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Alpha-Synuclein Antibody Shows Promise for Parkinson's Disease Treatment

BY LIZETTE BORRELI

Multiple intravenous infusions of PRX002, a humanized monoclonal antibody targeting neurotoxic forms of aggregated alpha-synuclein, was safe and well tolerated in patients with mild to moderate Parkinson's disease, according to a phase 1b study, published online on June 18 in JAMA Neurology.

The researchers reported a 97 percent reduction in serum levels of the protein alpha-synuclein after a single infusion of PRX002 at the highest dose, with similar reductions after two additional infusions.

"Notably, rapid and robust reductions in free serum α-synuclein levels were achieved without seriously affecting safety, consistent with a previous healthy volunteer PRX002 study," the researchers, led by Joseph Jankovic, MD, FAAN, professor of neurology and distinguished chair of movement disorders at Baylor College of Medicine, Houston, Texas, wrote.

Aggregated alpha-synuclein is believed to be central to the pathogenesis of PD. The researchers proposed that patients in the early stages of PD may benefit from PRX002, because it could potentially reduce the accumulation of toxic alpha-synuclein aggregates, and thus, limit the debilitating adverse effects and treatment-resistant symptoms that emerge with the disease.

PRX002 works by targeting aggregated forms of the alpha-synuclein, inhibiting the the neuron-to-neuron transfer of the pathogenic forms of alpha-synuclein. This process could result in neuronal protection and delayed disease progression, according to the researchers.

In an earlier ascending-dose phase 1 study, published in 2016 in Movement Disorders, PRX002 was safe and well tolerated up to the highest tested dose (30 mg/kg) and led to dose-dependent reductions in free serum synuclein in healthy volunteers.

In the current double-blind, multicenter, placebo-controlled study, 80 patients with idiopathic PD were randomized into one of six ascending-dose cohorts and received a total of three intravenous infusions of 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 every four weeks. Researchers monitored patients during a 24-week observational period. Until four weeks after final dosing, patients came in for pharmacokinetic and pharmacodynamic assessments and for clinical efficacy and safety assessment until 16 weeks after final dosing.

The findings revealed PRX002 was generally safe and well tolerated among participants.

No serious or severe PRX002-related treatment-emergent adverse effects were reported. Among participants who received PRX002, adverse effects included 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). Antidrug antibodies were not detected.

The study authors cited several study limitations. Among them were the small number of patients exposed to the agent and short duration of exposure. In addition, the dearth of demographic diversity and the possibility that other patients may later develop comorbid conditions with PD were limitations.

This study was funded by Prothena Biosciences and Hoffmann-La Roche Ltd.

Several study authors were consultants to and/or empoloyees of Prothena BioSciences. Dr. Jankovic disclosed that he 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 of Medicine Center of Excellence.

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Jankovic J, Goodman I, Safirstein B, et al. 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. JAMA Neurology 2018; Epub 2018 18 Jun.​