Assessing Cumulative, Meaningful Benefits of Disease-Modifying Therapies Targeting Synucleinopathies: Conference Proceedings and Roadmap for Research

Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative conditions associated with aberrant α-synuclein aggregation, predominating either in neurons (in PD and DLB) or in glial cells (in MSA). These conditions share underlying pathobiology and have many clinical similarities, including difficulties with movement, changes in cognition, sleep disturbances, and autonomic symptoms. Although there are some available symptomatic treatments for synucleinopathies, disease-modifying therapies (DMTs)—medications that address the underlying biological processes of illness—that target α-synuclein are under development as of this writing in 2025 and could slow or stop disease progression in any or all of these conditions.

As of this writing, it is possible that one or more DMTs addressing synucleinopathies will obtain regulatory approval in the next several years. However, many other factors contribute to whether patients will have access to these novel therapies. Government and private payers will need to assess whether the expected benefits justify the costs. Clinicians and medical professional specialty societies will need to know how effective and safe treatments are, including for diverse patient populations and patients with complex needs. Patients and their families will want to understand how their lives could change from the benefits and risks of DMTs. Governments, private payers, clinicians, medical professional specialty societies, patients, and care partners think about meaningful benefits differently from regulators, who focus on safety and efficacy.

DMTs might or might not change how patients experience symptoms over the short time frame of a clinical trial. If DMTs do slow disease progression, patients might not perceive the benefits in terms of delaying or preventing severe symptoms and disability. Understanding the value of DMTs for patients with synucleinopathies requires understanding the likely illness trajectory over the entire course of the disease, which can last many years. Therefore, it will be critical to develop frameworks and collect data to estimate the cumulative, meaningful benefits of DMTs for synucleinopathies. These frameworks need to address varied understandings of meaningful benefits for many individuals and groups, including patients, care partners, clinicians, medical experts, governments, and other payers. Understanding which data are important to collect to best demonstrate meaningful benefits for patients and their families could accelerate access to future DMTs.

What Are Cumulative, Meaningful Benefits of Disease-Modifying Therapies?

Meaningful benefits describe the spectrum of potentially desirable outcomes that might be demonstrated in clinical trials, extending the idea of clinical meaningfulness into populations without clinical symptoms. Meaningful benefits might emerge downstream from intervention in longer-term follow-up (Assunção et al., 2022).

Cumulative benefits reflect an accrual of effects of long-term therapy, such that the difference in outcomes between those treated with a placebo and those treated with the drug increases over time (Cummings and Fox, 2017).

Motivation for the Workshop

Synucleinopathies have enough clinical and pathobiological similarities that we can group them together when considering the value of DMTs. An international coalition of nonprofit organizations that serves people affected by synucleinopathies hosted an in-person workshop in 2024 to discuss opportunities for communication, coordination, and collaboration to advance new treatments for PD, DLB, MSA, and related conditions. This article summarizes that workshop, titled the Workshop on Assessing Cumulative Benefits of Disease-Modifying Therapies Targeting Synucleinopathies. The workshop brought together representatives from international research, industry, and advocacy communities and people with lived experiences of synucleinopathies to review the existing state of the field and to develop an actionable roadmap for assessing and understanding the holistic, long-term, and meaningful benefits of DMTs for synucleinopathies from multiple stakeholder perspectives. Specifically, the stated goals of the workshop were to

• identify lessons from the treatment of other progressive neurological conditions, such as Alzheimer's disease and multiple sclerosis, with commercial-stage DMTs and apply those lessons to conditions represented by the coalition (PD, DLB, and MSA)
• assess the state of the science and challenges for evaluating long-term, meaningful benefits and risks of DMTs for the synucleinopathies PD, DLB, and MSA
• define gaps in existing clinical outcome assessments, data, and other types of evidence that need to be filled to enable understanding of long-term benefits of novel therapies that slow development of disability, including benefits that are most meaningful to patients and their caregivers.

Main Themes from Workshop Presentations and Discussions

Several themes emerged from the workshop's presentations and discussions:

• The workshop included representatives concerned with PD, DLB, and MSA, so participants reflected on similarities and differences among these synucleinopathies to explore appropriate and inappropriate areas for collaboration across groups representing patients with each condition.
• The measurement of the cumulative, meaningful benefits of DMTs and the identification of fruitful areas for collaboration pose challenges for the field.
• Clinical trial recruitment and retention also face difficulties, which could raise issues for clinical care, especially in understanding what it means to slow disease progression.
• The experience of DMTs in other conditions, especially Alzheimer's disease, provides useful lessons for synucleinopathies.

Key Takeaways

• Synucleinopathies are a group of progressive neurodegenerative conditions associated with aberrant α-synuclein aggregation, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The different synucleinopathies share some important features, including many common symptoms and progressively increasing impairment and disability.
• DMTs for synucleinopathies—which would slow or stop disease progression—are not yet available, but many promising candidates are in the treatment development pipeline.
• These drugs could prevent, delay, or lessen the most-severe symptoms and disabilities that patients with synucleinopathies experience. Although some of these benefits might be observed over the short time frame of a clinical trial, the full benefits of these drugs would potentially accumulate over a patient's lifetime.
• Once these treatments receive regulatory approval, access to these treatments will be determined by such stakeholders as governments, payers, and clinicians. These stakeholders will evaluate whether the value of the cumulative, meaningful benefits of DMTs for synucleinopathies outweigh their risks and costs. Stakeholders have varying views of which data are most important to understanding cumulative, meaningful benefits.
• Future steps for the field include generating data to support health economics and outcomes research, developing frameworks and lessons learned for communicating the meaningful benefits of DMTs to different stakeholders, and engaging with interested parties (including regulators, payers, clinicians, patients, and their families) to anticipate access issues.
• Advocates for patients with synucleinopathies hope to avoid challenges that have impeded patient access to recently approved DMTs in other neurodegenerative diseases. Proactive planning for data generation and communication to understand the cumulative, meaningful benefits of DMTs for synucleinopathies and the value perspectives of all stakeholders might help mitigate these issues.