Intepirdine from Axovant is as an experimental oral, once daily treatment for people with mild to moderate Alzheimer’s disease who are also taking Aricept (donepezil). Intepirdine is a potent antagonist of the 5HT6 receptor. The 5HT6 receptor is expressed mainly in the brain and spinal cord and is involved in learning and memory processes, which are usually impaired in AD.

How intepirdine works

Intepirdine blocks the 5HT6 receptor promoting the release of acetylcholine within the brain, an important neurotransmitter responsible for alertness, memory, though, and judgment, key components of cognition and function that are compromised in people with AD.

Aricept, a cholinesterase inhibitor, also increases acetylcholine, but in a nonselective and indirect way, by preventing its breakdown.

When used together with Aricept, they increase the concentration of acetylcholine through a complementary mechanism without worsening Aricept’s side effects, such as nausea and vomiting.

Intepirdine in clinical trials

Results from a Phase 2b study were presented at the 2017 Annual Meeting of the American Association for Geriatric Psychiatry (AAGP). Participants with mild to moderate AD who were receiving stable Aricept treatment were randomized to either receive 35 mg of intepirdine, 15 mg of intepirdine, or a placebo. The primary objectives were assessed at week 24 and showed that participants receiving 35 mg of intepirdine had a statistically significant difference in the Instrumental and Total Independence Activities of Daily Living scales, a scale to use disease severity, suggesting that the 35 mg dose of intepirdine has the potential to provide benefits for AD patients.

A Phase 3 study (NCT02585934) called MINDSET to confirm the efficacy of intepirdine as an adjunctive therapy to Aricept for the treatment of AD has been completed. Primary objectives included changes on the Alzheimer’s Disease Assessment Scale and Alzheimer’s Disease Cooperative Study at 25 weeks, scales for assessing both behavior and functioning. Secondary objectives assessed the disease progression and adverse events.

Axovant has just announced negative results from this study as primary objectives were not met: although interpidine was well tolerated, participants treated with 35 mg of intepirdine did not improve in any of the disease assessment scales compared to participants treated with placebo.

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