Long-term benefits of galantamine (Reminyl ) in Alzheimer s disease. Michael Gold 1, Sean Lilienfeld 2, & Luc Truyen 1

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1 Long-term benefits of galantamine (Reminyl ) in Alzheimer s disease Michael Gold 1, Sean Lilienfeld 2, & Luc Truyen 1 1 Johnson & Johnson Pharmaceutical Research and Development, Titusville, New Jersey ; 2 Janssen Pharmaceutica, Titusville, New Jersey; Abstract The natural history of Alzheimer s disease, combined with recognition of the advantages of introducing specific treatment early in the course of the disease, means that patients may take medication for several years. Previous studies of galantamine (Reminyl ) have shown an excellent record of safety and efficacy over 12 months with a broad spectrum of benefits that includes functional and behavioural aspects as well as cholinergic nerve endings by the use of acetylcholinesterase inhibitors. 1 Of the currently available agents, galantamine (Reminyl ) is unique in having a dual mode of action, comprising not only competitive inhibition of acetylcholinesterase, but also allosteric nicotinic receptor modulation that increases the response to acetylcholine within the synaptic cleft. cognition. Results from an open-label study extension now indicate that continuous treatment with galantamine is associated with cognitive benefits for at least 36 months. The benefits were equivalent to slowing the progress of Alzheimer s disease by months. Expectations of early treatment in AD In the early stages of AD, the cognitive deficit is relatively mild and disturbances of behaviour and functional ability may be slight. Early treatment offers the greatest opportunities for preserving cognitive and functional Alzheimer s disease (AD) is a chronic neurological condition with an inexorable, progressive course. As the disease progresses, patients become increasingly dependent on others for all aspects of daily life and towards the end of their lives many require full-time care in an institution. ability and prolonging patient autonomy, and for reducing the overall level of patient and caregiver distress. Galantamine has a broad spectrum of action, 2 and an improvement in any clinically relevant area (e.g. cognition, functional ability, behaviour, and demands on caregivers) should be considered a response to treatment. Apart from amyloid plaques and neurofibrillary tangles, one of the core pathological features of AD is the loss of neurons, including cholinergic neurons, and reduced cholinergic neurotransmission. The most effective treatment option developed to date consists of enhancing transmission at the Patients with AD may survive for up to 8 years after the diagnosis of AD. Any interventions intended to slow or halt the progress of the disease will be needed over a long period, and the earlier treatment is introduced, the longer 1185

2 the total duration of treatment will be. It is therefore essential that therapeutic interventions demonstrate long-term safety and tolerability as well as efficacy. improvement was insufficient to regain baseline scores at 12 months. These patients had a significantly poorer outcome at endpoint than patients who received galantamine 24 mg/day throughout (p = 0.03). These Experience with galantamine over 12 months In a 6-month, double-blind study followed by a 6-month, openlabel extension, galantamine 24 mg/day has been demonstrated results confirm the theoretical expectation outlined above that early treatment has the greatest potential to delay progression. to be a safe and effective treatment in patients with mild-tomoderate AD. 3 During the double-blind phase, patients were randomized to receive galantamine, titrated up to 24 or 32 mg/day, or placebo. All patients then received galantamine 24 mg/day during the open-label study extension. Since these studies were designed, the optimum dose of galantamine has been clarified, and the standard maintenance dose is now 16 mg/day, with the option for further titration to 24 mg after individual assessment. Safety and tolerability of galantamine were good throughout the 12-month duration of treatment. The majority of adverse events were gastrointestinal in nature and of mild-to-moderate severity. Importantly, the incidence of adverse events reduced with continued use of galantamine (see Table 1). The number of discontinuations resulting from adverse events also fell with continued use: 42% of all galantamine discontinuations resulting from adverse events occurred during dose escalation, but during Improvements in cognitive function were apparent within 1 week of reaching a galantamine dose of 24 mg/day, and increased after 3 months of treatment. The differences the open-label extension the number fell to 16% overall, and to 8% in patients who had received galantamine during the double-blind phase. compared with placebo amounted to 3.9 and 3.8 points on the 11-item Alzheimer s Disease Assessment Scale cognitive subscale (ADAS-cog/11) with galantamine 24 mg and 32 mg, respectively (p < in both cases). Although a decline in cognitive function was seen thereafter, patients who received galantamine 24 mg/day throughout remained above baseline for the full 12-month duration of the study. Patients initially randomized to placebo showed an increase in ADAS-cog/11 scores (i.e. a decline in cognitive function) at 6 months. Following the introduction of galantamine, these patients showed some improvement in ADAS-cog/11, but the Prolonged treatment with galantamine Data from a further extension study on the safety and efficacy of galantamine for up to 3 years of continuous use have recently been presented at a congress. 4 The patient population consisted of patients who had already completed open-label extensions to one of two earlier double-blind studies, including the one discussed above. 3,5 All patients had received galantamine 24 mg/day during earlier open-label extensions, and had thus already completed at least 6 months of treatment with galantamine 1186

