Objective: To evaluate the safety, tolerability, and pharmacokinetics of FNP-223 (formerly ASN90) in healthy volunteers (HV).

Background: Proteinopathies remain largely untreatable and novel therapies are urgently needed. PSP is a tauopathy characterized by the intracellular accumulation of misfolded tau protein. FNP-223 is an oral OGA inhibitor that has been shown to prevent tau tangle formation, slow motor decline and extend survival in preclinical models.

Method: Phase 1, double-blind, randomized, placebo-controlled SAD and MAD study conducted in two parts: in part 1, HV (18-55y; part 1a and 55-80y; part 1b) received single ascending oral doses of FNP-223 or placebo; in part 2, HV (55-80y) received multiple oral doses of FNP-223 or placebo BID for 12 days. PK profile was assessed in plasma after single and multiple doses and in CSF after multiple-dose administration. Safety was assessed by physical examinations, clinical laboratory evaluations, vital signs, ECGs, telemetry and monitoring of AEs.

Results: 25 subjects received SAD up to 1000mg of FNP-223 or placebo, and 24 subjects received MAD up to 500mg BID of FNP-223 or placebo. FNP-223 was considered safe and well tolerated. No deaths, serious treatment-related AEs, or discontinuations due to an AE were reported. All AEs were rated as mild (except 1 headache of moderate intensity), with no treatment or dose-related trends in frequency or severity. Most common AEs were nausea, dysgeusia and dizziness. No clinically significant changes in physical, neurological exams, vital signs, telemetry, ECGs and laboratory findings or liver-related AE were reported. Dose proportionality was observed for C_max and AUC across the entire dose range of 100mg to 500mg bid. CSF-to-plasma ratios for C_max and AUC were 4.2% and 4.6%, respectively for the 500mg bid dose level.

Conclusion: The findings indicate that FNP-223 is safe and well-tolerated at doses ranging from 100 to 500 mg, administered twice a day in HV. Additionally, the observed dose proportionality, along with the CSF-to-plasma ratios for both Cmax and AUC, suggests that the unbound fraction of the drug can effectively diffuse across the human blood-brain barrier. This study, along with PET-based target engagement assessments, supports the continued clinical development of FNP-223 in the ongoing Phase 2 PROSPER trial involving patients with PSP.

References: 1. Permanne B, Sand A, Ousson S, et al. O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies. ACS Chem Neurosci 2022; 13(8): 1296-314. doi: 10.1021/acschemneuro.2c00057. Epub 2022 Mar 31. PMID: 35357812; PMCID: PMC9026285.
2. Ryan M, Quattropani A, Abd-Elaziz K, den Daas I, Schneider M, Ousson S, Neny M, Sand A, et al. Phase 1 study in healthy volunteers of the O-glcnacase inhibitor ASN120290 as a novel therapy for progressive supranuclear palsy and related tauopathies. Alzheimers Dement. 2018, vol. 14, no 7, p. P251. doi: 10.1016/j.jalz.2018.06.2400
3. ClinicalTrials.gov: A Randomized, Double-blind, Placebo-controlled, Phase 2 Study to Assess the Efficacy, Safety, and Pharmacokinetics of FNP-223 (Oral Formulation) to Slow the Disease Progression of Progressive Supranuclear Palsy (PSP) (PROSPER). ClinicalTrials.gov [Internet]. Available at: https://www.clinicaltrials.gov/study/NCT06355531. Accessed on 25/02/2025.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-tolerability-and-pharmacokinetics-of-a-novel-oral-oga-inhibitor-fnp-223-first-in-human-phase-1-study/