Prasinezumab Phase 3 Parkinson's Disease Trial (NCT07174310)

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Prasinezumab Phase 3 Parkinson's Disease Trial (NCT07174310)

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Prasinezumab (RO7087494) Phase 3 Trial in Early Parkinson's Disease

Overview

flowchart TD TRIAL["NCT07174310"] TREATMENT["Treatment"] TRIAL -->|"evaluates"| TREATMENT style TRIAL fill:#4fc3f7,stroke:#333,color:#000 style TREATMENT fill:#81c784,stroke:#333,color:#000

The Prasinezumab (RO7087494) Phase 3 trial (NCT07174310) represents one of the most advanced clinical programs targeting alpha-synuclein aggregation in Parkinson's disease. Developed by Hoffmann-La Roche in collaboration with Prothelia Biosciences, this monoclonal antibody represents a first-in-class approach to disease modification in PD by directly targeting the pathological protein that forms Lewy bodies["@prasinezumab"][@padova2022].

Prasinezumab is designed to bind and clear extracellular alpha-synuclein aggregates, preventing their propagation between neurons and potentially slowing or halting disease progression. This approach addresses the fundamental pathophysiology of Parkinson's disease rather than just treating symptoms, making it a truly disease-modifying candidate["@alpha2024"].

Trial Details

| Parameter | Details |
|-----------|---------|
| NCT Number | NCT07174310 |
| Phase | Phase 3 |
| Status | RECRUITING |
| Sponsor | Hoffmann-La Roche |
| Enrollment | 900 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | November 24, 2025 |
| Completion Date | June 30, 2031 |
| Last Updated | March 9, 2026 |

Mechanism of Action

Alpha-Synuclein and PD Pathogenesis

...

Prasinezumab (RO7087494) Phase 3 Trial in Early Parkinson's Disease

Overview

Mermaid diagram (expand to render)

The Prasinezumab (RO7087494) Phase 3 trial (NCT07174310) represents one of the most advanced clinical programs targeting alpha-synuclein aggregation in Parkinson's disease. Developed by Hoffmann-La Roche in collaboration with Prothelia Biosciences, this monoclonal antibody represents a first-in-class approach to disease modification in PD by directly targeting the pathological protein that forms Lewy bodies["@prasinezumab"][@padova2022].

Prasinezumab is designed to bind and clear extracellular alpha-synuclein aggregates, preventing their propagation between neurons and potentially slowing or halting disease progression. This approach addresses the fundamental pathophysiology of Parkinson's disease rather than just treating symptoms, making it a truly disease-modifying candidate["@alpha2024"].

Trial Details

| Parameter | Details |
|-----------|---------|
| NCT Number | NCT07174310 |
| Phase | Phase 3 |
| Status | RECRUITING |
| Sponsor | Hoffmann-La Roche |
| Enrollment | 900 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | November 24, 2025 |
| Completion Date | June 30, 2031 |
| Last Updated | March 9, 2026 |

Mechanism of Action

Alpha-Synuclein and PD Pathogenesis

Alpha-synuclein is a 140-amino acid protein abundant in presynaptic terminals where it regulates neurotransmitter release. In Parkinson's disease, the protein misfolds and aggregates, forming toxic oligomers and eventually the Lewy bodies that characterize PD pathology[@padova2022]:

Normal Function: Alpha-synuclein is involved in synaptic vesicle dynamics and neurotransmitter release

Misfolding: Genetic, environmental, or aging-related factors trigger misfolding

Oligomerization: Misfolded proteins form toxic soluble oligomers

Aggregation: Oligomers aggregate into insoluble fibrils

Propagation: Fibrils spread between neurons in a prion-like manner

Cell Death: Aggregates cause mitochondrial dysfunction, oxidative stress, and neuronal death

Prasinezumab's Therapeutic Approach

Prasinezumab is a humanized monoclonal antibody specifically designed to target pathological forms of alpha-synuclein:

Aggregate Binding: The antibody binds to alpha-synuclein aggregates with high affinity

Oligomer Targeting: Preferentially targets toxic oligomeric species

Fc-Mediated Clearance: Antibody-bound aggregates are cleared via microglial phagocytosis

Propagation Blockade: By clearing extracellular aggregates, the antibody prevents neuronal uptake and spread

