In the June 18 JAMA Neurology, researchers led by Joseph Jankovic at Baylor College of Medicine, Houston, published results from the Phase 1b safety and tolerability trial of Roche and Prothena’s anti-α-synuclein antibody PRX002/RG7935. Eighty people with mild to moderate Parkinson’s disease received three infusions of antibody or placebo at monthly intervals, at doses that ranged from 0.3 to 60 mg/kg. As Jankovic had previously reported at the 2017 International Conference on Alzheimer’s and Parkinson’s Diseases, patients tolerated the treatment well and did not make anti-drug antibodies (May 2017 conference news). Four participants in the highest-dose group had adverse reactions to drug infusion, including rashes, itching, numbness of the tongue, and a bad taste in the mouth. All of these symptoms cleared up after participants were given allergy medication. Two of the participants discontinued treatment, while the other two continued the trial and had no further adverse reactions.
Drug pharmacokinetics were as expected, with only 0.3 percent of the antibody making it into the central nervous system. The antibody was reported to have a half-life of 10.2 days, and PD patients cleared it as quickly as healthy controls had in previous trials.
PRX002/RG7935 recognizes aggregated α-synuclein, but the high levels of drug in the periphery engage monomeric protein as well, binding 97 percent of serum α-synuclein. This drop in unbound α-synuclein lasted for 30 days after the first infusion, and for up to 85 days after the third infusion. These pharmacodynamics support monthly dosing, the authors noted. As expected, they saw no change in monomeric α-synuclein in the CSF, where drug levels were lower. CSF drug concentrations peaked at about 1 μg/mL, a level that should be sufficient to bind aggregated α-synuclein, the authors claimed.
Jeffrey Kordower at Rush University, Chicago, said these findings suggest the drug will have access to the brain. “These data are encouraging, and I look forward to a study designed to test efficacy,” he wrote to Alzforum (full comment below). PRX002/RG7935 is now in Phase 2.
In an accompanying editorial, however, Fredric Manfredsson at Michigan State University, Grand Rapids, Malú Tansey at Emory University School of Medicine, Atlanta, and Todd Golde at the University of Florida, Gainesville, noted that many questions about passive immunotherapy approaches to PD remain unanswered. These include whether antibodies will engage aggregated α-synuclein intracellularly or extracellularly, and whether they will mop up monomeric α-synuclein in the CNS, potentially causing neurotoxicity. Perhaps the biggest unknown is whether clearing aggregated α-synuclein will stop disease propagation and neurodegeneration.
“Little direct clinical evidence that directly proves this prion hypothesis of Parkinson disease exists,” Manfredsson and colleagues wrote. “Although the PRX002 trial met its primary goals and is now poised to move forward into efficacy trials, it is clear that progress within the synuclein basic science field needs to follow suit.”—Madolyn Bowman Rogers
- Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK, Griffith SG, Grundman M, Soto J, Ostrowitzki S, Boess FG, Martin-Facklam M, Quinn JF, Isaacson SH, Omidvar O, Ellenbogen A, Kinney GG. 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 Neurol. 2018 Jun 18; PubMed.
- Manfredsson FP, Tansey MG, Golde TE. Challenges in Passive Immunization Strategies to Treat Parkinson Disease. JAMA Neurol. 2018 Jun 18; PubMed.