Parkinson’s disease (PD) is a neurodegenerative disorder whose motor and non-motor symptoms worsen over time and there are currently no treatments capable of modifying the progress of the disease, which is why the results of a new study that has just been published the scientific journal Nature Medicine represent a way of hope for those affected.
This is a phase 2 clinical trial of the drug prasinezumab, a monoclonal antibody that has reduced the worsening of motor symptoms in Parkinson’s patients experiencing rapid disease progression. The findings suggest that the clinical efficacy of prasinezumab, which acts by binding to alpha-synuclein protein aggregates, is observed after one year of treatment in these types of patients.
Although the study’s conclusions are promising, the authors acknowledged that further research is needed to determine whether the antibody can be effective in patients with slower disease progression after longer periods of treatment, and that new research should be conducted. clinical trials that confirm the results obtained.
Weigh the balance between cost, benefit and potential adverse effects
“This is a multicenter and multinational study sponsored by the pharmaceutical company F. Hoffmann-La Roche Ltd. that evaluates the effectiveness of a monoclonal antibody called prizenumab against the protein alpha-synuclein, whose intracellular accumulation produces the progressive death of neurons. dopamine producers in Parkinson’s disease,” explained José Luis Lanciego, Senior Researcher of the Gene Therapy Program in Neurodegenerative Diseases at the Applied Medical Research Center (CIMA) of the University of Navarra, who did not participate in the study, in statements to SMC Spain.
The study – continues the expert – has been carried out in 316 parkinsonian patients, divided into three equal groups to which a placebo was administered, prasinezumab at a dose of 1,500 mg and a third group at a higher dose (4,500 mg). The antibody has been administered intravenously once a month for a year of follow-up. The effect of the treatment has been evaluated using the MDS-UPDRS motor scales types I, II and III, hoping to find an improvement in the typical motor symptoms of the disease. Only a slight improvement has been observed in the MDS-UPDRS type III scale in the group of patients in whom the disease progressed more rapidly, with an improvement of approximately 5 points on said scale (an improvement was considered a positive result). higher than 4.63 points).
“In neurodegenerative diseases, the accumulation of misfolded proteins is typically observed in the brain, specifically, alpha-synuclein within dopamine-producing cells and others such as tau (intracellular) or amyloid (extracellular), the latter two in the case of Alzheimer’s disease. This new generation of monoclonal antibodies attempts to dissolve the accumulations of these misfolded proteins to improve the progression of these diseases and are currently the subject of heated controversy,” says Lanciego.
“The main limitation regarding the potential biological effect of the anti-Parkinson’s drug is that the study does not demonstrate improvement in the levels of neurodegeneration in the patients”
And he adds: “All of them are administered intravenously and their penetration into the brain is very low (less than 1%). Furthermore, once in the brain, it remains to be demonstrated whether they are capable of entering the neurons that accumulate these proteins to exert their effect. Finally, in the case of aducanumab and lecanemab (for the treatment of Alzheimer’s), their target is the amyloid (extracellular) protein. “Both antibodies present numerous very important side effects that must be taken into account when indicating their administration, especially edema and cerebral hemorrhages (present in more than 40% of patients treated with said antibodies).”
The researcher details that, although the studies that have been published so far with monoclonal antibodies against alpha-synuclein, specifically prasizenumab (PASADENA study) and cinpanemab (SPARK study), have not reported adverse effects, it is “evident” that at the moment The improvement obtained is very limited with a follow-up time of only one year. And he considers that “it is really difficult to predict the result of this type of treatment in the longer term, since it is completely unknown.”
“In summary, longer-term trials will be necessary in which the potential beneficial effects are measured using additional parameters to the motor scales. Furthermore, the balance between cost, benefit and potential adverse effects must be weighed in great detail before indicating this type of treatment to parkinsonian patients. Finally, it will be necessary to have a new generation of antibodies designed to increase their penetration into the target neurons or combine their administration with techniques already available today such as the permeabilization of the blood-brain barrier using high-intensity focused ultrasound ( HIFU technique)”, concludes Lanciego.
Limitations of the study on the anti-Parkinson’s drug
“The result at a clinical level is promising,” says Raúl Martínez Fernández, neurologist and clinical researcher at HM CINAC-Hospital Puerta del Sur, in statements to the same medium, adding that this study is the continuation of one published in August 2022 in which was already observed that patients receiving prasinezumab had a better motor status one year after starting treatment than those who did not receive it. Furthermore, there were no relevant adverse effects. The current study essentially follows those patients for up to four years, and the differences between the groups that receive the drug and another group of patients who do not receive it are not only maintained, but increased. This longer duration is key since, in a way, it is what allows us to determine that patients with the drug ‘have progressed less’.
Martínez also points out the limitations of the study: “There are some limitations: at a methodological level, the main ones are that the patients who did not receive the drug did not participate in the study, what we call an ‘external comparison’ is done. This implies that there may be quite a few confounding factors, since this group is not completely well controlled. Another methodological limitation is that the evaluation is not ‘blind’, that is, both the doctor and the patient know whether or not they are receiving the drug and it is already known that it can improve the results in the treated groups,” he explains.
“And for me, the main limitation in terms of the potential biological effect is that the neuroimaging results measuring the dopamine circuit (DaT-SPECT) (which is the main neurotransmitter related to Parkinson’s disease) do not demonstrate differences between groups . In other words, the study does not demonstrate improvement in levels of neurodegeneration. This is explainable for multiple reasons, but, if it had been positive, together with the clinical evidence, it would have represented a true milestone in the field,” concludes the neurologist.
