Galantamine (Shire/Janssen’s Razadyne) () is the most recent entrant in the Alzheimer’s disease market. Galantamine was approved for the treatment of mild to moderate Alzheimer’s disease in the United States and Europe in 2001. The agent is in Phase III clinical trials in Japan. Galantamine is currently in Phase III trials in the United States and Europe for mixed and vascular dementia. Few data are available evaluating galantamine for the treatment of moderate to severe Alzheimer’s disease. Shire and Janssen have just completed two trials investigating galantamine for treatment of MCI. Data from these trials showed a higher mortality rate for patients treated with galantamine than for those receiving placebo, and the companies have announced that they will no longer pursue approval for MCI (). Shire and Janssen have announced that they are considering applying for approval in the United Kingdom and the United States for the use of galantamine in the treatment of mixed and vascular dementia. Because of medication errors from confusion of the brand name Reminyl with Sanofi-Aventis’s type 2 diabetes product Amaryl (glimepiride), Janssen changed the brand name of its galantamine products (oral and extended-release formulations) to Razadyne and Razadyne ER, respectively, to avoid confusion with the Sanofi-Aventis’s diabetes therapy glimepiride (Amaryl).
In addition to its role in preventing the degradation of acetylcholine by inhibiting the action of acetylcholinesterase, galantamine exerts a secondary method of action on the cholinergic system by enhancing the response of pre- and postsynaptic nicotinic receptors to the acetylcholine that is present in the synaptic cleft (). Such an enhancement might potentially be beneficial because levels of nicotinic receptors are reduced in Alzheimer’s disease patients (), and these receptors have been shown to be important for attention, learning, and memory. However, such an effect has not been proven in clinical practice. Furthermore, in theory, enhancing presynaptic nicotinic acetylcholine receptors should lead not only to a greater release of acetylcholine from the presynaptic terminal but also to a greater release of glutamate and monoamines such as serotonin and norepinephrine (). Like acetylcholine levels, the levels of serotonin and norepinephrine are low in Alzheimer’s disease patients, which is thought to contribute to cognitive and behavioral symptoms. However, clinical trials and medical practice have not convincingly shown that this additional mechanism gives galantamine an advantage over other acetylcholinesterase inhibitors (AChEIs). Galantamine has also been reported to have antioxidant properties that may contribute to its beneficial effects ().
Several clinical trials have demonstrated the benefits of galantamine in forestalling cognitive decline in Alzheimer’s disease patients. In a six-month trial of 636 patients with mild to moderate Alzheimer’s disease, patients who received galantamine (24 or 32 mg daily) fared better at month 6 of the trial on the ADAS-cog (a primary end point) than did patients who received placebo; the improvement was 3.9 points on the ADAS-cog for the 24 mg dose and 3.8 points for the 32 mg dose (). In addition, at the end of six months, galantamine patients scored better than those taking placebo on the CIBIC-plus, the second primary end point of the trial, for disability assessment. Seventy percent of patients taking 24 mg/day of galantamine and 68% of those taking 32 mg/day remained stable or had improved CIBIC-plus ratings at six months compared with 55% of patients in the placebo group. When the patients in the placebo group crossed over to 24 mg of galantamine at the six-month mark, they had an increase in cognitive functions over the new baseline but never performed as well at the end of the additional six-month period as patients who had been treated with galantamine since the beginning of the trial. These data argue in favor of starting galantamine therapy early to optimize its effect in delaying cognitive decline.
Other data suggest that galantamine improves functional symptoms in Alzheimer’s disease patients (). In a five-month study, 659 patients with mild to moderate Alzheimer’s disease (MMSE scores, 10-22) received placebo or 16 or 24 mg/day of galantamine. The primary end point was the ADCS/ADL score. At study end, patients receiving galantamine showed significant improvement in ADL scores over patients receiving placebo.
