Reports

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PRIORITY PRESS - International Conference on Alzheimer’s Disease

Vienna, Austria / July 11-16, 2009

Early, uninterrupted treatment of Alzheimer’s disease (AD) results in clinically meaningful improvement in cognitive and global function according to various studies but longer-term strategies are still needed to prevent inevitable cell injury, synapse loss or death and neuronal impairment.

As cited by Prof. Lutz Frohlich, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany, Winblad et al. (Dement Geriatr Cogn Disorder 2006;21:353-63) demonstrated that delaying therapy in patients with AD reduced the beneficial effects of treatment. The study compared outcomes among patients with possible or probable AD who were treated with three years of continuous donepezil to those who were initially treated with placebo for one year, after which they received two years of the same treatment. Based on ratings using the Gottfries, Brane and Steen (GBS) scale, investigators reported that patients who received three years of active therapy tended to show less global deterioration at three-years follow-up compared with patients whose treatment was delayed for one year. Investigators also observed significant differences between the two groups in cognitive function as well as cognitive and functional abilities at the end of three years.

The importance of continuous treatment in AD was also demonstrated by Doody et al. (Arch Neurol 2001;58:427-33). In this phase III, open-label extension trial, patients with mild or moderate AD received donepezil 10 mg/day for 24 weeks, followed by a six-week placebo washout interval. Investigators found that discontinuation of active therapy led to a loss of treatment-associated benefits and a decrease in cognitive function after the six-week washout interval, as reflected by cognitive function scores that were below original baseline values. Reintroduction of treatment in the same cohort led to an improvement in cognitive function scores but they still remained below original baseline values.

An analysis of data from eight placebo-controlled trials of donepezil along with a seven-year follow-up registry also suggest that early diagnosis and treatment of AD is cost-effective. As presented by Denis Getsios, Center for Health Economics, Epidemiology and Science Policy, United Bioscience corporation, Bethesda, Maryland, both healthcare costs as well as costs of caregiver time were reducing by early screening and treatment based on a 10-year follow-up of simulated patients in the UK. Researchers calculated that patients who were screened and treated with donepezil spent on average almost five months less time with Mini Mental State Examination (MMSE) scores of less than 10 and over three months longer living in the community than might otherwise be expected for patients who were not screened and treated early.

New Targets in Delaying Disease Progression

Studies support both the cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine as useful therapies that delay disease progression in AD patients. Nevertheless, response to both treatments is limited and they all have a variable effect on cognitive function and behaviour. Among the more promising novel strategies under development are compounds aimed at either blocking the action of neurotoxic beta-amyloid proteins or at stabilizing the mitochondria. In preclinical studies, the investigational compound latrepirdine (previously known as dimebon) was shown to promote neurite outgrowth and preserve mitochondrial function after brain cells were challenged with amyloid beta.

More clinically relevant, Doody et al. (Lancet 2008;372:207-15) demonstrated benefit on five outcome measures of cognition and memory, function and behaviour in patients with mild to moderate AD who were treated initially for 26 weeks with oral latrepirdine 20 mg three times a day during a double-blind placebo-control trial, followed by a 26-week extension phase. The new agent was well tolerated. Dry mouth and depression were the most common adverse events in the active therapy arm, although the percentage of patients who experienced adverse events did not differ between active treatment and placebo.

Combination therapy using a ChEI and latrepirdine may also enhance clinical benefit. As presented by Dr. Pierre Tariot, Research Professor of Psychiatry, University of Arizona College of Medicine, Phoenix, 24 patients with mild to moderate AD who had been stable on donepezil 10 mg/day for at least 60 days were randomized to either latrepirdine three times daily or placebo for two to four weeks, depending on the dose-titration schedule used. For example, patients in one cohort initially received latrepirdine at 2.5 mg, then 5 mg, 10 mg and 20 mg over the course of a seven-day titration schedule, while patients in the second cohort received 10 mg and 20 mg each for seven days.

No changes in the pharmacokinetics of either compound were observed when they were co-administered over the 28-day treatment interval, and no serious adverse events were reported. Patients who received latrepirdine were more likely than placebo controls to report fatigue, abdominal distension, dizziness, falls, hyperkalemia and nightmare, but all adverse events were mild to moderate and resolved with continued treatments.

“Every patient is uniquely affected by AD and management is often complex,” Dr. Tariot remarked, “and 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.”

CONCERT is designed to evaluate the safety and efficacy of latrepirdine 5 mg or 20 mg t.i.d. added to background donepezil therapy in patients with mild to moderate AD. Treatment duration will be 12 months in total.

Neurotoxic Effects

Amyloid beta peptide, the main component of amyloid plaque, is believed to be a major cause of AD and ongoing trials are aimed at reducing its neurotoxic effects. For example, bapineuzumab, a monoclonal antibody that binds and removes amyloid beta from the brain, so far has been shown to behave pharmacokinetically as predicted and no antibodies to it were detected following infusion of the drug, suggesting a low likelihood of immunogenicity.

Intravenous immunoglobulin (IVIg), a human donor blood-derived product currently available for the treatment of other neurological disorders, contains natural antibodies to amyloid beta. As noted by researcher Dr. Alfred Weber, Vienna, Austria, IVIg also contains antibodies other than natural amyloid beta antibodies and these other antibodies may modulate amyloid beta transport and clearance. For example, IVIg contains antibodies against soluble low-density lipoprotein receptor-related protein (sLRP)—the major amyloid beta binding protein in plasma—as well as antibodies against the receptor for advanced glycation end products, which bind amyloid beta in the brain. Researchers speculate that this latter antibody may inhibit receptor-mediated transport of amyloid beta across the blood-brain barrier into the central nervous system, while sLRP may lower the amyloid beta burden in the brain by increasing plasma levels.

Summary

Studies indicate that both early initiation of therapy with currently available agents as well as continuous treatment may delay loss of functional abilities and the need for long-term care in patients with AD. Yet the impact of treatment is both variable and limited in duration, and research attention is now turning to the development of agents that may neutralize the neurotoxic effects of amyloid beta in the brain and stabilize mitochondrial function. Immunotherapy using IVIg, which contains natural antibodies against amyloid beta among other potentially effective antibodies, may have a broader mechanism of action in AD and research into its use is ongoing. In the meantime, management of AD must rely on early diagnosis and introduction of therapy to maximize clinical benefits and stave off the need for long-term care.