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In the search for ways to slow down the progression of Parkinson’s disease, researchers currently have α-synuclein in their crosshairs. A handful of approaches are in development, and immunotherapy strategies are now advancing through clinical trials. At the 13th International Conference on Alzheimer’s and Parkinson’s Diseases, held March29 to April2 in Vienna, speakers from Prothena and Biogen presented Phase 1 data on their respective α-synuclein antibodies. Prothena discussed plans for Phase2, including smartphone monitoring to collect more detailed clinical data (see related AD/PD story). At the same time, researchers bemoaned the continued absence of good biomarkers to track disease progression and show efficacy of their drugs. What they really want is a PET tracer that detects pathological forms of the protein in living brain. Motivated by a large prize, scientists are working feverishly to find tracers, and in Vienna, Andreas Muhs of AC Immune, Lausanne, Switzerland, showed preclinical data on a candidate that selectively binds aggregated α-synuclein and appears to have suitable pharmacokinetics studies in rodents.
Academic and pharmaceutical researchers at AD/PD said they feel more hopeful than ever for meaningful progress on this disease. “The science has gotten more sophisticated, and we’re taking good bets in the clinical space,” noted Gene Kinney, who leads Prothena. At the same time, Kinney cautioned that many unknowns in these new types of trials make the way forward unclear.
The antibody appeared safe, Jankovic said. Participants did not make anti-drug antibodies. There were no serious adverse events, though some people reported skin reactions such as rash at the infusion site, and others had gastrointestinal complaints, headaches, or peripheral edema. Participants showed no improvement whatsoever on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), though that was not expected in this relatively short study, Jankovic said.
The pharmacokinetic profile was largely typical for an antibody, although the half-life was on the short side at 14 days. As with other antibodies, only 0.3 percent of the amount in blood made it into CSF. This CSF/serum ratio was the same for all dose groups at week nine. Unbound α-synuclein in serum dropped by as much as 97 percent at the highest antibody dose, indicating target engagement in the periphery. Antibody levels rose in CSF in accordance with dose, but the amount of monomeric α-synuclein in CSF did not change. This was expected, since PRX002 targets primarily aggregates, Jankovic noted. The scientists do not have an assay to measure the concentration of α-syn aggregates in CSF before and after treatment.
Based on these findings, Prothena and Roche will begin a Phase 2, year-long efficacy study in 300 PD patients this year, with the primary outcome being change on the MDS-UPDRS.
Meanwhile, Biogen’s antibody BIIB054 is not far behind. Like PRX002, this human monoclonal antibody binds pathological, aggregated α-synuclein while sparing physiological forms. It was not clear whether physiological means the monomer or a postulated tetramer, and Biogen researchers could not be reached for comment. In Vienna, Andreas Weihofen of Biogen, Cambridge, Massachusetts, presented preclinical findings. In cell culture, BIIB054 reduced spreading of aggregated α-synuclein between neurons, and in mice injected with α-synuclein fibrils, BIIB054 slowed down pathology and improved motor function, Weihofen said.
In 2015, Biogen started a Phase 1 single ascending dose study in 48 healthy people between age 40 and 65. At two U.S. sites, volunteers received infusions of either 1, 5, 15, 45, 90, or a whopping 135 mg/kg, reported Biogen’s Miroslaw Brys in Vienna. Participants underwent three MRI scans, at baseline, day three, and week four. They donated CSF samples at baseline, eight hours, 24 hours, and week three. Researchers followed participants for 16 weeks after dosing, doing clinical assessments and electrocardiograms in search of adverse effects.
Doses up to 90 mg/kg were well-tolerated, with similar adverse events on placebo and drug, Brys said. In the 135 mg/kg cohort—which translates to 9.4 grams in a person weighing 70 kg, or 154 pounds—one participant developed asymptomatic ischemia in the right parietal lobe; this dose will not be used further. Some participants complained of headache, dizziness, or pain related to the infusion, and one person developed a skin rash at the infusion site.
The pharmacokinetic studies profile was as expected, with a half-life of 28 days and a CSF/serum ratio of 0.2 percent at all doses. The maximum concentration in blood was proportional to the antibody dose given. The researchers are still analyzing what happens to plasma α-synuclein, Brys noted. This trial is ongoing, aiming to enroll 66 people, but based on the preliminary data, the researchers are already planning to take BIIB054 into Phase 2, Brys said.