α-Synuclein Antibody Appears Safe, Reaches Brain
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 Oct 1;75(10):1206-1214. PubMed.
- Manfredsson FP, Tansey MG, Golde TE. Challenges in Passive Immunization Strategies to Treat Parkinson Disease. JAMA Neurol. 2018 Oct 1;75(10):1180-1181. PubMed.
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Rush University, Chicago, and Van Andel Research Institute, Grand Rapids, Michigan
There are a number of very positive findings in this study. First, the study was well-performed, with no deviations from the protocol. The treatment appears to be safe and well-tolerated and there were increases of PRX002 in the cerebrospinal fluid, suggesting, although not proving, that this immunotherapy will have access to the brain. Also, robust and dose-dependent decreases in α-synuclein in the serum indicate that following treatment, the immunotherapy is working in a cell type that is accessible for examination. These data are encouraging, and I look forward to a study designed to test efficacy.
Associate Director of the Van Andel Research Institute, and Director of the Center for Neurodegenerative Science
I have received conference/lecture honorariums from Prothena and have been a scientific consultant to Roche.
This year represents the 10th anniversary of the birth of the concept of prion-like propagation of α-synuclein pathology, and it is gratifying to see that it has resulted in numerous clinical research programs. Several immunotherapy programs, at various stages of clinical development, target α-synuclein in different ways. I think it is truly exciting that so many efforts are underway to mitigate the cell-to-cell transfer propagation of α-synuclein pathology. In just a few years from now, we should know if this is a viable approach to significantly slow progression of Parkinson’s disease. This would be a much-needed success in a disease where there still only exist symptomatic therapies.
It is encouraging to see that PRX002 had a good favorable safety and tolerability profile in this Phase 1b trial in people with Parkinson’s disease, so the clinical testing of this approach can continue as planned in Phase 2. While it is unclear that there is any value of decreasing α-synuclein in serum in Parkinson’s disease, it nevertheless demonstrates biological activity of the therapeutic. Furthermore, the antibodies did enter the CNS at levels that appear biologically relevant.
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