An early clinical trial of a monoclonal antibody targeting what could be one of the underlying causes of Parkinson’s disease (PD) has shown some encouraging results, the researchers say.
The antibody is directed against the protein α-synuclein: specifically, accumulations of aggregated forms of the protein in the brain that have been implicated in Parkinson’s pathology.
“α-Synuclein is a normal protein found in the body, but in Parkinson’s disease this protein builds up into aggregates which have been seen in the brains Parkinson’s patients on postmortem,” lead author of the current study, Joseph Jankovic, MD, Baylor College of Medicine, Houston, Texas, explained to Medscape Medical News. “The hypothesis is that the protein misfolds, preventing its clearance and forms aggregates which cause damage to dopaminergic neurons.”
The phase 1B study, published online in JAMA Neurology on June 18, evaluated a humanized monoclonal antibody (PRX002, Prothena Biosciences/Roche) directed against the α-synuclein aggregates.
“The results are pretty much what we expected — encouraging safety and tolerance. We didn’t expect to see clinical benefits as the study was quite short, but there are signs of target engagement and CSF [cerebrospinal fluid] penetration.” Jankovic said. “I don’t want to overstate what we have found, but I do believe this is a promising therapeutic strategy.”
But an accompanying editorial is cautious about this approach, saying that there is not yet enough evidence in humans to support the validity of the α-synuclein hypotheses in Parkinson’s pathology.
Jankovic explained that current treatments for Parkinson’s primarily target symptoms but do not slow or halt the underlying neurodegeneration. This new strategy is a different approach targeting one of the key pathological changes seen in the condition.
“Preclinical studies with transgenic mice have shown that overexpression of α-synuclein leads to the development of key PD features, including accumulation of α-synuclein aggregates and motor and cognitive deficits,” the researchers note.
In animal models, a murine antibody to α-synuclein has been shown to bind to these aggregates and reduce intracellular accumulation of α-synuclein in cell bodies and synapses, protect against synaptic loss and gliosis, and ameliorate motor and cognitive behavior deficits, they add.
In a previous single ascending-dose phase 1 study in healthy volunteers, PRX002 was safe and well tolerated up to the highest tested dose (30 mg/kg) and resulted in dose-dependent reductions in free serum synuclein.
This phase 1b study tested multiple doses of the antibody up to 60 mg/kg in 80 participants with mild to moderate PD.
“This study mainly focused on safety and tolerance and showed no serious adverse effects. We also found a dose-dependent increase of antibody in the CSF, giving clear evidence that it can enter the brain,” Jankovic said.
“It is difficult to measure levels of α-synuclein in the brain as concentrations are too low, but we saw a 97% reduction in serum levels of the protein, suggesting that the antibody is engaging with its target,” he added.
For the study, patients were enrolled sequentially into one of six escalating-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, administered approximately once every 28 days.
Results showed that no serious PRX002-related treatment-emergent adverse events were reported. Adverse effects in patients receiving PRX002 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). No antidrug antibodies were detected.
Serum PRX002 levels increased in an approximately dose-proportional manner, and mean terminal elimination half-life was similar across all doses (10.2 days). Mean CSF PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.
Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose, with similar reductions after two additional infusions.
A larger phase 2 placebo-controlled study is now underway with clinical endpoints in patients with early stages of Parkinson’s who are not receiving levodopa.
Jankovic believes it is this group of early patients who could benefit the most from the antibody, with the hope of reducing the build-up of α- synuclein aggregates as early as possible to try to prevent disease progression.
“Heavily Debated” Research
However, in their editorial, Fredric Manfredsson, PhD, Michigan State University, Grand Rapids; Malú Tansey, PhD, Emory University, Atlanta, Georgia; and Todd Golde, PhD, University of Florida, Gainesville, say the study is based on “heavily debated preclinical research in a field that is lacking animal models with strong face validity.”
“The entire premise of the current PRX002 clinical trial is based on the notion that extracellular or aggregated α-synuclein is capable of cell-to-cell transmission and thus capable of propagating the disease process and resultant neurodegeneration,” they write. “This phenomenon is documented to occur in model systems, but whether it occurs in humans is, to our knowledge, completely unknown at this point.”
They also point out that although the PRX002 antibody exhibits a higher affinity for aggregated α-synuclein, the molecule effectively also clears monomeric forms of the protein, and some research has suggested that too much removal of soluble α-synuclein from neurons may result in neurotoxicity.
“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 also note that the current study does not provide direct evidence for central nervous system engagement of the antibody.
“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 conclude. “The neurodegenerative disease field has been marred by many encouraging clinical trials that failed in the end, creating a situation that belabors patients, clinicians, and researchers and potentially hampers future progress.”
This study was sponsored by Prothena Biosciences and Hoffmann-La Roche Ltd. Jankovic has served as a consultant to Prothena Biosciences. Tansey reports receiving personal fees as a consultant/collaborator from INmune Bio Inc, Above and Beyond, Hygieia Sciences, UCB, and The Michael J. Fox Foundation for Parkinson’s Research science advisory board.
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