SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.
Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.
The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional endpoints were secondary. It comprised only 32 patients at baseline, 25 of whom completed both the 5-week, randomized, dose-finding, crossoverand the 52-week, open-label, extension . There was no placebo comparator. Instead, the study used three different sets of historical control data taken from other Alzheimer’s studies.
Nevertheless, the positive results are enough to propel ANAVEX 2-73 forward. The company will continue to treat and follow the extension study cohort, and plans to launch a placebo-controlled study in 2017, said Dr. Macfarlane, head of clinical governance for The Dementia Centre in Melbourne.
The 5-week, randomized, dose-finding, crossover trial started one group of patients on 30 or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 11 days of 3 mg/day or 5 mg/day intravenously. A second group first received 11 days of 3 mg/day or 5 mg/day ANAVEX 2-73 intravenously after an initial 2-day, single-dose, pharmacokinetic analysis, followed by an 11-day washout period, and then 30 or 50 mg/day oral ANAVEX 2-73 for 11 days. This was followed by a 52-week, open-label, extension trial of 10-50 mg/day orally, titrating each patient to the maximum tolerated dose. The extension phase was originally planned to last 6 months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.
The sigma-1 receptor targeted by ANAVEX 2-73 is 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 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, seeming to display a cognition-enhancing effect in both wild-type and AD model mice.
The mean age of the patients in the extension study was 71 years. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of acetylcholinesterase inhibitor. During the extension phase, they were titrated to the maximum tolerated dose; 14 mg was the minimum dose necessary to achieve a therapeutic effect and keep the MMSE stable, but Dr. Macfarlane didn’t discuss detailed dosing.
The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogramMMSE score, the and the . The was also employed as a neuropsychiatric symptom measure.
The cohort had low baseline depression scores, with a mean score of 2 on the HAM-D. By study’s end, that had decreased to a mean of 1 point. The biggest change was seen in insomnia; all patients who endorsed it at baseline reported it gone by 12 weeks into treatment.
Patients also reported improvements in their ability to work or do other activities, in anxiety, agitation, hypochondriasis, and insight.
The P300 wave amplitude showed a small initial bump from about 6 to 7 microvolts by 4 weeks, and then a dip back down to about 6 microvolts until about week 32. Thereafter it steadily improved, landing at around 8 microvolts by 57 weeks – a level usually seen in healthy age-matched controls. There was a significant separation from the P300 decline seen in a matched historical Alzheimer’s, which dropped to about 4 microvolts over a 52-week period while patients were taking donepezil.
The study employed a second historical control group in another cognitive assessment using the Computerized Cogstate Alzheimer’s Battery. All subjects in the large Australian prospective cohort study, called(Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing), were taking standard of care Alzheimer’s drugs. Compared with that cohort, the ANAVEX 2-73 group experienced benefits in processing speed, attention, and working memory, which became statistically significant at week 31 and continued to grow.
At 57 weeks, the mean MMSE score was stable, hovering around the baseline of 20. The ADCS-ADL declined slightly, from a mean of around 70 to around 65.
Finally, the investigators used yet another historical cohort as a comparator in a statistical analysis of projected cognitive and functional benefit. Compared with a pooled, placebo-arm, cohort study conducted by the Alzheimer Disease Cooperative Study Group over 12 months, ANAVEX 2-73 would have been associated with 1.8-point bump in score on the MMSE (P less than .016) and a 4-point benefit on the ADCS-ADL (P less than .019).
“The MMSE declined 45% less and the ADCS-ADL declined 56% less than what we would have expected from the historical control data,” Dr. Macfarlane said. “This is not only statistically significant, but clearly clinically meaningful for patients.”
Nearly all patients (98%) had some sort of adverse event, but most of them were mild transitory dizziness or headache; 76% of the events were grade 1, and 2% were grade 2. There were no serious adverse events. Three subjects dropped out because of adverse events (delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care AD medications.
Dr. Macfarlane has no financial interest in ANAVEX 2-73. He reported consultancies with Eli Lilly, Janssen-Cilag, and Lundbeck.