Metrifonate: Another Cholinesterase Inhibitor for Alzheimer's Disease Palliation
ABSTRACTS & COMMENTARY
Sources: Cummings JL, et al. Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Neurology 1998;50: 1214-1221; Morris J, et al. Metrifonate benefits cognitive, behavioral and global function in patients with Alzheimer's disease. Neurology 1998;50:1222-1230.
These two double-blind, placebo-controlled, clinical trials indicate that once-a-day treatment with metrifonate, an irreversible acetylcholinesterase inhibitor, provides symptomatic benefits for patients with mild to moderate Alzheimer's disease (AD). The benefits and the adverse events associated with metrifonate may be comparable to that of the already-approved AD therapies. Metrifonate, which has been used for many years as a treatment for schistosomiasis, is metabolized non-enzymatically into a molecular form that binds stably to the catalytic site of acetylcholinesterase (AChE). The result produces a sustained inhibition of both AChE and butylcholinesterase, permitting once daily dosing of metrifonate for symptomatic AD.
Patients included in these company-sponsored (Bayer) trials met criteria for probable AD and had baseline Minimental State Examination (MMSE) scores between 10 and 26. Both studies employed two-week loading doses of metrifonate to accelerate steady state levels of AChE inhibition. Patients treated in the Cummings' 30-week, dose-finding study (n = 480) received maintenance therapy with low-, medium-, or high-dose metrifonate or placebo, while patients in the 36-week Morris-studied group (n = 408) received either high-dose (0.65 mg/kg) metrifonate or placebo. Primary outcome measures included the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinician's Interview-based Impression of Change with Caregiver Input (CIBIC-plus). Morris et al also evaluated behavioral measures with the Neuropsychiatric Inventory (NPI). Both studies evaluated safety and compliance issues.
Both intent-to-treat and valid-for-efficacy analyses indicated that metrifonate significantly improved the primary outcome measures in both studies. Cummings found the magnitude of the improvement was dose dependent, with the most robust improvement associated with the 0.65 mg/kg maintenance dose. At this dose, gains on the ADAS-Cog averaged 2.94 points, while the CIBIC-plus improved an average of 0.35 points. Similar benefits accompanied in Morris' study; 0.65 mg/kg metrifonate yielded an average gain of 2.86 points on the ADAS-cog and 0.28 points on the CIBIC-plus. Morris reported an average improvement on the NPI of 3.9 points, with hallucinations being the only subitem that changed significantly. Changes in MMSE, which was employed as a secondary outcome measure of cognition, differed between the two studies. Cummings found a small (< 1.4 point) but statistically significant improvement on the MMSE after 12 weeks at all dosages studied; Morris reported no significant change in MMSE after 26 weeks of treatment.
A high percentage of study participants completed these studies. In the Cummings study, 96% of placebo subjects and 94% of metrifonate receivers completed the study. In the Morris study, 88% of placebo-treated and 78% of metrifonate-treated participants completed the trial. Adverse events between the two studies were similar and mostly comparable to those occurring with other acetylcholinesterase inhibitors, namely diarrhea, abdominal pain, nausea, leg cramps, flatulence, and rhinitis. Metrifonate at 0.65 mg/kg reduced heart rate by an average of five beats per minute relative to placebo-treated controls. Three patients in Cummings' study developed symptomatic bradycardia and discontinued the medication during the loading dose phase. Both studies concluded that metrifonate was generally well-tolerated and effective for symptomatic treatment of mild to moderate AD.
COMMENTARY
Metrifonate is one of several cholinesterase inhibitors reportedly under consideration by the FDA for AD palliation, making it likely that one or more agents will soon be approved as alternatives to Cognex and Aricept. The published studies show little difference between Cognex, Aricept, and metrifonate in terms of efficacy, although some differences affect their relative ease of use and side effects. Currently, Cognex's hepatic toxicity and qid dosing make it the least attractive of these agents. No published studies of cognitive effect directly indicate any clear advantage of metrifonate over Aricept. Nevertheless, large-scale clinical trials do not always predict individual responses, and, conceivably, some patients may respond better to one agent or the other. Despite the fact that metrifonate was associated with a symptomatic bradycardia of five beats per minute in a single person, this was a rarity. Neither study reported the percentage of patients responding to metrifonate, nor did they discuss whether or not a loading dose of metrifonate should be given.
Several studies have clearly demonstrated that acetylcholinesterase inhibitors can provide a modest degree of symptomatic improvement in a subset of AD patients. The positive effect of these agents on cognition, as well as on some aspects of comportment and daily function, are often sustained for at least several months. Sometimes the response has been to postpone by several months undesirable and expensive nursing home admission. In the absence of curative treatments, cholinesterase inhibitors can be recommended for symptomatic treatment of mild to moderate AD. Nevertheless, both physicians and caregivers must be realistic about treatment outcome, since cholinesterase inhibitors often have little or no functional effect on AD behavior. Better results, hopefully, lie in the future. -nrr
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