Background

SAM-760 is an orally available antagonist of the serotonin 6 receptor (5-HT₆). By modulating serotonin levels in the brain, 5-HT₆ antagonists are thought to lead to secondary increases in the levels of the neurotransmitters acetylcholine and glutamate, benefitting learning and memory. Wyeth originally developed PF-5212377 as WYE-103760, also known as SAM-760, before becoming a subsidiary of Pfizer in 2009.

Findings

Between 2009 and 2014, Wyeth and then Pfizer conducted four Phase 1 trials of PF-05212377 in about 230 healthy volunteers. One trial, conducted in France, evaluated the effect of a single dose of PF-5212377 on scopolamine-induced cognitive impairments for its ability to improve performance in the Groton Maze Learning Task. Also in France, a multiple-ascending-dose study assessed safety, tolerability, and pharmacokinetics of once-daily dosing for 14 days, and a similar study evaluated ascending single doses of PF-5212377. A U.S. trial using positron emission tomography (PET) correlated plasma drug levels and 5-HT₆ receptor binding in the brain following a single dose.

In November 2012, Pfizer initiated a Phase 2 study to assess the efficacy of a 30 mg capsule of PF 5212377, taken once daily, in mild to moderate Alzheimer's patients with neuropsychiatric symptoms who are on a stable dose of donepezil (NCT01712074). Change on the ADAS-cog 13 was the primary outcome measure, change on the NPI the secondary outcome. This trial was intended to enroll 342 patients from the United States, but stopped after 186. In October 2015, Pfizer terminated this study because a futility analysis indicated lack of efficacy; results were published in 2016 at AAIC (Fullerton et al., 2016).

In November 2013, Pfizer started a Phase 1 study in four healthy volunteers to determine 5-HT₆ receptor occupancy levels achieved with single oral doses of 70 mg of PF-5212377 and less. News coverage of the trial's termination included claims of receptor occupancy needed to achieve efficacy (see Feb 2016 FierceBiotech story).

Clinical Trial Timeline