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Patients taking the highest dose of EVP-6124, a selective partial agonist of alpha-7 nicotinic receptors, in the 24-week trial showed a mean increase of 1.6 points from baseline in the 13-item cognition part of the Alzheimer's Disease Assessment Scale (ADAS-Cog-13), said Dana Hilt, MD, of EnVivo Pharmaceuticals in Watertown, Mass., which is developing the product.
The mean change from baseline at week 24 in a placebo group was -0.4 points (P=0.0189), Hilt reported at the Alzheimer's Association International Conference.
Speaking at a press briefing held before his formal presentation, Hilt said the scale of this effect was substantially greater than has been seen with existing drugs that boost cognition without altering the underlying Alzheimer's disease pathology.
Whereas cholinesterase inhibitors such as donepezil (Aricept) have had a so-called effect size of 0.15 to 0.28 points in similar trials, depending on the dose, the effect size with 2 mg/day of EVP-6124 was 0.39 points.
Such comparisons could be questioned since the EnVivo drug was not tested directly against those drugs, only placebo, but Hilt said the effect was clearly big enough to warrant a phase III study. The company expects to begin one next year, he said.
The cognition-enhancing effect of nicotine, at least in the short term, is well known -- it's one reason why people smoke. The challenge has been to separate the cognitive benefit from the chemical's addictive properties and adverse cardiovascular effects.
EVP-6124 was designed to minimize the adverse impacts while maintaining the cognitive enhancement by targeting a specific subtype of nicotinic receptors with a partial agonist. Hilt and colleagues believe it sensitizes the receptors to endogenous acetylcholine, such that existing levels of the neurotransmitter produce a stronger effect and therefore activate the pathway more strongly.
According to EnVivo, this mechanism has the potential to be less toxic than cholinesterase inhibitors (which increase acetylcholine by blocking its degradation) and also appears to increase levels of other neurotransmitters including dopamine and glutamate.
In addition to Alzheimer's disease, the company believes the product may be helpful in schizophrenia.
In the study Hilt reported here, 409 patients were randomized to placebo and three doses of EVP-6124 (0.3, 1, and 2 mg once a day).
Patients had mild to moderate Alzheimer's disease, defined as Mini-Mental State Examination scores of 14 to 24. Those already taking cholinesterase inhibitors were not excluded and could continue on these agents; about two-thirds of participants were in this category.
Only the 2-mg dose of EVP-6124 appeared to be effective in the trial. Those taking the two lower doses had responses virtually identical to placebo, in which ADAS-Cog-13 scores rose during the first 12 weeks but then fell back to baseline levels or below by week 24.
On the Clinical Dementia Rating-Sum of Boxes, the 2-mg EVP-6124 group showed little change from baseline, whereas the placebo group had a decline of 0.3 points by week 24 (P=0.0253), Hilt reported. Neither of the lower-dosage drug groups differed significantly from the placebo group.
Secondary cognitive endpoints such as a composite of several different tests also showed significant advantages for the 2-mg dose versus placebo.
Hilt noted that no plateau in the drug's effect was seen in the 24-week study, suggesting that the advantage over placebo could grow even larger with continued treatment.
Treatment-emergent adverse effects were seen in about half of the high-dose patients, compared with 40% of the placebo and low-dose EVP-6124 patients. Such events were more common in those also receiving cholinesterase inhibitors.
The adverse effects were mostly gastrointestinal and involved mild nausea and constipation, Hilt said. Serious events of the types and frequency normally seen in an aging population did occur, he said, but with no difference between placebo and the active drug.
He added that about 1,700 people had taken the drug in the company's trials, including those targeting schizophrenia, with no safety problems that the company considers significant.
Maria Carillo, PhD, senior director of medical and scientific relations at the Alzheimer's Association, told MedPage Today that the alpha-7 nicotinic receptor is a plausible and promising therapeutic target in Alzheimer's disease and other forms of dementia as well.
It's been extensively studied in animal models, but "this is the first time we actually see positive results in a phase II [study]," she said.
Carillo said it was encouraging that varied therapies are now rising toward clinical application. "We need to be open to different therapeutic avenues and approaches," she said.
Primary source:
Alzheimer's Association International Conference
Source reference:
Hilts D, et al EVP-6124, "a selective alpha-7 partial agonist, has positive effects on cognition and clinical function in mild to moderate Alzheimer's disease patients: Results of a six-month, double-blind, placebo controlled, dose ranging study" AAIC 2012; Abstract O4-12-04.
for new streams of revenue as their blockbuster drugs expire from patent protection.
They did this with melatonin - making a pharmaceutical analog to melatonin and charging $3 a pill for it. And the docs went for it hook line and sinker, even though time-tested melatonin was available for about one hundredth the cost.
Now they're trying it with nicotine. If they get this through, it will be unbelievably expensive, and undoubtedly less safe than nicotine.