VANCOUVER, B.C. – An investigational drug has shown promise in improving memory and cognition in patients with mild to moderate Alzheimer’s disease in a 6-month, randomized, placebo-controlled trial that was presented at the Alzheimer’s Association International Conference 2012.
The fact that the patients were still continuing to improve on statistically significant measurements of those aspects of the disease provided a hint, at least, that the drug EVP-6124, an alpha-7 nicotinic acetylcholine receptor partial agonist, could change the course of Alzheimer’s.
But it’s too soon to place any long-term bets, Dr. Dana Hilt said in an interview.
"This is being investigated as a procognitive and symptomatic drug," said Dr. Hilt, senior vice president of clinical development and chief medical officer of EnVivo Pharmaceuticals, which funded the trial. "It certainly appears to improve cognition in a clinically beneficial way at 6 months. But if the curves continue to diverge, is it possible that something more fundamental could be going on? Could this be maintained at 12 months? That’s what we need to know."
Dr. Paul S. Aisen, director of the Alzheimer's Disease Cooperative Study and a professor of neurosciences at the University of California, San Diego, said that EVP-6124’s phase II data looked very good.
"Reviewing the results, I would consider this to be a solidly positive trial," he said in an interview. "While we cannot rely on a relatively small phase II trial to accurately indicate the size of a treatment effect, the consistency of the findings here are encouraging. If efficacy is confirmed in additional trials, this may prove to be an important therapeutic option."
The study group comprised 409 patients who were randomized to one of three drug doses (0.3 mg, 1 mg, or 2 mg daily), or to placebo.
Half of the group were on stable doses of donepezil (Aricept) or rivastigmine (Exelon) and half were not taking any acetylcholinesterase inhibitor (AChEI), at least at the time of the trial, Dr. Hilt said. "Some of them had never taken an AChEI, and some had taken them in the past but were now off, for a number of reasons," including insurance coverage and lack of efficacy.
The subjects’ mean MMSE (Mini-Mental State Exam) at baseline score was 20, but the range was wide, from 12 to 29; the mean score on the CDR (Clinical Dementia Rating) scale was 6.
The primary end points were changes in the ADAS Cog-13 (Alzheimer’s Disease Assessment Scale Cognitive-13) and the CDR sum of boxes scores. Additional prespecified end points were the ADAS Cog-11 and composite measures of cognition and memory.
In each finding, Dr. Hilt noted effect size as well as statistical significance. Effect size is important in clinical trials because it suggests clinical efficacy better than statistical findings, he said in an interview.
"The effect size of approved drugs is somewhere around 0.15-0.28. In terms of clinical change, an effect size of 0.2 is something a trained clinician could detect. And effect size of 0.4 is something the next-door neighbor could detect."
During the first month of the study, the lower-dose groups and the placebo groups all improved their ADAS Cog-13 scores, a finding consistent with a placebo effect often seen in such studies. Interestingly, the 2-mg group remained at baseline for the first 4 months of the trial; after 4 months, cognition scores increased rapidly and outstripped all of the other groups. By the end of the study, the 2-mg group had a mean improvement of 1.5 points over baseline, whereas the placebo group had dropped below baseline, giving a total group separation of 2.2 points (P = .0189; effect size 0.39). This effect size is higher than the 0.28 estimated for high doses of donepezil, rivastigmine, or memantine (Namenda), Dr. Hilt said.
At the end of the treatment period, the curves were still diverging, suggesting that longer treatment might confer more benefit.
On the CDR sum of boxes, the 2-mg dose also performed significantly better than placebo. Again, there was the early upward trend for all groups, including placebo. But after 4 months, the placebo group and the active groups of 0.3 mg and 1 mg began losing those gains. The 2-mg group maintained its gain (P = .0253; effect size 0.31).
Findings on the secondary end points were similarly encouraging, although all were not statistically significant, Dr. Hilt said.
On the ADAS Cog-11, those taking the 2-mg dose faired significantly better than did those in any of the other groups. By the end of the study period, the lower-dose groups and placebo group had declined below baseline to the same degree. The 2-mg group had improved significantly and was still on an upward trend (P = .0151; effect size 0.34).