Background

PF-06648671 is a γ-secretase modulator Pfizer was developing for the treatment of Alzheimer's disease. No preclinical information is publicly available on this compound.

Findings

From December 2014 to March 2015, Pfizer conducted a single-ascending-dose study in 18 healthy volunteers to assess routine safety and pharmacokinetic parameters, as well as measures related to the pharmacodynamics of plasma Aβ40 and Aβ42.  

From May 2015 to October 2016, a second study enrolled 92 healthy elderly volunteers in Belgium for a two-week, once-daily regimen of ascending doses ranging from 4 to 100 mg of PF-06648671. It aimed to determine the maximum tolerated dose and assess drug interactions with the cytochrome P450 probe midalozam at that dose. Besides safety, pharmacokinetic, and pharmacodynamic measures of PF-06648671 in blood, CSF, and urine, additional outcome measures assessed the change from baseline in CSF concentrations of Aβ37, 38, 40, 42. 

From October 2015 to March 2016, Pfizer enrolled 22 healthy volunteers in California to characterize the effect of single doses on the dynamics of CSF Aβ37, 38, 40, 42, and Aβ total concentration using serial sampling of spinal fluid over 36 hours. This study used doses of 300 mg and lower. In the fall of 2016, Pfizer conducted a small drug interaction study with the CYP3A4 inhibitor itroconazole in 12 healthy volunteers.

At the 2016 AAIC conference, Pfizer reported that this γ-secretase modulator was safe and well-tolerated at single doses of up to 360 mg and dose-dependently lowered plasma Aβ40 and Aβ42 (Qiu et al., 2016). At the 2017 AAIC conference, Pfizer scientists reported that, as modeled, PF-06648671 shifted APP cleavage away from Aβ42 production and toward Aβ37 and Aβ38 production in CSF, without changing total Aβ levels (Ahn et al., 2017).

In January 2018, Pfizer announced it was discontinuing research and development in neurology, including this compound. Trial results were subsquently published (Ahn et al., 2020).

For all trial listings on this drug, see clinicaltrials.gov.