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Adults with mild to moderate Parkinson’s disease showed reductions in free serum alpha-synuclein levels without notable side effects after intravenous treatment with a monoclonal antibody known as PRX002.
“Pathologically, PD [Parkinson’s disease] is typically associated with an accumulation of aggregated alpha-synuclein protein in the central nervous system and the peripheral nervous system,” making alpha-synuclein a target for treatment in preclinical studies, wrote Joseph Jankovic, MD, of Baylor College of Medicine, Houston, and his colleagues.
“Notably, rapid and robust reductions in free serum alpha-synuclein levels were achieved without seriously affecting safety,” the researchers said. Overall, reductions in free serum alpha-synuclein occurred quickly and were similar throughout the study period, and treatment with PRX002 was safe, well tolerated, and effective at doses up to 60 mg/kg.
The most relevant adverse events were mild to moderate infusion-related reactions in four patients in the highest-dose group; two of these patients discontinued the study. No anti-PRX002 antibodies were seen, and no serious adverse events or deaths occurred during the study period.
Statistically significant reductions from baseline were noted at 1 and 4 hours after the first and third infusion in all dose groups, compared with placebo, and these reductions lasted longer after the higher doses.
Over the longer term, statistically significant reductions after the third infusion were noted at day 64 for the 1.0-mg/kg through 60-mg/kg dose groups, day 71 for the 1.0-mg/kg through 60-mg/kg dose groups, and at day 85 for the 3-mg/kg through 60-mg/kg dose groups.
The study findings were limited by several factors, including the relatively small sample size, short period of exposure to the treatment, homogeneous population, and lack of imaging to monitor brain pathology, the researchers noted. However, the results support the safety of PRX002 and the progression of the follow-up phase 2 study known as PASADENA.
The study was funded by Prothena Biosciences and F. Hoffmann-LaRoche. Lead author Dr. Jankovich disclosed relationships with both of those companies and has received funding from the Parkinson’s Foundation. Many of the other authors are employees of Prothena Biosciences or F. Hoffmann-LaRoche or a subsidiary.
SOURCE: Jankovic J et al. JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.1487.
The study results met the endpoints for safety and tolerance; however, “the question remains: To what extent does this process reflect the role of alpha-synuclein in the causal mechanisms of Parkinson disease?” wrote Fredric P. Manfredsson, PhD; Malú G. Tansey, PhD; and Todd E. Golde, PhD, in an accompanying editorial (JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.0346).
The trio noted that the potential of alpha-synuclein for cell-to-cell transmission and disease propagation and progression remains unknown and the research behind the passive immunization technique remains limited and controversial at the preclinical level. In addition, they emphasized the need to consider the potential for neurotoxicity with the removal of soluble alpha-synuclein from neurons.
“Thus, the potential negative consequences following sustained treatment with PRX002 must also be heavily scrutinized before it can be said to be safe for long-term use in elderly individuals,” they wrote.
The study also lacked data on whether the antibody directly engaged its target in the CNS, they said.
“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,” they concluded.
Dr. Manfredsson is affiliated with Michigan State University in Grand Rapids. Dr. Tansey is affiliated with Emory University in Atlanta. Dr. Golde is affiliated with the University of Florida, Gainesville. Dr. Tansey disclosed relationships with INmune Bio, Above and Beyond, Hygieia Sciences, UCB, and the Michael J. Fox Foundation for Parkinson’s Research.
The study results met the endpoints for safety and tolerance; however, “the question remains: To what extent does this process reflect the role of alpha-synuclein in the causal mechanisms of Parkinson disease?” wrote Fredric P. Manfredsson, PhD; Malú G. Tansey, PhD; and Todd E. Golde, PhD, in an accompanying editorial (JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.0346).
The trio noted that the potential of alpha-synuclein for cell-to-cell transmission and disease propagation and progression remains unknown and the research behind the passive immunization technique remains limited and controversial at the preclinical level. In addition, they emphasized the need to consider the potential for neurotoxicity with the removal of soluble alpha-synuclein from neurons.
“Thus, the potential negative consequences following sustained treatment with PRX002 must also be heavily scrutinized before it can be said to be safe for long-term use in elderly individuals,” they wrote.
The study also lacked data on whether the antibody directly engaged its target in the CNS, they said.
“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,” they concluded.
Dr. Manfredsson is affiliated with Michigan State University in Grand Rapids. Dr. Tansey is affiliated with Emory University in Atlanta. Dr. Golde is affiliated with the University of Florida, Gainesville. Dr. Tansey disclosed relationships with INmune Bio, Above and Beyond, Hygieia Sciences, UCB, and the Michael J. Fox Foundation for Parkinson’s Research.
The study results met the endpoints for safety and tolerance; however, “the question remains: To what extent does this process reflect the role of alpha-synuclein in the causal mechanisms of Parkinson disease?” wrote Fredric P. Manfredsson, PhD; Malú G. Tansey, PhD; and Todd E. Golde, PhD, in an accompanying editorial (JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.0346).
The trio noted that the potential of alpha-synuclein for cell-to-cell transmission and disease propagation and progression remains unknown and the research behind the passive immunization technique remains limited and controversial at the preclinical level. In addition, they emphasized the need to consider the potential for neurotoxicity with the removal of soluble alpha-synuclein from neurons.
“Thus, the potential negative consequences following sustained treatment with PRX002 must also be heavily scrutinized before it can be said to be safe for long-term use in elderly individuals,” they wrote.
The study also lacked data on whether the antibody directly engaged its target in the CNS, they said.
