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Alzheimer's Patients Who Fail On Aricept (Donepezil) May Benefit From Exelon (Rivastigmine)

BASEL, SWITZERLAND -- May 2, 2002 -- More than half (56 percent) of Alzheimer's disease patients who had failed to show sustained benefit from treatment with Aricept® (donepezil) therapy may benefit from treatment with Exelon® (rivastigmine, Novartis), according to a new multicenter study (1) published in last month's issue of Current Medical Research and Opinion. Both drugs are members of a class called cholinesterase inhibitors, currently the only type of drug approved for the treatment of mild to moderate Alzheimer's disease (AD).

The findings suggest a new approach to treating AD: switching to another cholinesterase inhibitor if one agent fails. Switching therapies is common in managing many diseases, but not currently in the treatment of AD because many physicians assume - apparently incorrectly - that all cholinesterase inhibitor drugs are similar. If a patient fails on one agent, it is often assumed another agent would be equally ineffective, so cholinesterase inhibitor therapy is discontinued all together.

"Our findings show switching patients from one cholinesterase inhibitor to another - in this case, from donepezil to Exelon - can be a valuable therapeutic strategy, offering renewed hope to physicians, AD patients and caregivers alike," said Sophie Auriacombe, MD, the lead author of the study at the Clinique St. Augustin in Bordeaux, France. She and her colleagues decided to study switching patients to Exelon because "it has a number of characteristics that make it an especially attractive treatment for AD," she said.

Although its exact causes are not understood, AD is associated with decreased transmission of signals between nerves in the brain, especially those that rely on the neurotransmitter acetylcholine. Exelon is unique because it treats AD by inhibiting the two key enzymes that breakdown acetylcholine - acetylcholinesterase and butyrylcholinesterase - thus prolonging the neurotransmitter's action. Other drugs commonly used to treat AD, such as donepezil and galantamine, inhibit acetylcholinesterase but not butyrylcholinesterase. Recent research suggests that butyrylcholinesterase may play an increasingly important role in regulating acetylcholine levels as AD progresses, and that the dual inhibitory action of Exelon may provide greater and more sustained efficacy in treating patients with the disorder.(2) In addition, unlike donepezil,(3,4) long-term use of Exelon does not increase target enzyme activity, which can lead to decreased inhibition and, possibly, diminished effectiveness.

Study and Findings
Involving 91 specialist treatment centers in France, the prospective, open-label study evaluated the efficacy and safety of six months of rivastigmine therapy in 382 outpatients with mild to moderately severe AD who, within the previous 12 months, had failed to show sustained benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, and 9% for both reasons). Lack of sustained benefit was shown over at least a six-month period by a decline in scores on a short, standard test of cognitive function (the Mini-Mental State Examination) or a noticeable loss of ability to function. Because AD usually progresses slowly, changes in the status of patients often require at least six months to be observable.

On average, the patients had Alzheimer's disease for two years, and had been previously treated with donepezil for 14 months (10 mg/day for most patients, or 5 mg/day if the higher dose was poorly tolerated). Donepezil treatment was discontinued for at least even days and up to a maximum of three months before the start of rivastigmine therapy.

Patients began treatment with rivastigmine 1.5 mg b.i.d. and, after four weeks in most cases, the dosage was progressively increased by 3 mg/day every four weeks, up to a maximum of 12 mg/day. By the end of the study, most patients (91.4%) were receiving > 6 mg/day, with more than one-third (38.4%) receiving 12 mg/day.

At the study's completion, 56.2% of patients responded to rivastigmine by either stabilizing (30.1%) or improving (26.1%) based on physicians' assessments (the Clinicians' Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by Instrumental Activities of Daily Living scale) improved or stabilized in 48.9% and 57.0% of patients, respectively.

Rivastigmine was generally well tolerated; the most common adverse events were nausea and vomiting, consistent with reports from previous clinical studies. Serious adverse events related to rivastigmine were reported in 2.4% of patients. Most (84.6%) who experienced tolerability problems with donepezil tolerated rivastigmine treatment for the full study duration, and more than half (54.5%) who discontinued donepezil treatment due to lack of efficacy responded to rivastigmine.

"The benefits of Exelon seen in these patients who failed on donepezil may be due to Exelon's unique, dual inhibitory action and other characteristics, and the gradual dose escalation made the treatment highly tolerable," said Dr. Auriacombe. She said that, taken together with other evidence,(5,6) the study's findings "provide strong support for physicians to consider switching cholinesterase therapies when patients fail on one agent - particularly switching to Exelon if patients fail on donepezil," she said.

About Alzheimer's Disease
Alzheimer's disease (AD) is a progressive, degenerative disease that alters the brain, causing impaired memory, thinking and behaviour. Affecting approximately 15 million people worldwide and 5 to 10 percent of those over 65 years of age, it is the most common form of dementia and the leading cause of death after cardiovascular disease and cancer.


This press release contains forward looking statements which can be identified by the use of forward-looking terminology such as "suggest," "new and better approach," "valuable therapeutic strategy", "especially attractive treatment," "may," "strong support" or similar expressions. Such forward looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. Any commercialisation can be affected by, amongst other things, uncertainties relating to product development, regulatory actions or delays or government regulation generally, the ability to obtain or maintain patent or other proprietary intellectual property protection and competition in general, as well as factors discussed in Novartis AG's Form 20F filed with the Securities and Exchange Commission. Any of these and other factors can cause the actual results to differ materially from the expected or predicted results.

Novartis AG (NYSE: NVS) is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 2001, the Group's businesses achieved sales of CHF 32.0 billion (USD 19.1 billion) and a net income of CHF 7.0 billion (USD 4.2 billion). The Group invested approximately CHF 4.2 billion (USD 2.5 billion) in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 72 600 people and operate in over 140 countries around the world. For further information please consult <http://www.novartis.com>.


References
1Auriacombe S, Vellas B, Pere J-J, Loria-Kanza Y. Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil. CMRO 2002; 18; 129-138.
2 Ballard CG. Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. Eur Neurol 2002; 2002;47(1):64-70.
3 Davidsson P, Blennow K, Andreasen N, Eriksson B, Minthon L, Hesse C. Differential increase in cerebrospinal fluid acetylcholinesterase after treatment with acetylcholinesterase inhibitors in patients with Alzheimer's disease. Neurosci Lett 2001;300:157-60.
4 Amici S, Lanari A, Romani R, Antognelli C, Gallai V, Parnetti L. Cerebrospinal fluid acetylcholinesterase activity after long-term treatment with donepezil and rivastigmine. Mech Ageing Dev 2001;122:2057-62.
5 Bullock R, Connolly C. Switching cholinesterase inhibitory therapy in Alzheimer's disease - UK experience. Poster presented at Pathways from science to effective patient management in dementia meeting. Istanbul, Turkey: 23-25 March, 2001.
6 Shua-Haim JR, Smith JM, Amin S. Crossover results from donepezil to rivastigmine in Alzheimer's disease patients: an overall analysis of three prospective studies. J Am Geriatr Soc 2001;49:S115.

SOURCE: Novartis

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