3 prior to entering this extension study. Patients initially randomized to active treatment during the double-blind studies had received up to 12 months of continuous prior treatment with galantamine. During this extension study, patients received open-label galantamine, 24 mg/day, for a further period of 24 months. analysis (i.e. up to 24 months of galantamine) have already been reported. 7 At this stage, the mean decline in ADAScog/11 was 5.4 points. If patients had been treated with placebo, the expected decline would be ADAScog/11 points, depending on the method of calculation used. Thus, galantamine treatment for 24 months preserved cognitive function by 7 9 ADAS-cog/11 points. Inclusion criteria for the original double-blind studies included a diagnosis of probable AD, according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA), of mild-tomoderate severity, as indicated by a score of on the Mini-Mental State Examination (MMSE). The efficacy outcome was the change in ADAS-cog/11 score from the start of the extension study until Months 12 and 24. The interim results are now confirmed and supported by the results from the completed study. The mean changes in ADAS-cog/11 scores, compared with those of an extrapolated historical placebo group, are shown in Figure 1. The rate of cognitive decline was substantially slowed by galantamine, with a treatment difference at 36 months of approximately 11 ADAS-cog/11 points. Figure 1 can also be used to estimate the length of time for which cognition was preserved. At 24 months, the mean decline Ethical considerations make it difficult to include a placebo group in long-term studies of dementia when treatments that are known to be effective, such as galantamine, are available. Drop-out rates tend to rise with increasing study duration and can further confound the results. The probable effect of placebo can be estimated using historical data from the placebo groups in other studies or by extrapolating short-term placebo in ADAS-cog/11 in patients taking galantamine was 5.4 points. Patients taking placebo could have been expected to reach this point at least 12 months earlier. Similarly, the level of decline seen at 36 months with galantamine would have been reached approximately 18 months earlier with placebo. Galantamine therefore slowed the progress of AD by months. 4 results. 6 In this analysis, historical control data were provided by The total number of patients enrolled in this study was 327, of whom 225 had received galantamine from the start. More than half (55%) of the patients completed the full study, and ADAS-cog/11 data from every visit were available for 81 patients. Interim results, based on the 12-month efficacy the placebo group from an earlier 12-month study of AD. 8 The expected rate of decline in ADAS-cog/11 for patients receiving placebo during the initial double-blind phases was also calculated using the methods described by Stern et al. 6 As shown in Figure 1, the two methods used 1187

4 produced almost identical results and thus provide reassurance that these calculated results could be considered realistic. Previous studies of galantamine have shown that its benefits are not restricted to preservation of cognitive function, but that it offers a broad range of benefits Data from a small group of 17 patients using galantamine for up to 5 years indicate that prolonged treatment may be associated with the greatest benefits. 9 Patients taking galantamine for more than 3 years lost an average of 1.19 MMSE points per year, compared with 2.63 points per year in patients treated for less than 3 years. The expected rate of decline without treatment is 2 4 MMSE points per year. including maintenance of functional ability, delayed emergence of behavioural symptoms, and reduction in caregiver burden. 2 These new results, coupled with the established safety and tolerability data, indicate that galantamine may have the ability to provide worthwhile preservation of function in patients with AD for at least 36 months. 1188

5 References 1. Maelicke A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer s disease. Dement Geriatr Cogn Disord 2000;11(Suppl 1): Tariot P. Current status and new developments with galantamine in the treatment of Alzheimer s disease. Expert Opin Pharmacother 2001;2: Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-month randomized, placebocontrolled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54: Truyen L, Kershaw P. Patients taking galantamine show cognitive benefits during three years of continuous treatment. Poster presented at the 7th International Symposium on Advances in Alzheimer s Disease Therapy, Geneva, Switzerland, Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer s disease: a randomized, controlled trial. J Neurol Neurosurg Psychiatry 2001;71: Stern RG, Mohs RC, Davidson M, Schmeidler J, Silverman J, Kramer-Ginsberg E, et al. A longitudinal study of Alzheimer s disease: measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 1994;151: Doody RS, Kershaw P. The cognitive benefits of galantamine are sustained for at least 24 months: results of a long-term extension trial in Alzheimer s disease. Neurology 2001;56(Suppl 3):A Torfs K, Feldman H. 12-Month decline in cognitive and daily function in patients with mild-to-moderate Alzheimer s disease treated with placebo in two randomized studies. Poster presented at the 7th International World Alzheimer Congress, Washington, DC, Data on file, Janssen Pharmaceutica. 1189

6 Table 1. Treatment-emergent adverse events reported during 6 months of double-blind treatment and a 6-month open-label extension (from Raskind et al. 3 ). Adverse event Double-blind phase Extension phase GAL 24 mg GAL 32 mg PLA GAL patients from (n = 212) (n = 211) (n = 213) double-blind phase (n = 218) Nausea 79 (37.3%) 92 (43.6%) 28 (13.1%) 23 (20.6%) Vomiting 44 (20.8%) 54 (25.6%) 16 (7.5%) 15 (4.6%) Dizziness 29 (13.7%) 39 (18.5%) 24 (11.3%) 15 (6.9%) Diarrhoea 26 (12.3%) 41 (19.4%) 21 (9.9%) 20 (9.2%) Anorexia 29 (13.7%) 43 (20.4%) 12 (5.6%) 12 (5.5%) Weight loss 26 (12.3%) 23 (10.9%) 10 (4.7%) 10 (4.6%) Abdominal pain 14 (6.6%) 23 (10.9%) 9 (4.2%) 13 (6.0%) Tremor 11 (5.2%) 7 (3.3%) 1 (0.5%) 11 (5.0%) Any adverse event 195 (92.0%) 195 (92.4%) 168 (78.9%) 186 (85.3%) The table shows adverse events occurring at least 5% more frequently with either galantamine dose than with placebo during the double-blind phase of the study. GAL: galantamine; PLA: placebo. 1190

7 Figure 1. Change from baseline in ADAS-cog/11 scores over 36 months of galantamine treatment. 1191