“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,” they concluded.
Dr. Manfredsson is affiliated with Michigan State University in Grand Rapids. Dr. Tansey is affiliated with Emory University in Atlanta. Dr. Golde is affiliated with the University of Florida, Gainesville. Dr. Tansey disclosed relationships with INmune Bio, Above and Beyond, Hygieia Sciences, UCB, and the Michael J. Fox Foundation for Parkinson’s Research.
Adults with mild to moderate Parkinson’s disease showed reductions in free serum alpha-synuclein levels without notable side effects after intravenous treatment with a monoclonal antibody known as PRX002.
“Pathologically, PD [Parkinson’s disease] is typically associated with an accumulation of aggregated alpha-synuclein protein in the central nervous system and the peripheral nervous system,” making alpha-synuclein a target for treatment in preclinical studies, wrote Joseph Jankovic, MD, of Baylor College of Medicine, Houston, and his colleagues.
“Notably, rapid and robust reductions in free serum alpha-synuclein levels were achieved without seriously affecting safety,” the researchers said. Overall, reductions in free serum alpha-synuclein occurred quickly and were similar throughout the study period, and treatment with PRX002 was safe, well tolerated, and effective at doses up to 60 mg/kg.
The most relevant adverse events were mild to moderate infusion-related reactions in four patients in the highest-dose group; two of these patients discontinued the study. No anti-PRX002 antibodies were seen, and no serious adverse events or deaths occurred during the study period.
Statistically significant reductions from baseline were noted at 1 and 4 hours after the first and third infusion in all dose groups, compared with placebo, and these reductions lasted longer after the higher doses.
Over the longer term, statistically significant reductions after the third infusion were noted at day 64 for the 1.0-mg/kg through 60-mg/kg dose groups, day 71 for the 1.0-mg/kg through 60-mg/kg dose groups, and at day 85 for the 3-mg/kg through 60-mg/kg dose groups.
The study findings were limited by several factors, including the relatively small sample size, short period of exposure to the treatment, homogeneous population, and lack of imaging to monitor brain pathology, the researchers noted. However, the results support the safety of PRX002 and the progression of the follow-up phase 2 study known as PASADENA.
The study was funded by Prothena Biosciences and F. Hoffmann-LaRoche. Lead author Dr. Jankovich disclosed relationships with both of those companies and has received funding from the Parkinson’s Foundation. Many of the other authors are employees of Prothena Biosciences or F. Hoffmann-LaRoche or a subsidiary.
SOURCE: Jankovic J et al. JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.1487.
Adults with mild to moderate Parkinson’s disease showed reductions in free serum alpha-synuclein levels without notable side effects after intravenous treatment with a monoclonal antibody known as PRX002.
“Pathologically, PD [Parkinson’s disease] is typically associated with an accumulation of aggregated alpha-synuclein protein in the central nervous system and the peripheral nervous system,” making alpha-synuclein a target for treatment in preclinical studies, wrote Joseph Jankovic, MD, of Baylor College of Medicine, Houston, and his colleagues.
“Notably, rapid and robust reductions in free serum alpha-synuclein levels were achieved without seriously affecting safety,” the researchers said. Overall, reductions in free serum alpha-synuclein occurred quickly and were similar throughout the study period, and treatment with PRX002 was safe, well tolerated, and effective at doses up to 60 mg/kg.
The most relevant adverse events were mild to moderate infusion-related reactions in four patients in the highest-dose group; two of these patients discontinued the study. No anti-PRX002 antibodies were seen, and no serious adverse events or deaths occurred during the study period.
Statistically significant reductions from baseline were noted at 1 and 4 hours after the first and third infusion in all dose groups, compared with placebo, and these reductions lasted longer after the higher doses.
Over the longer term, statistically significant reductions after the third infusion were noted at day 64 for the 1.0-mg/kg through 60-mg/kg dose groups, day 71 for the 1.0-mg/kg through 60-mg/kg dose groups, and at day 85 for the 3-mg/kg through 60-mg/kg dose groups.
The study findings were limited by several factors, including the relatively small sample size, short period of exposure to the treatment, homogeneous population, and lack of imaging to monitor brain pathology, the researchers noted. However, the results support the safety of PRX002 and the progression of the follow-up phase 2 study known as PASADENA.
The study was funded by Prothena Biosciences and F. Hoffmann-LaRoche. Lead author Dr. Jankovich disclosed relationships with both of those companies and has received funding from the Parkinson’s Foundation. Many of the other authors are employees of Prothena Biosciences or F. Hoffmann-LaRoche or a subsidiary.
SOURCE: Jankovic J et al. JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.1487.
FROM JAMA NEUROLOGY
Key clinical point: Treatment with a monoclonal antibody for alpha-synuclein known as PRX002 was safe and effective in a preliminary study of Parkinson’s disease patients.
Major finding: Significant reductions in free serum alpha-synuclein levels persisted at 85 days after the third infusion in the 3-mg/kg through 60-mg/kg dose groups.
Study details: The data come from a randomized, phase 1b trial of 80 adults aged 40-80 years with Parkinson’s disease.
Disclosures: The study was funded by Prothena Biosciences and F. Hoffmann-LaRoche. Lead author Dr. Jankovich disclosed relationships with both of those companies and has received funding from the Parkinson’s Foundation. Many of the other authors are employees of Prothena Biosciences or F. Hoffmann-LaRoche or a subsidiary.
Source: Jankovic J et al. JAMA Neurol. 2018 June 18. doi: 10.1001/jamaneurol.2018.1487.