introduction
Parkinson's disease (PD) is a neurodegenerative disease whose main symptoms include motor dysfunction, muscle stiffness, tremor, and balance disorders, posing significant challenges to the lives of patients. April 15 Nature Medicine report "Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease" The potential therapeutic effect of prasinezumab, a monoclonal antibody, in early Parkinson's disease, was explored, especially in the phase II clinical trial of PASADENA for rapidly progressing cases, which showed a certain slowing effect on the progression of motor symptoms. The research and application of prasinezumab attempts to intervene in disease progression by targeting aggregated α-synuclein (α-synuclein), a key protein in the pathological process of Parkinson's disease. α-synuclein aggregates abnormally in the brains of patients with Parkinson's disease and is thought to be one of the main causes of disease progression. Prasinezumab acts as an experimental therapeutic monoclonal antibody with the aim of binding to these abnormal proteins, thereby slowing their spread between neurons. In the PASADENA trial, individuals using Prasinezumab showed slower progression than placebo in the third part of the score dealing with signs of movement, despite failing to meet the primary endpoint of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score. The study also focused specifically on rapidly progressing subgroups to explore the potential benefits of prasinezumab in these specific populations. The results showed that prasinezumab was more effective in inhibiting worsening of symptoms in the baseline subset receiving monoamine oxidase B inhibitors (MAO-B). The variability of this effect may be related to the rate and extent of α-synuclein aggregation, suggesting that α-synuclein may be more effective in intervening in aggregation in rapidly progressive PD subtypes.
Highlights
Prasinezumab as a Potential Disease-Modifying Therapy In this study, Prasinezumab is a monoclonal antibody against α α-synuclein, a key protein in the pathological process of Parkinson's disease (PD). By targeting this protein, which aggregates abnormally in PD, prasinezumab demonstrates the potential ability to slow disease progression. Although the primary clinical endpoint was not met, Prasinezumab-treated individuals showed slower progression of motor symptoms in some subgroups than in the placebo group.
专注于快速进展患者的显著效果在快速进展的帕金森病患者中，Prasinezumab表现出更为显著的治疗效果。 特别是在使用单胺氧化酶B抑制剂(Monoamine Oxidase B inhibitors, MAO-B)的患者群体中，该药物在运动障碍社会统一帕金森病评分量表第三部分(Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, MDS-UPDRS Part III)显示出更低的症状进展速度。
Implications of Exploratory AnalysisAlthough these results are derived from exploratory analyses and need to be further validated through randomized clinical trials, they provide new insights into the role of prasinezumab in the treatment of early Parkinson's disease. These findings highlight the potential importance of treatment in specific fast-progressing subgroups, which may help to target and intervene more precisely in future treatment strategies.
Strategies
Study DesignThis study is a multicenter, randomized, placebo-controlled, Phase 2 clinical trial to evaluate the safety, tolerability, and potential disease-altering effects of prasinezumab in patients with early-stage Parkinson's disease. Studies were designed to be double-blind, with participants randomly assigned to groups that received different doses of Prasinezumab or placebo.
Eligibility Criteria Patients are selected to meet specific diagnostic criteria, including characteristic clinical signs of Parkinson's disease (eg, resting tremor, muscle stiffness, and bradykinesia), age between 40 and 80 years, and Dopamine Transporter Single Photon Emission Computed Tomography (DaT-SPECT) confirms brain dopamine levels consistent with Parkinson's disease.
Intervention and grouping participants were randomly assigned to three treatment groups: high-dose prasinezumab, low-dose prasinezumab, and placebo. All patients received intravenous injections every 4 weeks for 52 weeks. Grouping took into account gender, age (<60 versus ≥60), and the use of monoamine oxidase B inhibitors (MAO-B) at baseline.
The main assessment tool of the Clinical Assessment Tools is the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), with particular attention paid to the third part of the Movement Disorder Society, which deals with assessing the patient's exercise capacity. This scale was used to measure symptom severity at baseline as well as changes during follow-up.
Analysis Strategy: The study employs two analytical strategies to process data. The first is the Hypothetical Strategy, which assumes that no symptomatic improvement treatment has been used throughout the study period. The second is the Treatment Policy Strategy, which includes all data in the analysis, regardless of whether or not symptoms are started or changed to improve treatment. Both strategies assessed the difference between prasinezumab and placebo by statistical analysis using Mixed Models for Repeated Measures.
The Subgroup Analysis study also performed a subgroup analysis to evaluate the effects of prasinezumab in different patient subpopulations. These subpopulations are pre-defined based on preclinical assumptions, including factors such as different stages of disease progression, use of MAO-B inhibitors, and more.
Behind the Scenes
Prasinezumab showed positive effects in a subgroup of rapidly progressive Parkinson's disease patients in the PASADENA Phase II study, although it did not meet the criteria using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, MDS-UPDRS), but subgroup analyses suggest that prasinezumab has shown a beneficial effect in slowing motor symptoms in rapidly progressing patients, particularly in patients who are taking monoamine oxidase B inhibitors (MAO-B) at baseline.
