Oral UCB0599 in participants with early Parkinson’s Disease
Research type
Research Study
Full title
A Double-Blind, Placebo-Controlled, Randomized, 18-Month Phase 2a Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Oral UCB0599 in Study Participants With Early Parkinson’s Disease
IRAS ID
1003518
Contact name
Janet Davies
Contact email
Sponsor organisation
UCB Biopharma SRL
Eudract number
2020-003265-19
Research summary
Summary of Research
Parkinson’s disease (PD) is the second most common neurodegenerative disease. It is estimated that 6.3 million people are living with PD worldwide. PD is a progressive nervous system disorder that affects movement. In patients with PD, specialised brain cells (neurons) that are involved with movement, stop working or die (a process known as neurodegeneration). The loss of these neurons is seen as the major cause of PD symptoms. In people living with PD, symptoms slowly worsen. The most common symptoms are slowness of movement, uncontrollable shaking, and stiffness of muscles. These types of symptoms related to movement are called motor symptoms.
Clumped, or aggregated, forms of alpha-synuclein (ASYN) are seen in neurons of patients with PD. The study medication, UCB0599, is an inhibitor of ASYN misfolding and subsequent aggregation. Early studies have suggested that UCB0599 may slow disease progression in PD, which remains the main unmet medical need in PD as current therapies only target PD related motor symptoms.
The purpose of this study is to provide proof of concept for the effectiveness of UCB0599 in reducing disease progression (worsening) in study participants with early-stage PD. The study will compare the safety, tolerability, pharmacokinetics and effectiveness of UCB0599 to placebo (an inactive substance).
Participants will take UCB0599 or placebo twice a day as a capsule for 18 months. During the study neither the doctor nor the participant will know whether they are receiving UCB0599 or placebo. Participants will be assigned to receive UCB0599 or placebo by chance and will have a 50:50 chance (like flipping a coin) of being in each of the groups.
Approximately 300 patients living with PD will take part in this study.
Summary of Results
Study participant disposition:
A total of 801 participants were screened and 305 (38.1%) participants screen failed. Of the 496 participants who started the study, 431 (86.9%) completed it. The most common reason for discontinuation was adverse events (AEs), affecting a total of 37 (7.5%) participants, most of whom discontinued before Month 12 (32 [6.5%] participants). Discontinuation due to AEs was more common in the UCB0599 treatment groups (a total of 33 [9.97%] participants) compared with the placebo group (4 [2.4%] participants). There were no differences in rates of discontinuation due to AEs between the UCB0599 360mg/day group and the UCB0599 180mg/day group. A total of 442 (89.1%) participants completed the Month 12 Visit, and 427 (86.1%) participants entered the Extension Study.
Demographic and other baseline characteristics:
The mean (SD) age of participants was 60.8 (8.2) years. The majority of participants were male (60.6%), White (84.6%), and not Hispanic/Latino (84.2%). The mean (SD) BMI was 25.9 (3.7) kg/m2. Males and females were evenly distributed across treatment groups, as sex was a stratification factor during randomization. All other demographic characteristics were balanced across treatment groups.
At Baseline, disease duration (mean [SD]: 6.27 [6.23] months for total participants), MoCA score (median score for all groups: 28), and Hoehn and Yahr stages (57.4% of total participants were rated Stage 2) were comparable across treatment groups. The UCB0599 360mg/day group had lower mean Movement Disorder SocietyUnified Parkinson’s Disease Rating Scale (MDSUPDRS) Parts IIII scores (Parts I-III sum score mean [SD]: 30.6 [13.4]) than the UCB0599 180mg/day (34.0 [16.4]) and placebo (34.0 [13.2]) groups, suggesting lesser severity of disease.
Exposure:
The median exposure duration and median number of capsules taken was comparable across treatment groups. While the mean for duration of exposure and number of capsules taken was higher in the placebo group, these higher numbers in the placebo group were driven by higher early dropout rates in the UCB0599 groups due to AEs.
