The ADCS-ADL (Alzheimer's Disease Cooperative Study Activities of Daily Living) scale showed the pattern of early improvement observed with other scales. The 2-mg group maintained its gains, but the between-group difference was not significant at the end of the study (P = .0925; effect size 0.20). Nor was there a significant 24-month difference in the MMSE (P = 0.0955; effect size 0.21).
A composite measure of cognition that included word recall on the ADAS-Cog, word recognition, word association, and orientation significantly favored the 2-mg group (P = .0037; effect size 0.42), as did a composite measure of memory (P = 0.0088; effect size 0.37).
Besides being richly distributed in the hippocampus and frontal cortex, alpha-7 nicotinic acetylcholine receptors are found in many other tissues, including the gut and skeletal muscles. A compound that attaches nonselectively could be loaded with adverse effects, including cardiovascular changes and unpleasant GI reactions. These adverse effects have proved difficult to overcome, and in fact are one reason that a number of nicotinic acetylcholine receptor studies have been discontinued.
"A number of companies tried to develop these, but at high dose levels that had indiscriminate stimulation of the receptors," Dr. Hilt said. "When you give a neurotransmitter to affect receptors in the brain, you have to live with the consequences of stimulating that receptor everywhere. The way we have dealt with this is to use a drug with a very long half-life, in very low concentrations."
The long half-life allows the drug to build up slowly, and keeps levels at a steady concentration without extreme peaks or nadirs. "It turns out this receptor is very finicky. Too high a level overstimulates it and too low a level doesn’t stimulate it at all. I’m convinced this is the major trouble with some of these other drugs."
Adverse events in the trial were mild gastrointestinal issues, including nausea and constipation. No patients of the active-drug study groups withdrew because of an adverse effect. The rate of adverse events in the 2-mg group also varied by baseline medication status, with more among those already taking an AChEI at baseline than among those not on the drugs (64% vs. 42%). Similar differences in adverse events rates occurred in the other treatment groups, although the rates were lower than in the 2-mg group. These differences reflect the expected problems with AChEI drugs, with the additional increase due to EVP-6124, Dr. Hilt said.
All told, there were 23 serious adverse events in the study: 4 in the placebo group, and 19 in the active groups. The investigators deemed that only two were treatment related; two additional events were considered possibly related to treatment.
Dr. Hilt said that EnVivo plans to go forward with a phase III trial early next year.
Dr. Aisen serves as a consultant to Eisai, Pfizer, Novartis, and other companies. He also receives research support from Pfizer and others.