In particular, the subgroup analysis noted that prasinezumab significantly slowed the progression of motor symptoms in the subgroup classified as rapidly progressing. This includes those who were on MAO-B inhibitors at the start of the study. For these patients, treatment showed a 39.0% relative reduction in motor symptom progression in MDS-UPDRS Part III compared to placebo, indicating a significant remission of disease progression over a one-year period. The analysis showed that from baseline to week 52, the mean change score in the third part of the MDS-UPDRS was -2.66 points in the prasinezumab group, compared to -0.87 points in the treatment-free subgroup. This significant difference underscores the potential efficacy of prasinezumab in patients already taking MAO-B inhibitors, suggesting a possible synergistic effect or a more pronounced response due to more severe motor symptoms in this subgroup.
Potential limitations
Post Hoc Exploratory AnalysisThe subgroup analyses in the PASADENA study were ex-post interpretive, meaning that these analyses were not the primary objectives predefined prior to the start of the study. Therefore, these findings may be influenced by data dredging bias, and the results may be contingent and need to be further validated in randomized controlled trials.
Sample SizeAlthough the study involved 316 patients with early-stage Parkinson's disease, the sample size may be smaller in specific subgroups, especially those who are specifically looking for MAO-B inhibitors. The small sample size limits statistical power and may not accurately detect the effect of prasinezumab.
Lack of correction for multiple comparisonsFalse-positive results are possible because multiple subgroups were compared without statistical multiple comparisons. This statistical omission can lead to misleading interpretations of the results.
Duration of TreatmentThe duration of treatment in this study is one year, which may not be sufficient for long-term disease-modifying effects for chronic progressive diseases such as Parkinson's disease. Long-term effects and potential delayed effects may not have been captured in this study.
Restrictions on Initial Medication UseAt the start of the study, the use of commonly used symptomatic drugs for Parkinson's disease, such as levodopa and dopamine agonists, in addition to MAO-B inhibitors, was restricted. This may affect the generalizability of the study, i.e., the results may not be applicable to patients who need these drugs for daily functioning.
Lack of Quantitative Biomarkers: The study failed to use quantitative biomarkers to track changes in α-synucle α in in the brain. The lack of biomarkers to directly measure the mechanism of action of drugs limits the in-depth understanding of their disease-modifying mechanisms of action.
Selection of Patients and InterventionsThe results may not be applicable to a broader or distinct population of patients with Parkinson's disease due to the selection of specific types of patients with early-stage Parkinson's disease (e.g., groupings based specifically on Hoehn and Yahr stage) and limitations of interventions (e.g., stable doses of MAO-B inhibitors).
Potential research directions: Research on disease subtypes: Prasinezumab may be particularly effective in slowing motor progression in subsets of early Parkinson's disease with rapid progression. Future studies could continue to explore and validate these findings in larger and more diverse patient subpopulations. Identifying subgroups of patients based on rate of disease progression, motor phenotype, and other biomarkers, such as monoamine oxidase B (MAO-B) inhibitors used at baseline, can enhance the precision of treatment strategies.
Longitudinal studies versus dose optimization, given the mixed results of various trials and endpoints, long-term studies longer than one year can provide deeper insights into the efficacy and safety of prasinezumab and similar therapies. In addition, optimizing dosing strategies to maximize efficacy and minimize side effects remains a key area of ongoing research.
Biomarker Development This study highlights the need for validation of biomarkers that can reliably measure pathological α-synuclein in vivo. The development of such biomarkers will significantly advance the ability to more accurately diagnose PD and monitor disease progression and response to treatment. This can facilitate earlier intervention and a more tailored approach to treatment.
Synergistic therapies may be promising to explore the potential synergies of prasinezumab with other symptomatic treatments, such as MAO-B inhibitors. Understanding the interactions between different therapeutic agents and their collective impact on disease progression can lead to more effective combination treatments for PD.
Mechanistic studies require further mechanistic studies to explore α-synuclein pathology and its effects on neuronal health. Studying how α-synuclein aggregation affects neuronal function and how its clearance may restore neuronal health could provide key insights into disease processes and therapeutic mechanisms.
Comparative studies comparing different monoclonal antibodies against α-synuclein can shed light on their mechanism of action, efficacy, and safety differences. This type of study can help tailor specific treatments to individual patients' unique disease characteristics and response patterns.
Link to original article
Pagano G, Taylor KI, Anzures Cabrera J, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Brockmann K, Svoboda H, Trundell D, Monnet A, Doody R, Fontoura P, Kerchner GA, Brundin P, Nikolcheva T, Bonni A; PASADENA Investigators; Prasinezumab Study Group. Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease. Nat Med. 2024 Apr 15. doi: 10.1038/s41591-024-02886-y. Epub ahead of print. PMID: 38622249.
https://www.nature.com/articles/s41591-024-02886-y
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