diagnosis of early-stage disease and effective targeted treatment to slow cognitive function decline and improve quality of life, both of which lead to reduced healthcare costs and caregiver burden.

At time of printing, latrepirdine and bapineuzumab are not available for use in Canada.