Today, Axovant Sciences in Basel, Switzerland, released topline results from its Phase 3 MINDSET trial of the 5-HT6 inhibitor intepirdine. The drug failed to improve cognition or activities of daily living relative to placebo in patients with mild to moderate Alzheimer’s disease (AD). The data comes a year after the Danish pharmaceutical company Lundbeck reported that another 5-HT6 antagonist, idalopirdine, had failed in a Phase 3 AD trial (Sep 2016 news; Aug 2017 conference news). Pfizer also recently closed the door on its 5-HT6 antagonist PF-05212377 after it was projected to miss primary endpoints. GlaxoSmithKline developed intepirdine, formerly SB-742457, through Phase 2, but based on the efficacy results decided to discontinue the drug. GSK sold the rights to Axovant in December 2014 for $5 million.

  • Intepirdine failed in Phase 3.
  • The drug did not improve cognition or activities of daily living in patients with mild to moderate AD.
  • News of the failure sent Axovant’s share price plunging.

Axovant’s announcement today came as no shock to AD clinicians. Lon Schneider, University of Southern California, Los Angeles, noted that only one of four Phase 2 trials of intepirdine indicated the drug could slow cognitive decline. “Although I was not surprised by the outcome, there was always the chance that the study could have been positive,” he wrote to Alzforum (see full comment below). Because of the trial design, it could have detected a drug-placebo difference on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as small as 0.8 points, wrote Schneider. 

MINDSET enrolled 1,315 patients already taking the acetylcholinesterase inhibitor donepezil. Additionally, they received a daily oral dose of either 35 mg intepirdine or placebo for 24 weeks. At the end of the trial, treated patients showed no statistically significant improvement in either primary endpoint, the ADAS-Cog, or the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL). Researchers detected a hint of improvement in the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), which was a secondary endpoint.

News of the drug failure sent the company’s share price plunging more than 70 percent, after recent activity had pushed it above $26 last Friday.

"It is not entirely surprising, given the history of the related drugs and the history of this particular drug, that there was a negative Phase 3 readout on this study,” said Lawrence Honig, Columbia University, New York. Axovant is still pursuing intepirdine as a treatment for dementia with Lewy bodies (DLB) in the Phase 3 HEADWAY trial (for which Honig is an investigator). Researchers expect results by October 2017. An open-label extension of MINDSET will continue, according to an Axovant press release.—Gwyneth Dickey Zakaib


  1. Consider that what we are doing in Alzheimer-related drug development is trying to develop drugs that are expected to have very small statistical and clinical effects. The Phase 3 trials are based on the outcomes from negative Phase 2 trials. The very few Phase 2 trials that proffer “statistical significance” usually are not significant on primary or secondary outcomes, but only on a post hoc or subset analysis. The one or two Phase 2 trials that did report statistical significance on a primary or co-primary outcome didn’t show support from their secondary outcomes (e.g., p values of 0.12 are not supportive).

    The follow-on Phase 3 trials that are considered to be confirmatory are designed largely to account for the uncertain information provided by Phase 2 and to ensure that there is statistical power to detect very small or uncertain effects.

    Axovant modelled their MINDSET Phase 3 trial on the only one of four Phase 2 trials that showed an ADAScog signal favoring intepirdine over placebo: a -1.5 point difference with a 95 percent CI of -2.7 to -0.3. They contributed a bit to advancing trials methods by building added features into the trial to enhance signal detection and precision by including central monitoring, a screening ADAScog before baseline, essentially monthly ADAScogs and ADLs measures, and a sample size of 1,150 (expanded to 1,315 midway into the study).

    The MINDSET trial probably could have detected an ADAScog drug-placebo difference as small as 0.8 points at p =.05, if intepirdine had had that effect. Interestingly, the 0.36 ADAScog difference they reported today is within the 95 percent confidence interval of the Phase 2 trial; so in an important sense they confirmed their Phase 2 trials outcomes.

    An interesting thought experiment is “what if” intepirdine had shown, say, a 1 point, statistically significant ADAScog advantage along with its reported 0.12 point advantage on the CGIC (which was given a p value = .02)? How would the community and FDA have received it? The nominally significant CGIC often taken as a measure of “clinical meaningfulness,” and the obligatory subset analyses will raise interesting questions for some. So, although I was not surprised by the outcome, there was always the chance that the study could have been positive.

  2. This is another disappointment for a field that has seen so many over the past 14 years. There was reason to hope that this drug would provide a cognitive benefit on top of background donepezil therapy; the study failed to demonstrate this. We have no choice but to redouble our efforts to advance AD therapeutics.

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Therapeutics Citations

  1. Intepirdine
  2. Idalopirdine
  3. PF-05212377
  4. Donepezil

News Citations

  1. STARSHINE Trial Loses its Luster
  2. At AAIC, Yet Another Phase 3 Flop While Phase 1 Trials Forge Ahead

External Citations

  1. results

Further Reading

No Available Further Reading