Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial

Abstract

Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression.

Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD.

Design, setting, and participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3).

Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned 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. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period.

Main outcomes and measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life.

Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to 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. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). 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 (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.

Conclusions and relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149).

Trial registration: ClinicalTrials.gov Identifier: NCT02157714.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jankovic has served as a consultant to Prothena Biosciences Limited and Prothena Biosciences Inc and has received funding from the Parkinson’s Foundation to support the Baylor College of Medicine Center of Excellence. Dr Goodman is an employee of Bioclinica. Drs Marmon and Ness and Mr Soto are employees of Prothena Biosciences Inc and shareholders of Prothena Corporation plc. Dr Grundman is a consultant to Prothena Biosciences Limited and a shareholder of Prothena Corporation plc. Dr Schenk was an employee of Prothena Biosciences Inc and an officer and shareholder of Prothena Corporation plc. Dr Koller was an employee of and is a consultant to Prothena Biosciences Inc and was an officer and a shareholder of Prothena Corporation plc. Dr Zago is an employee of Prothena Biosciences Inc and an officer and shareholder of Prothena Corporation plc. Dr Griffith is a consultant to Prothena Biosciences Inc. Dr Ostrowitzki is an employee and stock owner of Genentech Inc, a member of the Roche group. Dr Boess is an employee and stock owner of F. Hoffmann-La Roche Ltd. Dr Martin-Facklam is an employee of F. Hoffmann-La Roche Ltd. Dr Quinn received compensation for serving on a data and safety monitoring board for vTv Therapeutics. Dr Ellenbogen is an employee of the QUEST Research Institute. Dr Kinney is an employee of Prothena Biosciences Inc and an officer and a shareholder of Prothena Corporation plc. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flowchart

Eligibility exclusions were counted more than once for the inclusion/exclusion criteria they did not meet. AE indicates adverse event; MRI, magnetic resonance imaging; PD, Parkinson disease.

Figure 2.. Cerebrospinal Fluid (CSF) and Serum PRX002 Concentrations Approximately 9 Weeks After the First Infusion

Study drug was administered at baseline, week 4, and week 8. The ratio of CSF to serum concentrations was approximately the same across all dose levels.

Figure 3.. Pharmacodynamics of Free-to-Total Serum α-Synuclein

Pharmacodynamics after the first (A) and third (B) infusions of PRX002. Data represent free serum α-synuclein levels normalized to total α-synuclein. P values represent statistical significance compared with placebo. aP < .001. bP < .05.