Phase 1/1b Studies of UCB0599, an Oral Inhibitor of α-Synuclein Misfolding, Including a Randomized Study in Parkinson's Disease

Abstract

Background: Parkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of α-synuclein (ASYN). UCB0599 is an oral, small-molecule inhibitor of ASYN misfolding, aimed at slowing disease progression.

Objective: The aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599.

Methods: Safety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo-controlled, dose-escalation, crossover study, N = 65] and UP0078 [open-label study, N = 22]). Safety/tolerability and multi-dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double-blind, placebo-controlled study of participants with PD (UP0077 [NCT04875962], N = 31).

Results: Across all studies, UCB0599 displayed rapid absorption with linear, time-independent PK properties; PK of multiple doses of UCB0599 were predictable from single-dose exposures. No notable food-effect was observed; co-administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased ~1.3- and ~2 to 3-fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment-related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild-to-moderate in intensity and were not dose related.

Conclusions: Seventy-three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early-stage PD is underway (NCT04658186). © 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; disease modification; misfolding inhibitor; phase 1 clinical trial; α-synuclein.

© 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Figures

FIG 1

Ratio of cerebrospinal fluid (CSF) to estimated unbound UCB0599 plasma concentration 2 hours after drug intake, by treatment group in UP0030 (phase 1 study in healthy participants [HPs]). Unbound plasma concentration is estimated by multiplying concentration by 0.011 (fraction unbound). Per protocol, plasma concentrations were measured at 2 hours post‐dose, shortly before CSF sampling. The symbol ◊ indicates the mean values of the calculated ratios in the boxplots. The concentrations of UCB0599 in the CSF increased linearly with increasing doses. BID, twice daily; CSF, cerebrospinal fluid; HPs, healthy participants; SD, single dose.

FIG 2

Overview of PK (pharmacokinetic) data from the UCB0599 phase 1/1b studies. Violin plots show the distribution of data in each group. Medians (white spots), interquartile range delimited by 25th and 75th percentiles (violin plot), 1.5 × interquartile range (whiskers), and individual data are shown. Across the studies, a linear, time‐independent, PK profile was observed, and the PK of multiple doses of UCB0599 were predictable from single‐dose exposures. AUC, area under the plasma concentration–time curve; Cmax, maximum plasma concentration; PK, pharmacokinetics; MD, multiple dose; MD 180 mg at steady state (twice daily dosing 90 mg and includes data from UP0030 and UP0077); MD 360 mg at steady state (twice daily dosing 180 mg and includes data from UP0077 only); SD, single dose.