April 15, 2024

expert reaction to study of Prasinezumab for motor progression in Parkinson’s disease

A study published in Nature Medicine looks at Prasinezumab and motor progression in Parkinson’s disease.

The following comments were provided by our friends at SMC Spain:

Raúl Martínez Fernández, neurologist and clinical researcher at HM CINAC-Puerta del Sur Hospital, says:

“The design of the study is of good quality; you don’t publish in a journal of this level if the study is not well conducted. A different issue is whether the design is adequate to answer the question it aims to answer, i.e. whether the drug improves disease progression. This methodological aspect is a complex and contested issue in the field. What we can say is that the clinical outcome is promising. This study is a follow-up to one published in August 2022 that showed hints of what is seen here. Essentially, the previous study already showed that patients receiving prasinezumab (an antibody that reduces the concentration of a protein related to the pathogenesis of Parkinson’s disease called alpha-synuclein) had better motor function one year after starting it than those who did not receive it. In addition, there were no relevant adverse effects. In the current study, these patients are essentially followed for up to four years, and the differences between groups receiving the drug and another group of patients not receiving the drug are not only maintained, but increased. This longer duration is key because, in a way, it is what allows us to determine that patients on the drug ‘have progressed less’. It has some limitations: at the methodological level, the main ones are that the patients who did not receive the drug did not participate in the study, we do what we call an ‘external comparison’. This implies that there may be a lot of confounding factors as this group is not well controlled. Another methodological limitation is that the evaluation is not ‘blind’, that is, both the doctor and the patient know whether they are receiving the drug or not, and this is already known to improve the results in the treated groups. And for me, the main limitation in terms of the potential biological effect is that the neuroimaging results measuring the dopamine circuitry (DaT-SPECT) (which is the main neurotransmitter related to Parkinson’s disease) show no differences between groups. In other words, the study shows no improvement in levels of neurodegeneration. This is explainable for many reasons but, if it had been positive, together with the clinical evidence, it would have been a real milestone in the field.”

José Luis Lanciego, Senior Researcher in the Gene Therapy in Neurodegenerative Diseases Programme at the Centre for Applied Medical Research (CIMA), University of Navarra (Spain), says:

“This is a multi-centre, multinational study sponsored by the pharmaceutical company F. Hoffmann-La Roche Ltd. to evaluate the efficacy of a monoclonal antibody called prasizenumab against a protein called alpha-synuclein. The accumulation of this protein in the cells causes the progressive death of dopamine-producing neurons in Parkinson’s disease. The study was conducted in 316 Parkinson’s patients, divided into three equal groups: one group received a placebo, the second group was treated with prazisenumab at a dose of 1,500mg and a third group at a higher dose (4,500mg). The antibody was administered intravenously once a month during one year of follow-up. The effect of the treatment was evaluated using the MDS-UPDRS motor scales types I, II and III, expecting an improvement in the typical motor symptoms of the disease. Only a slight improvement on the MDS-UPDRS type III scale was observed in the group of patients who had a faster disease progression, with an improvement of approximately 5 points on this scale (an improvement of more than 4.63 points was considered a positive result).In neurodegenerative diseases, the accumulation of misfolded proteins is typically observed in the brain, specifically alpha-synuclein within dopamine-producing cells, and other proteins such as tau (intracellular) or amyloid (extracellular) in the case of Alzheimer’s disease. This new generation of monoclonal antibodies attempts to dissolve the accumulations of these misfolded proteins to ameliorate the progression of these diseases, and are currently causing heated controversy. All of them are administered intravenously and their penetration into the brain is very low (less than 1%). Moreover, once in the brain, it remains to be seen whether the antibodies are able to enter the neurons that accumulate these proteins in order to exert their effect. In the case of aducanumab and lecanemab (to treat Alzheimer’s disease), the target is the amyloid protein (extracellular). Both antibodies have a number of very important side effects that need to be taken into account when considering their administration, especially oedema and brain haemorrhages (present in more than 40% of patients treated with these antibodies. Although the studies published to date with monoclonal antibodies against alpha-synuclein, specifically prasizenumab (PASADENA study) and cinpanemab (SPARK study) have not reported adverse effects, it is clear that for the moment that the improvement obtained is very small, with a follow-up time of only one year. It is really difficult to predict the outcome of this type of treatment over a longer period of time, as it is completely unknown. Another aspect to take into account before considering these new drugs for Parkinson’s patients is their high price. In the case of the monoclonal antibodies against the amyloid protein for the treatment of Alzheimer’s (aducanumab and lecanemab), their price in the United States is approximately US $26,500, 80% of which is covered by Medicare. For the patient, this means an annual cost of just over 5,000 dollars, which has important social implications for access to this medication by racial minorities such as African-American and Hispanic communities. In the EU, this cost is high and will have to be covered by national health systems. In summary, longer-term trials will be needed in which potential benefits are measured using other parameters in addition to motor scales. Besides, the balance between cost, benefit and potential adverse effects needs to be carefully weighed before such treatments are given to Parkinson’s patients. Finally, it will be necessary to have a new generation of antibodies designed to increase their penetration into target neurons or to combine their administration with other techniques that are already available today, such as the permeabilisation of the blood-brain barrier using high-intensity focused ultrasound (HIFU technique).”

‘Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease ‘ by Gennaro Pagano et al. was published in Nature Medicine at 16:00 UK time on Monday 15^th April.

DOI: https://doi.org/10.1038/s41591-024-02886-y

Declared interests

Raúl Martínez Fernández: Did not provide a statement regarding conflicts of interest.

José Luis Lanciego: Did not provide a statement regarding conflicts of interest.