Synonyms: BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Pfizer developed the BACE 1 inhibitor PF-06751979 for the treatment of Alzheimer's disease to Phase 1. This inhibitor is selective for BACE1 over BACE2 and the related aspartyl protease Cathepsin D. It enters the brain, and reduces the CSF Aβ42 concentration in mice and dogs. In contrast to nonselective BACE inhibitors, PF-06751979 induced no depigmentation in human melanocyte cultures, and chronic administration to dogs for up to nine months causes no loss in coat pigmentation (O’Neill et al., 2018). This drug was given as an oral suspension.
Between July 2015 and July 2016, Pfizer conducted a first-in-human, single- and multiple-ascending-dose trial of PF-06751979 in 55 healthy people in California. Doses ranged from 3 to 160 mg; treatment duration was up to two weeks. Primary outcome measures included a wide range of safety measures; secondary outcomes included plasma pharmacokinetics, as well as quantification of various CSF Aβ fragments at baseline and at two weeks.
In June 2016, a second trial started enrolling 46 elderly volunteers to evaluate single- and multiple-ascending doses ranging from 200 to 700 mg against placebo. Outcomes included numerous safety and pharmacokinetic and -dynamic measures, as well as measurement of these Aβ fragments: Aβ1-40, Aβ1-42, Aβ total, Aβx-40, Aβx 42, sAPPα, sAPPβ. This trial took place in Belgium. At the 2017 AAIC conference, Pfizer published results of these two trials as showing PF-06751979 to have been safe and well-tolerated, and to have reduced plasma and CSF Aβ in a dose-dependent fashion (podium presentation by Qiu et al., 2017).
In April 2017, a third trial evaluated the effect of this drug on the pharmacokinetics of midalozam in 12 healthy volunteers.P fizer published results of all three trials as showing PF-06751979 to have been safe and well-tolerated, with no drug interaction with midalozam. PF-06751979 reduced plasma and CSF Aβ in a dose-dependent fashion (Qui et al., 2019).
In January 2018, Pfizer announced it was ending its research and development in neurology, including this compound.
For all trials on this compound, see clinicaltrials.gov.
Last Updated: 29 Nov 2019
- Qiu R, Ahn JE, Alexander R, Brodney MA, He P, Leurent C, Mancuso J, Margolin RA, Tankisheva E, Chen D. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects. J Alzheimers Dis. 2019;71(2):581-595. PubMed.
- O'Neill BT, Beck EM, Butler CR, Nolan CE, Gonzales C, Zhang L, Doran SD, Lapham K, Buzon LM, Dutra JK, Barreiro G, Hou X, Martinez-Alsina LA, Rogers BN, Villalobos A, Murray JC, Ogilvie K, LaChapelle EA, Chang C, Lanyon LF, Steppan CM, Robshaw A, Hales K, Boucher GG, Pandher K, Houle C, Ambroise CW, Karanian D, Riddell D, Bales KR, Brodney MA. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. J Med Chem. 2018 May 24;61(10):4476-4504. Epub 2018 Apr 17 PubMed.