Objective: To determine the brain O-GlcNAcase (OGA) occupancy, following a single oral dose of FNP-223 (formerly ASN90) and to determine PK-EO relationship.

Background: Preclinical evidence suggests that a high degree of target engagement is desirable for modifying the in vivo formation of intracellular tau tangles in the brain, a key driver of neurodegeneration in PSP. Given the role of OGA inhibition in reducing tau pathology, precise dose selection based on OGA enzyme occupancy is critical to optimizing therapeutic potential of FNP-223.

Method: Open-label, adaptive-design PET study to investigate the occupancy of OGA by FNP-223 after single oral dose in healthy subjects (25-75y). Subjects had 3 imaging sessions and received an IV dose of OGA-specific tracer [¹⁸F]‑IMA601 at the start of each PET scan, and FNP-223 before the scan at sessions 2 and 3. For PK assessments, blood samples were collected to evaluate the PK-EO relationship. Target occupancy was determined by the changes in V_T between baseline and post-dose.  OGA regional activity was quantified using the 2 Tissue Compartment (2TC) model.

Results: 18 PET scans were successfully acquired. Administration of FNP-223 led to a dose and time-dependent reduction in the binding of [¹⁸F]‑IMA601. The receptor/target occupancy model was fitted to the pooled occupancy and FNP-223 plasma concentration data. The model fit was satisfactory and yielded an estimated half maximal effective concentration (EC₅₀) of 84·1 ng/mL. OGA occupancy over time was proportional to the reduction in FNP-223 plasma concentration and consistent with direct plasma-brain kinetics for FNP-223. The estimated EC₅₀ of 84.1 ng/mL indicates that the administration of 100 – 500 mg BID of FNP-223, which results in trough plasma concentrations of (84.0 – 743 ng/mL), leads to >50% brain OGA occupancy over 24 hours.

Conclusion: Plasma concentrations and safety data for FNP-223 align with first-time-in-human study findings. Pharmacokinetic modeling suggests that a high CNS target engagement can be achieved with a well-tolerated dose of 300 mg TID. The ongoing PROSPER Study is a randomized, double-blind, placebo-controlled Phase 2 trial assessing the efficacy, safety, and pharmacokinetics of FNP-223 in patients with progressive supranuclear palsy.

References: 1. Hastings NB, Wang X, Song L, et al. Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Mol Neurodegener 2017; 12(1): 39.
2. Permanne B, Sand A, Ousson S, Nény M, Hantson J, Schubert R, Wiessner C, Quattropani A, Beher D. O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies. ACS Chem Neurosci. 2022 Apr 20;13(8):1296-1314. doi: 10.1021/acschemneuro.2c00057. Epub 2022 Mar 31. PMID: 35357812; PMCID: PMC9026285.
3. Lee JH, Liow JS, Paul S, et al. PET quantification of brain O-GlcNAcase with [(18)F]LSN3316612 in healthy human volunteers. EJNMMI Res 2020; 10(1): 20.
4. 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
5. 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/brain-target-engagement-and-pharmacokinetic-enzyme-occupancy-pk-eo-relationship-of-fnp-223-a-novel-oral-oga-inhibitor-for-progressive-supranuclear-palsy-phase-1-pet-study/