Efficacy results:
Using the MDS-UPDRS Part I-III -based primary estimand, the study was not able to demonstrate superiority of UCB0599 over placebo during the 12-month observation period.
Secondary estimands:
For the MDS-UPDRS secondary (and other) estimands, no differences between placebo and the UCB0599 treatment groups were identified.For the DaT-SPECT whole striatum specific binding ratio (SBR) estimands, numerical differences favoring UCB0599 over placebo were observed at Month 12 and Month 18.
For the initiation of symptomatic treatment (ST) estimands, a higher percentage of participants in the placebo group initiated ST compared with both UCB0599 treatment groups. In addition, gender differences in ST initiation were observed in the UCB0599 treatment groups, with a higher percentage of male vs female participants initiating ST over the course of the trial (at Month 18, 69.1% vs 56.9% in the UCB0599 180mg/day group and 68.2% vs 54.5% in the 360mg/day group, respectively).
Safety results:
The incidence of treatment-emergent adverse events (TEAEs) reported during the study was similar in participants receiving placebo or active treatment (144 [87.8%] participants had at least 1 TEAE in the placebo group vs 286 [86.9%] participants receiving UCB0599), and no dose-dependent increase was observed between the UCB0599 180mg/day and 360mg/day groups (143 [86.7%] participants vs 143 [87.2%] participants).
The incidence of serious TEAEs, participant discontinuations from the study due to TEAEs, TEAEs related to study intervention, and permanent withdrawal of study intervention due to TEAEs was higher in participants receiving UCB0599 than in participants receiving placebo, but there was no dose-dependent increase between the UCB0599 180mg/day and 360mg/day groups.
A total of 5 (1.5%) participants receiving UCB0599 (total) experienced serious TEAEs in the system organ class (SOC) Injury, poisoning and procedural complications (vs 0 participants in the placebo group), including the events of postoperative ileus, hip fracture, jaw fracture, and fall (all of them considered not related to study intervention by the investigator).
The majority of TEAEs leading to study discontinuations were in the SOC of Skin and subcutaneous tissue disorders (in 2 [1.2%] participants receiving placebo vs 23 [7.0%] receiving UCB0599 [total]). The most common TEAEs leading to study discontinuation (rash and urticaria) were in this SOC and are considered hypersensitivity reaction adverse events of special interest (AESIs); hypersensitivity was a protocol-defined discontinuation criterion.
There were 2 deaths reported in the study, both considered not related to study intervention by the investigator: 1 (0.6%) fatal TEAE of cardiac arrest was reported in the UCB0599 180mg/day group and 1 (0.6%) fatal TEAE of metastatic gastric cancer was reported in the UCB0599 360mg/day group.
Overall, there were no clinically meaningful mean changes from Baseline in hematology laboratory results across groups except for a small and temporary increase in eosinophil levels at Month 1 that was observed in the UCB0599 groups; it was not considered a safety concern. There were no clinically meaningful mean changes from Baseline in clinical chemistry laboratory values across groups, except liver function test increases (ie, potential drug-induced liver injury cases) in the UCB0599 groups, with no dose effect observed. There were no clinically meaningful changes from Baseline in vital sign and electrocardiogram evaluations in any treatment group, and no Hy’s Law cases were reported.
Pharmacokinetics:
Concentrations of UCB0599 in cerebrospinal fluid (CSF) increased from Screening to Month 18 in the UCB0599 180mg/day group (Screening: median=below quantifiable limit [BLQ]; Month 18: median=2.29, range=BLQ to 3.71) and in the 360mg/day group (Screening: median=BLQ; Month 18: median=9.07, range=2.36 to 23.3). The median CSF concentration was higher in the 360mg/day group compared to the 180mg/day group at both Month 12 and Month 18. Interpretation of these results is limited by the small number of samples available (N=13 and N=7 in the UCB0599 180mg/day group and 360mg/day group, respectively, at Month 18).
Small quantifiable N-oxide metabolite concentrations were observed in CSF in the UCB0599 180mg/day group (Month 12 range=BLQ to 2.31ng/mL; Month 18 range=BLQ to 2.54ng/mL).
