In the pursuit of effective treatments for Parkinson's disease (PD), recent breakthroughs have illuminated the potential of novel disease-modifying drugs aiming to alter the trajectory of this complex neurological condition. While the pursuit has long revolved around targeting α-synuclein, a protein implicated in PD progression, the landscape is evolving with the emergence of prasinezumab and lixisenatide. As these two drugs offer fresh avenues in PD management, their nuanced mechanisms and tailored approaches underscore the imperative for personalised treatment strategies in tackling this multifaceted disease, as mitigating motor disability progression in early PD patients marks a significant stride in the quest for effective therapies.
Prasinezumab's Potential in Slowing PD Progression
Prasinezumab, a monoclonal antibody, emerged as a potential therapeutic agent designed to target aggregated forms of α-synuclein. Initial trials, such as the PASADENA study, aimed to assess its impact on early-stage PD patients. However, the primary outcome of the PASADENA study did not demonstrate significant differences between prasinezumab and placebo groups. Despite this, further analysis revealed intriguing findings. Subpopulations within the study, characterised by markers of faster disease progression, exhibited promising responses to prasinezumab. These findings suggested that prasinezumab might slow motor symptom progression in individuals with rapid disease advancement. Notably, the use of MAO-B inhibitors emerged as a potential factor influencing treatment response, although its precise role remains to be fully elucidated.
Unlocking Potential: PASADENA's Secondary Insights
A recent study's outcomes underscored the importance of robust clinical endpoints in evaluating disease-modifying therapies for PD. Motor symptoms, assessed through the MDS-UPDRS Part III scale, emerged as a reliable indicator of disease progression. Interestingly, while motor symptoms progressed more rapidly in certain subpopulations, nonmotor symptoms showed minimal changes over the study period. The potential efficacy of prasinezumab in targeting α-synuclein aggregates aligns with emerging insights into PD pathology. Moreover, its distinct mechanism of action, targeting both aggregated and monomeric forms of α-synuclein, distinguishes it from other experimental therapies like cinpanemab. The varying responses observed in different subpopulations highlight the need for personalised treatment approaches in PD management.
The need for a personalised therapeutic approach
Despite promising findings, caution is warranted in interpreting the results of the PASADENA study. The need for longer-term trials to fully assess treatment effects in slower-progressing subpopulations is evident. Ongoing research, such as the PADOVA study, seeks to further elucidate the potential of prasinezumab in slowing disease progression. While the PASADENA study did not meet its primary endpoint, secondary analyses shed light on prasinezumab's potential in specific PD subpopulations. These findings underscore the complexity of PD progression and the importance of tailored therapeutic approaches. Moving forward, continued research efforts are crucial in unlocking effective treatments for this challenging neurological disorder.
Lixisenatide's Therapeutic Trail
On another emerging front, a recent phase 2 clinical trial has revealed promising results regarding the potential of the diabetes drug, lixisenatide, in slowing the progression of Parkinson's disease. Lixisenatide, known for its glucagon-like peptide-1 receptor agonist properties, demonstrated neuroprotective effects in a mouse model of Parkinson’s.
Steps toward impact on motor disability
The double-blind, randomised, placebo-controlled trial involved 156 participants diagnosed with Parkinson's within the past three years. Over 12 months, participants received either daily subcutaneous doses of lixisenatide or a placebo, followed by a 2-month washout period. The primary measure of effectiveness was the change in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, which assesses motor disability.
Promising results despite the presence of side effects
Results showed that at the end of the trial, participants receiving lixisenatide experienced minimal change in motor disability scores, indicating improvement, whereas those on the placebo demonstrated worsening disability. However, gastrointestinal side effects such as nausea (46%) and vomiting (13%) were reported among those receiving lixisenatide. These findings suggest that lixisenatide therapy holds promise in slowing the progression of motor disability in early Parkinson’s disease. Nonetheless, further extensive trials are necessary to ascertain its efficacy and safety in larger populations.
Source: New England Journal of Medicine / Nature Medicine
Image Credit: iStock
References:
Pagano, G., Taylor, K.I., Anzures Cabrera, J. et al. Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nat Med (2024). https://doi.org/10.1038/s41591-024-02886-y
Wassilios G. Meissner, Philippe Remy, Caroline Giordana et al.; Trial of Lixisenatide in Early Parkinson’s Disease; N Engl J Med 2024;390:1176-1185
