Can a Sigma-1 Agonist Stabilize Cognition and Function in Alzheimer’s Disease?

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 disease who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on the Mini-Mental State Examination (MMSE) and 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.

ANAVEX 2-73 (Anavex Life Sciences, New York) also conferred an unexpected benefit upon subjects with insomnia. “Any patient who scored on the insomnia measure [of the Hamilton Depression Rating Scale] at baseline had no sleep disturbance at all by weeks 12 and 26,” Stephen Macfarlane, MBBS, said at the Clinical Trials on Alzheimer’s Disease conference.

Stephen Macfarlane, MBBS

The findings must be interpreted cautiously. The phase IIa study was designed to assess safety and tolerability; cognitive and functional end points were secondary. It comprised 32 patients at baseline, 25 of whom completed both a five-week, randomized, dose-finding, crossover trial and a 52-week, open-label, extension study. There was no placebo comparator. Instead, researchers used three different sets of historical control data.

Investigators will continue to treat and follow the extension study cohort, and plan to launch a placebo-controlled study in 2017, said Dr. Macfarlane, Head of Clinical Governance for the Dementia Centre in Melbourne.

The five-week, randomized, dose-finding, crossover trial started one group of patients on 30 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days after an initial two-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 mg/day or 50 mg/day oral ANAVEX 2-73 for 11 days. This trial 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 six months, but patients and caregivers wanted to continue on the medication, so the company extended it to 12 months. It is ongoing.

An Attractive Drug Target

The sigma-1 receptor targeted by ANAVEX 2-73 is found on neurons and glia in many areas of the CNS. 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 seemed to enhance cognition in wild-type and Alzheimer’s disease–model mice.

The mean age of patients in the extension study was 71. The median MMSE score was 20.5. Most patients (78%) were taking a stable dose of an 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.

The primary end points were safety, tolerability, and pharmacokinetics. The exploratory measures included the P300 electroencephalogram, MMSE score, the Computerized Cogstate Alzheimer’s Battery, and the ADCS-ADL. The Hamilton Depression (HAM-D) Scale 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 the study’s end, it had decreased to a mean of 1 point. Patients also reported improvements in their ability to work or do other activities, and in anxiety, agitation, hypochondriasis, and insight.

Electrophysiologic Measures

The P300 wave amplitude showed a small initial increase from about 6 microvolts to 7 microvolts by four weeks, and then returned to about 6 microvolts until about week 32. Thereafter, it steadily improved to about 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 disease cohort, which decreased to about 4 microvolts over a 52-week period while patients were taking donepezil.

Researchers used a second historical control group to assess changes on the Computerized Cogstate Alzheimer’s Battery. All subjects in a large Australian prospective cohort study, called AIBL (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 improve.

At 57 weeks, patients’ mean MMSE score was near the baseline mean score of 20. ADCS-ADL scores declined slightly, from a mean of about 70 to approximately 65.

Finally, the investigators used another historical cohort to assess 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 benefit on the MMSE and a 4-point benefit on the ADCS-ADL.

“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%) experienced an adverse event. Most events 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 of the trial because of adverse events (ie, delirium, dizziness, and a combination of confusion, disorientation, and lethargy). There were no problematic interactions between the study drug and any standard of care Alzheimer’s disease medications.

—Michelle G. Sullivan