Jankovic J, et al. - In this multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial, the researchers assessed the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic Parkinson disease (PD). Findings suggested that single and multiple doses of PRX002 resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that could be expected to engage extracellular aggregated α-synuclein in the brain. Data reported that all tested dose levels of PRX002 had acceptable safety and tolerability profiles, supporting the design of an ongoing phase 2 clinical study.

Methods

• From July 2014 to September 2016, this trial was conducted at eight US study centers.
• Participants in the study were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3).
• Participants were enlisted into six ascending-dose cohorts and randomized to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo.
• Patients received three intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period.
• Physical and neurological examinations, laboratory tests, vital signs, and adverse events were the included safety and tolerability assessments.
• Maximum PRX002 concentration, area under the curve, and half-life were the included pharmacokinetic parameters.

Results

• According to the findings, of the 80 patients, most were white (97.5%; n = 78) and male (80%; n = 64), and the median (SD) age was 58 (8.4) years.
• Data reported that PRX002 was generally safe and well tolerated, without any serious or severe PRX002-related treatment-emergent adverse events (TEAEs) reported.
• Data revealed that the TEAEs experienced by at least 5% of subjects receiving PRX002, regardless of whether they were related to the study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post–lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3).
• No antidrug antibodies were detected in this analysis.
• Findings revealed that serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days).
• It was noted that rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F_78,284 = 1.66; P=.002), with similar reductions after two additional infusions.
• The study results showed that mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.