The geometric mean (GeoMean) plasma concentration-time profiles indicated increasing predose and postdose UCB0599 plasma concentrations with UCB0599 dose level (180mg/day and 360mg/day). Trough concentrations of UCB0599 were higher for the UCB0599 360mg/day group compared to the UCB0599 180mg/day group with a minimal concentration overlap, indicating a difference between the 2 dose levels.
No conclusions can be drawn regarding plasma:CSF ratio concentrations of UCB0599 and its Noxide metabolite due to the limited number of participants with CSF samples at Month 12 and Month 18 (N≤15 participants in each treatment group at each timepoint).
Conclusions:
Using an MDS-UPDRS Part I-III-based primary estimand where censoring was applied to any data collected post ST initiation, it was not possible to demonstrate superiority of UCB0599 over placebo during the 12-month observation period.
No differences between the UCB0599 treatment groups and the placebo group were observed for any of the MDS-UPDRS-based secondary or supplementary estimands, including when considering the following attributes:
The use of the MDS-UPDRS Part III subscale and of a revised version of this subscale targeted at the early-stage PD population (ie, early-stage PD subscore) The application of a strategy of ST de-mediation in an attempt to estimate the impact of UCB0599 as if no participant had initiated ST during the study However, it was noted that the DaT-SPECT whole brain striatum SBR signal generally decreased less over time in UCB0599 treatment groups compared with the placebo group.
More participants initiated ST in the placebo group compared with either of the UCB0599 treatment groups. This difference was driven by a lesser proportion of female participants randomized to the UCB0599 treatment groups initiating ST during the course of the study.
Overall, the incidences of TEAEs were comparable between the active treatment groups. The most commonly reported TEAEs were coronavirus disease 2019 (COVID-19), urinary tract infection, and fall.
TEAEs leading to treatment discontinuation occurred more frequently in the active treatment groups (10.9% and 9.1% in the UCB0599 180mg/day group and 360mg/day group, respectively) compared with the placebo group (2.4%). Most cases were related to hypersensitivity, a protocol-defined discontinuation criterion. No dose-related differences were observed.
The incidence of serious TEAEs was slightly higher in the active treatment groups (7.9% and 8.5% in the UCB0599 180mg/day group and 360mg/day group, respectively) compared to the placebo group (5.5%). This difference was driven primarily by serious TEAEs related to known risks, including 3 cases of hypersensitivity and 1 liver event. An imbalance of serious TEAEs in the SOC “Injury, poisoning, and procedural complications” also contributed to this difference, with a higher incidence under this SOC observed in the active treatment groups (5 [1.5%] participants receiving UCB0599 [total] vs 0 participants receiving placebo), including cases of postoperative ileus (1 case), fall (2 cases), hip fracture (1 case), and jaw fracture (1 case), none of which was assessed as related to study intervention. No dose relationship was observed in the incidence of serious TEAEs.
The incidence of treatment-emergent AESIs of hypersensitivity was higher in the active treatment groups (7.9% and 9.1% in the UCB0599 180mg/day group and 360mg/day group, respectively) compared to the placebo group (1.2%). No dose-related differences or anaphylactic reactions were reported.
No Hy’s Law cases were reported. Nine participants had ALT or AST values ≥3×upper limit of normal (1 in placebo due to Hepatitis E, 4 in the UCB0599 180mg/day group, and 4 in the UCB0599 360mg/day group). No dose-related effects were observed.
Trough concentrations (GeoMeans) of UCB0599 were higher for the UCB0599 360mg/day group compared to the UCB0599 180mg/day group and remained stable throughout the observation period for both groups.
Both UCB0599 and its N-oxide metabolite were detected in CSF.
No new safety or tolerability concerns were identified following UCB0599 administration at 180mg/day or 360mg/day over the 18-month Treatment Period.REC name
East of Scotland Research Ethics Service REC 2
REC reference
21/ES/0016
Date of REC Opinion
31 Mar 2021
REC opinion
Further Information Favourable Opinion