Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects

Abstract

CHF5074 has been shown to inhibit brain β-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.

γ-Secretase inhibitors and modulators

“…TheGSM, CHF5074, based on R-flurbiprofen developed by Chiesi Pharmaceuticals has advanced the furthest in human testing completing a phase II trial [157]. Recent data suggest that while this compound may possess GSM activity it may have a rich pharmacology and may have additional mechanism(s) of action besides altering Aβ42 [187-189]. One clear challenge in the development of potent GSMs that have been recently reviewed [160], is the balance between liophillicity and potency.…”

Amyloid beta modulators and neuroprotection in Alzheimer's disease: a critical appraisal

“…However, the study was stopped because of non-mechanism-based liver toxicity [54,55]. By contrast, CHF-5074 and NIC5-15 are γ-secretase inhibitors that have been found to reduce Aβ levels in patients with AD (https://clinicaltrials.gov/ct2/show/NCT01203384; https://clinicaltrials.gov/ct2/show/NCT01303744 [56]). The Phase II trial investigating NIC5-15 is ongoing, whereas the Phase II trial studying CHF-5074 was terminated because of adverse effects (Table 3) (https://clinicaltrials.gov/ct2/show/NCT00470418 [57]).…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…Interestingly, AICD-overexpressing TG mice show AD-like tau HP, GSK-3b activation, memory deficits, and neuroinflammation [94,95]in vivo neuroprotection by CHF5074 may at least partially depend on AICD modulation. A short-term Phase I study of CHF5074 in healthy volunteers (p.o., 200/400/600 mg/day, 2 weeks' treatment) shows absence of relevant AEs, a linear PK profile, limited brain exposure (≈0.6% of plasma concentration), no effects on plasma and brain Ab levels, and preliminary evidence of reduction of microglia activation [96]. A small Phase II study on MCI patients (p.o., 200/400/600 mg/day, 12 weeks' treatment) shows good tolerability and an acceptable AE profile [95].…”

“…A small Phase II study on MCI patients (p.o., 200/400/600 mg/day, 12 weeks' treatment) shows good tolerability and an acceptable AE profile [95]. CHF5074 causes dose-dependent reduction of biomarkers of neuroinflammation in the CSF of patients, while Ab and tau levels are unchanged [96]. An open label extension of the study shows a non-significant trend of cognitive improvements, especially in patients carrying the apolipoprotein E4 (ApoE4) gene [97].…”