Results from a Phase 1b Study of UCB0599, an Orally Available, Brain-penetrant Inhibitor of Alpha-synuclein (ASYN) Misfolding in People Living with Parkinson’s Disease (PD)
Just Genius1, Daniela Dastros-Pitei2, Laurent Detalle1, Coralie Domange3, Helene Kadima4, Maria Key-Prato5, Jeff Long6, François-Xavier Mathy7, Astrid Schmidt8, Johan W. Smit9, Johannes Streffer1, Peter Basile10
1Translational Medicine Neuroscience, 2Early PV Missions, 3Global Regulatory Affairs, 4Clinical Project Management, 5Early Development Statistics, 6Translational Biomarkers and Bioanalysis, 7Non clinical Safety Evaluation, 8Program Delivery, 9Quantitative Pharmacology & DMPK, 10Safety Risk Management, UCB Pharma
Objective:
Assess safety and tolerability of UCB0599, a brain-penetrant oral small molecule inhibitor of ASYN misfolding, in people living with PD.
Background:
ASYN misfolding is one of the best genetically and pre-clinically validated first steps in the cascade leading to dopaminergic neuron loss, the hallmark of PD. UCB0599 is under development to address an urgent need, slowing PD progression; with pre-clinical data showing inhibition of the earliest events in the PD pathological cascade.
Design/Methods:
Thirty-one people with PD (Hoehn-Yahr stage 1–3, aged 40–80 years) were enrolled and received two discrete doses of UCB0599 (n=21) or placebo (n=10) over four weeks.
Results:

In people living with PD (mean age: 64.3 years), with multiple age-related comorbidities, treatment-emergent adverse events (TEAEs) were reported in 81.0% (n=17) and 70.0% (n=7) of the UCB0599 and placebo groups, respectively. The most frequently reported TEAEs were: headache (33.3%), post-lumbar puncture syndrome, decreased glomerular filtration rate, and hypotension (9.5% each) in the UCB0599 groups, and headache, decreased glomerular filtration rate, and syncope (20.0% each) in the placebo group. The majority of TEAEs were mild/moderate in intensity (UCB0599: 61.9%; placebo: 60.0%).

TEAEs of special interest were reported in two participants from one UCB0599 group: unspecified hypersensitivity and urticaria (not serious or severe in intensity). One serious adverse event was reported with placebo (syncope), and two with UCB0599 (kidney injury updated to chronic renal failure after drug washout and non-cardiac chest pain).

No consistent or clinically relevant treatment-related patterns were observed for laboratory, vital sign, or electrocardiogram findings. No UCB0599 dose effect was observed on frequency or intensity of adverse events.

Conclusions:
UCB0599 was generally well tolerated with no significant safety or tolerability concerns identified in a population of older individuals with PD with age-related comorbidity; supporting further investigation of UCB0599 for the potential to slow PD progression.