PF-06648671 / Pfizer - LARVOL DELTA

Discovery and chemical biology of gamma-secretase modulators for Alzheimer's disease (ACS-Fall 2025) - "This presentation will describe the medicinal chemistry design strategies that resulted in the GSM clinical candidate PF-06648671. In addition, chemical biology approaches using clickable photoaffinity probes to determine the target of GSMs and GSIs within the γ-secretase complex will be discussed."

Alzheimer's Disease • CNS Disorders • APP • Aβ42

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease. (PubMed, J Med Chem) - "This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF)."

Journal • Alzheimer's Disease • CNS Disorders • Aβ42

Pharmacokinetic and pharmacodynamic effects of a γ-secretase modulator, PF-06648671, on CSF amyloid-β peptides in randomized Phase 1 studies. (PubMed, Clin Pharmacol Ther) - P1 | "No significant change in total Aβ was observed. The PKPD model well described the tendency of observed CSF Aβ data and steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials."

Biomarker • Clinical • Journal • P1 data • PK/PD data • Alzheimer's Disease • CNS Disorders