BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer listsas a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.