Another Alzheimer's failure: A Phase 3 trial of the 5-HT6 antagonist, intepirdine, in over 1,300 people with mild to moderate AD fails to delay memory loss or improve physical function.

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This morning Axovant Sciences announced that the Phase 3 clinical trial of its potential Alzheimer's drug, intepirdine, in patients with mild to moderate Alzheimer's disease (AD) did not meet either of its co-primary efficacy endpoints. That is, the trial failed. Intepirdine is now yet another bullet point in an increasingly long list of drugs which fail to demonstrate a benefit for AD patients in late stage clinical trials.

What is intepirdine?

Intepirdine is a strong antagonist of the 5-HT6 receptor, a largely central nervous system-specific member of the serotonin receptor subfamily. There is some evidence that the serotonergic neurotransmitter system is impaired as Alzheimer’s develops and progresses, and modulating it is seen as a potential therapeutic avenue. People were excited about intepirdine because it has been shown to reverse experimentally induced and age-related learning deficits in rats. Further it is an AD drug that doesn't target the amyloid pathway - an area which has repeatedly failed to yield a useful drug.

There were a number of caveats, though, going into this study. First, a common theme in neuroscience is that serotonin seems to be involved in everything, yet modulating it rarely has a meaningful effect. Second, and most important, several other companies had previously tested different 5-HT6 antagonists in AD and they had all failed. Even this exact drug, intepirdine, had failed to impress in a Phase 2 study sponsored by GSK. Axovant argued that GSK's trial was poorly done and that the drug, given to the right patients at the right dose, could demonstrate a benefit.

How was the trial set up?

Intepirdine was tested in a global, randomized, double-blind, placebo-controlled study, termed the MINDSET trial. The trial evaluated the efficacy, safety and tolerability of intepirdine in patients with mild to moderate AD on donepezil therapy over 24 weeks. The trial compared once-daily oral doses of intepirdine 35 mg to placebo in 1,315 patients ages 50 to 85. The Mini-Mental State Examination (MMSE) score at baseline ranged from 10 to 26. Co-primary efficacy endpoints were ADAS-Cog - a measure of disturbances of memory, language, praxis, attention and other cognitive abilities - and the ADCS-ADL - a measurement of how patients are able to perform in more functional, day to day tasks.

What were the results?

We don't yet have a detailed report of the results. We know the trial failed to demonstrate a stat sig improvement in either of its two co-primary endpoints. Specifically, at 24 weeks, patients treated with 35 mg of intepirdine did not experience improvement in ADAS-Cog (0.36 ADAS-Cog points; p-value = 0.22) or ADCS-ADL (0.09 ADCS-ADL points; p-value = 0.83), compared to patients treated with placebo. It may be that some subgroups did better than others on the drug, time will tell. In the meantime, though, Axovant has discontinued clinical activity with this drug.

Where are we with AD drug development?

Suffice it to say, the research has not been going well. Last year we saw two more high profile failures of amyloid-targeting agents. We don't even have another strong shot on goal until 2019 (Biogen's abeta antibody, aducanumab). I think it is safe to say that the idea of targeting 5-HT6 is dead. The amyloid hypothesis is in critical condition. So what does that leave us? Tau? Anti-inflammatories? Obviously something is needed because AD is a devastating disease and it is becoming increasingly common as we live to older ages.

">Another Alzheimer's failure: A Phase 3 trial of the 5-HT6 antagonist, intepirdine, in over 1,300 people with mild to moderate AD fails to delay memory loss or improve physical function.