In addition to having stabilizing effects on cognition, galantamine offers some stabilization of behavioral symptoms (apathy, delusions, hallucinations), although the magnitude of its effect is minimal (). In a five-month, multicenter, placebo-controlled, double-blind study, 978 participants with mild to moderate Alzheimer’s disease (MMSE scores, 10-22) were randomly assigned to receive galantamine or placebo for 21 weeks after an initial four-week, single-blind placebo period. The primary end point was the NPI total score. At study end, mean NPI total scores worsened for patients receiving placebo and stabilized for patients receiving either 16 or 24 mg/day of galantamine. The resulting treatment-placebo difference in NPI total scores for patients treated with either dose of galantamine was statistically significant.
Like rivastigmine, galantamine may have a disease-modifying effect, albeit a minimal one, in mild to moderate Alzheimer’s disease cases. Data presented by Janssen at the 2003 European Federation of Neurological Societies conference followed galantamine-treated patients over the course of a four-year trial (). One hundred and eighty-five participants in the four-year analysis had originally enrolled in an open-label extension of two double-blind, placebo-controlled trials. Patients received 24 to 32 mg of galantamine daily during the three-to-six-month blinded portion of the study. During the open-label extensions, the patients received 24 mg of galantamine daily. Four years into the trial, the score of galantamine-treated patients declined by an average of 12.8 points on the ADAS-cog scale, which is less than half of the cognitive decline predicted for placebo-treated patients by regression analysis (cognitive deterioration of 26 to 32 points). (Regression analysis must be used to extrapolate placebo trends because it is unethical to administer placebo to patients over extended lengths of time.) More than 12% of galantamine-treated patients showed no decline over the course of the study. The researchers estimated that galantamine-treated patients gained approximately 12 to 18 months in preservation of cognition versus the projected decline in untreated Alzheimer’s disease patients. Experts suggest that if a treatment only has symptomatic effects, the performance of placebo-treated patients who are then placed on the drug should begin approaching that of patients treated since the beginning of the trial (). Because patients formerly on placebo for three to six months still experience a cognitive deficit compared with patients continually treated with galantamine after four years, researchers hypothesize that the drug affects underlying causes of Alzheimer’s disease.
Galantamine dosing must be carefully titrated because its side effects are more common than those that occur with donepezil. Side effects include nausea (in 40% of those treated with galantamine, compared with 13% of those given placebo), diarrhea (16% versus 10%), and vomiting (23% versus 7.5%) ().
Recent data from studies of patients with MCI have uncovered a higher risk of mortality in patients treated with galantamine, although the extent to which the same risk applies for Alzheimer’s disease patients is unknown. In GAL-INT-11, 6 of 442 MCI patients receiving galantamine and 1 of 452 MCI patients receiving placebo died because of treatment-emergent adverse events during the double-blind treatment period. In GAL-INT-18, 7 of 498 MCI patients receiving galantamine and no patients receiving placebo (n = 511) died because of treatment-emergent adverse events during the double-blind treatment phase or within 30 days after the end of treatment. Although study investigators did not attribute any of the deaths to galantamine, these data are being analyzed further in a study with the protocol number GAL-COG-3002. According to an interim analysis of data collected from 89% of patients, the relative risk of mortality is 1.73 for galantamine as compared with placebo based on an intention-to-treat analysis at 24 months (plus a 30-day follow-up period). The revised incidence of mortality in the two double-blind MCI studies is 0.5% in the placebo group and 1.5% in the galantamine group. Separation in death rates of the placebo and galantamine treatment groups becomes apparent within the first three months of exposure in these MCI studies, but the authors note that there were no differences in death rates between placebo and galantamine treatments during Alzheimer’s disease placebo-controlled studies of up to six months. The authors suggest that these findings indicate that the mortality rates from the MCI studies cannot be generalized to the Alzheimer’s disease population. Furthermore, the authors note that the MCI clinical studies analyzed were not designed with adequate statistical power to compare mortality; thus, the results are preliminary. Although galantamine will likely still be used for the treatment of Alzheimer’s disease, if a warning is placed on the label, doctors may hesitate to prescribe galantamine to their Alzheimer’s disease patients.