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A first clinical study with a monoclonal antibody targeting alpha-synuclein – or rather, the accumulation of aggregated forms of the protein that could be one of the causes of Parkinson's disease ( PD) – showed encouraging results. This is demonstrated by the results of a study published online in "JAMA Neurology".
An initial clinical study with a monoclonal antibody targeting alpha-synuclein – or rather, the accumulation of aggregated forms of the protein that could be one of the underlying causes of the disease from Parkinson (PD) – showed encouraging results. The results of a study published online in "JAMA Neurology" demonstrate this.
"Alpha-synuclein is a protein normally present in the body, but in Parkinson's disease it accumulates in aggregates observed post mortem in the brain of patients with PD," recall the authors, under the direction of Joseph Jankovic of the Baylor College of Medicine in Houston (USA). "The hypothesis is that the protein is misfolded, preventing its clearance, and aggregated form that causes damage to dopaminergic neurons."
The researchers point out that current treatments for PD are primarily symptom-based, but they do not slow down or stop underlying neurodegeneration. This new strategy is a different approach targeting one of the major pathological changes seen in the disease.
"Preclinical studies with transgenic mice have shown that overexpression of alpha-synuclein leads to the development of key characteristics of PM, including accumulation of aggregates. alpha-synuclein and motor and cognitive impairments, "notes the researchers
In animal models, it has been shown that a murine antibody directed against alpha-synuclein binds to these aggregates and reduces the Intracellular accumulation of protein in the cell bodies and synapses, protects against synaptic loss and gliosis and improves motor and cognitive deficits, they add
Demonstrated in Phase 2 of safety and Tolerability of PRX002
The current phase 1B study evaluated multiple doses of a humanized monoclonal antibody (PRX002, Prothena Biosciences / Roche) directed against alpha-synuclein aggregates up to 30 days. ; In a previous Phase 1, escalating study in healthy volunteers, PRX002 was safe and well tolerated up to the highest dose tested (30 mg / kg) and resulted in dose-dependent reductions in free serum sinuclein.
The present study focused primarily on safety and tolerability and did not reveal any serious adverse effects. We also detected a dose-dependent increase in antibodies in cerebrospinal fluid (CSF), which clearly shows that it can enter the brain, "say Jankovic and colleagues
. 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, given about once every 28 days. The results showed that no serious adverse events related to treatment with PRX002 were reported.
Adverse events in patients treated with 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), retrolumbar puncture syndrome (5.5%, n = 3) and pathway infection upper respiratory tract (5.5%,%, n = 3). No anti-drug antibodies were detected
Serum levels of PRX002 increased approximately in proportion to the dose, and the mean terminal elimination half-life was similar for all doses (10.2%). days). The mean concentration of PRX002 in cerebrospinal fluid was increased with the dose of PRX002 and was approximately 0.3% relative to serum concentration in all cohorts.
Rapid dose- and time-dependent mean reductions compared to placebo serum-free serum-synuclein sera were observed up to 97% after a single infusion at the highest dose, with similar reductions after two other infusions
"The results are more or less in line with our expectations: encouraging in terms of safety and tolerance.We did not expect to see any clinical benefits because the study was rather short , but there are signs of target involvement and cerebrospinal fluid penetration, "note the authors, whom they consider a promising therapeutic strategy.
A larger phase study 2 placebo-controlled is currently underway with clinical endpoints in patients at the initial stages of Parkinson's disease who are not taking levodopa.The Jankovic team is ime that this group of patients at an early stage could benefit the most from the antibody, in the hope of reducing as much as possible the accumulation of aggregates of alpha-synuclein for try to prevent the progression of the disease. [19659003] Strong reservations on the research expressed by three chroniclers
However, an editorial commentary (2) is cautious on this approach, stating that there is not yet sufficient evidence to support the validity hypotheses concerning the role of alpha-sinuclein in PD
Fredric Manfredsson of Michigan State University in Grand Rapids, Malú Tansey of Emory University in Atlanta and Todd Golde of the University of Florida in Gainesville, they claim that the study is based on "highly discussed preclinical research in an area that does not have valid animal models".
"The whole premise of present hope The clinical significance of PRX002 is based on the notion that extracellular or aggregated alpha-synuclein is able to transmit cell-to-cell and therefore to propagate the pathological process and the neurodegeneration that results, "they write. "This phenomenon is documented that occurs in model systems, but for the moment, to our knowledge, if it is present in humans, it is completely unknown."
The three editors also point out that the PRX002 antibody shows a higher affinity for the alpha-synuclein aggregate, the molecule also effectively reverses the monomeric forms of the protein and some research has suggested that an excessive elimination of soluble alpha-synuclein from neurons can cause neurotoxicity.
"Therefore, the potential negative consequences after prolonged treatment with PRX002 must be carefully considered before they can be considered safe for long-term use in the elderly," they conclude.
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References: [19659007] 1) Jankovic J, Goodman I, Safirstein B, et al. The safety and tolerability of multiple increasing doses of PRX002 / RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson's disease: a randomized clinical trial. JAMA Neurol, 2018 June 18. doi: 10.1001 / jamaneurol.2018.1487. [Epub ahead of print] Read
2) FP Manfredsson, MG Tansey, Golde TE. Challenges in pbadive immunization strategies to treat Parkinson's disease. JAMA Neurol, 2018 June 18. doi: 10.1001 / jamaneurol.2018.0346. [Epub ahead of print] read
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