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
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