Evaluation and Application of a PET Tracer in Preclinical and Phase 1 Studies to Determine the Brain Biodistribution of Minzasolmin (UCB0599).

PURPOSE: Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson's disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. PROCEDURES: In the preclinical study, two radiolabeling positions were investigated on the S-enantiomer of minzasolmin (UCB2713): [11C]methylamine UCB2713 ([11C-N-CH3]UCB2713) and [11C]carbonyl UCB2713 ([11C-CO]UCB2713). Male C57 black 6 mice (N = 10) received intravenous [11C-N-CH3]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice (n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [11C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. PRIMARY OBJECTIVE: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. RESULTS: Preclinical data supported the use of [11C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers (N = 4). The mean estimated whole brain total distribution volume (VT) at equilibrium across all regions of interest was 0.512 mL/cm3, no difference in VT was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% (n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. CONCLUSION: Following positive preclinical results with the N-methyl labeled PET tracer, [11C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood-brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).

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

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.