Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease

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 (F 78,284 = 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).

Updates and advances in the treatment of Parkinson disease

“…A further therapeutic approach involves using active and passive immunisation techniques. A vaccine (PD01A) that produces antibodies to oligomeric α‐synuclein has been reported to show proof of principle and there are phase I studies utilising monoclonal antibodies against aggregated α‐synuclein, a form of passive immunisation …”

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

“…However, a caveat to anticipating trans‐BBB delivery of monoclonal antibodies has arisen from recent findings with one of the studies with an antibody against α‐synuclein. In the trial testing PRX002 (Prothena/Roche Pharmaceuticals), only a small amount of the intravenously administered antibody subsequently appeared in CSF samples, indicating limited CNS penetration …”

The good and bad of therapeutic strategies that directly target α‐synuclein

“…At present, two main antibodies targeting α‐syn have been tested in clinical trials: BIIB054 and PRX002 . The first one is an aggregate‐selective human‐α‐syn‐derived antibody, which could ameliorate disease phenotype in mouse models of synucleinopathy .…”