BARCELONA – A novel small molecule that may help clear misfolded proteins imparted some significant cognitive benefits to Alzheimer’s patients after 5 weeks, even with a mid-study washout period in which patients stopped taking the drug, according to the results of a small, open-label, uncontrolled, phase IIa crossover trial.
The investigational drug, called Anavex 2-73, also was associated with significant improvements in the P300 electroencephalogram wave, a measure of nerve conduction associated with cognitive processing, Dr. Stephen Macfarlane said at the Clinical Trials on Alzheimer’s disease conference.
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The study was small – just 32 patients with mild to moderate Alzheimer’s disease – and not powered for cognitive endpoints, said Dr. Macfarlane, director of Aged Psychiatry for Alfred Health, Victoria, Australia. Nevertheless, its clinical findings add an intriguing cachet to the study’s successful pharmacokinetic data, he said.
The results were encouraging enough for the manufacturer, Anavex Life Sciences to lengthen its preplanned 26-week extension trial to 52 weeks and move ahead with phase III planning, Dr. Macfarlane said.
Anavex 2-73 is an agonist of the sigma-1 receptor but also activates the muscarinic receptor. The sigma-1 receptoris found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is also some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. The sigma-1 receptor also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
In preclinical testing, Anavex 2-73 showed an additional cognitive property, Dr. Macfarlane said. “It seems to have a cognitive-enhancing effect, not only on transgenic mice, but on wild-type mice as well. When the [Alzheimer’s model] mice were fed it, they did significantly better on the water maze test. But when wild-type mice consumed it, they did better as well. This does suggest that it can enhance cognition.”
The study that Dr. Macfarlane presented at the conference randomized patients to either oral or intravenous treatment for 12 days, followed by a 12-day washout period, then crossed to the opposite administration for 12 days. At the end of 5 weeks, all patients were invited to continue with oral treatment out to 52 weeks. All of the 30 patients who finished the 5-week study elected to participate.
Patients were a mean of 71 years old. The median Mini-Mental State Examination (MMSE) score was 20.5. Most (78%) were taking a stable dose of acetylcholinesterase inhibitor.
The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory cognitive measures included electroencephalogram/event-related potential, MMSE, and the Cogstate battery. Function was assessed with the Alzheimer’s Disease Cooperative Study activities of daily living scale (ADCS-ADL) in patients who had completed at least 12 weeks of the follow-up study.
There were no safety concerns, Dr. Macfarlane said. While 94% of the subjects did have an adverse event, only one was considered serious. This was a case of delirium that developed in a patient who had several risk factors for the disorder, including a prior episode; it was not considered related to the study drug.
Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All incidents were considered mild or moderate.
At the end of 5 weeks, the drug was associated with a median MMSE score increase of 1.5 points. While this change was not statistically significant, improvements on five of the six Cogstate battery measures were significant, with the biggest boost seen in the one-back test of working memory.
Dr. Macfarlane compared the magnitude of improvement to that which has been seen in a large Australian prospective cohort study, AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing). The Anavex 2-73 cohort made significant gains relative to the AIBL cohort taking acetylcholinesterase inhibitors at the same time period.
“Our group improved by 1.5 standard deviations across 5 weeks [compared with AIBL subjects], which included that 12-day period with no exposure to the study drug,” Dr. Macfarlane said. “This was quite an unexpected finding but potentially an important one.”
Anavex 2-73 was also associated with significant changes on EEG measures of event-related potential, particularly the P300 wave, which measures decision-making speed. The drug closed 80% of the gap between patients and historical controls in P300 amplitude. It also closed 85% of the gap in task accuracy and 66% of that in reaction time. Finally, patients taking Anavex 2-73 exceeded control performance on false-alarm reactions by 4%.