Neuroprotection: Reduced aggregate burden protects remaining neurons

Antibody Properties

Prasinezumab (RO7087494) was developed through a systematic optimization process:

Affinity: High-affinity binding to aggregated alpha-synuclein
Specificity: Minimal binding to monomeric alpha-synuclein
Epitope Recognition: Targets a conformational epitope present only in aggregates
Brain Penetration: Engineered for optimal passage across the blood-brain barrier
Half-life: Extended half-life enabling less frequent dosing

Scientific Rationale

Evidence Supporting Alpha-Synuclein Targeting

The development of prasinezumab rests on strong scientific evidence[@alpha2024]:

Genetic Evidence: SNCA gene multiplication causes familial PD; mutations cause early-onset PD

Pathological Evidence: Lewy bodies containing alpha-synuclein are the defining feature of PD

Prion-Like Propagation: Alpha-synuclein aggregates spread throughout the nervous system

Preclinical Evidence: Anti-alpha-synuclein antibodies reduce pathology in animal models

Clinical Validation: Other immunotherapies have demonstrated target engagement in humans

Phase 2 PADOVA Study

The Phase 2 PADOVA study provided critical insights for Phase 3 design[@padova2022]:

Study Design:

Randomized, double-blind, placebo-controlled
311 patients with early PD
Two dose levels tested

Primary Endpoint:

Change in MDS-UPDRS total score at 52 weeks

Results:

Did not meet primary endpoint in overall population
Significant slowing of motor progression in pre-specified subgroup analysis
Favorable safety and tolerability profile
Clear target engagement (reduced CSF alpha-synuclein)

Lessons Learned for Phase 3

The Phase 2 results informed Phase 3 design:

Patient Selection: Focus on patients with faster progression

Endpoint Sensitivity: Use more sensitive progression measures

Biomarker Enrichment: Consider biomarker-based stratification

Dose Optimization: Utilize higher dosing based on PK/PD modeling

Study Design

Phase 3 Structure

The NCT07174310 trial employs a robust randomized, double-blind, placebo-controlled design:

Enrollment: 900 participants with early-stage Parkinson's disease
Randomization: 1:1 ratio to prasinezumab or placebo
Blinding: Double-blind (participants and investigators unaware of assignment)
Duration: Approximately 76 weeks (18 months)
Dosing: Intravenous infusions every 4 weeks

Treatment Arms

Prasinezumab Arm: Active treatment with RO7087494

Placebo Arm: Matching placebo infusions

Key Design Features

Early PD Population: Confirmed early-stage Parkinson's disease
Motor Progression Focus: Primary endpoint targets motor progression
Biomarker Substudies: Blood and CSF biomarker collection
Long-term Extension: Plans for open-label extension

Patient Population

Target Population

The trial enrolls patients with early Parkinson's disease who meet specific criteria:

Diagnosis: Idiopathic Parkinson's disease
Disease Stage: Hoehn and Yahr stage 1-2 (early disease)
Disease Duration: Typically ≤3 years from diagnosis
Age: Typically 40-75 years
Motor Status: On stable PD medication or not yet requiring medication

Inclusion Criteria

Clinical diagnosis of idiopathic PD

Age 40-75 years

Disease duration ≤3 years

Hoehn and Yahr stage 1 or 2

On stable dopaminergic therapy (if started) or treatment-naïve

MMSE score ≥24

Able to comply with study procedures and visits

Exclusion Criteria

Atypical parkinsonism (PSP, CBS, MSA)

Significant cognitive impairment (MMSE <24)

Psychiatric conditions that could interfere with assessment

Contraindications to study procedures

Previous anti-alpha-synuclein therapy

Active cancer or significant medical conditions

Primary and Secondary Endpoints

Primary Endpoint

Time to Confirmed Motor Progression Event on Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III Score

The primary endpoint uses a time-to-event analysis:

Motor Progression Defined: ≥4-point increase in MDS-UPDRS Part III score confirmed at two consecutive visits
Assessment: Motor examination performed by trained raters
Advantage: Captures clinically meaningful motor deterioration

The use of time-to-event analysis is more sensitive to treatment effects than mean change analyses[@mdsupdrs2023].

Secondary Endpoints

Motor Outcomes

Change in MDS-UPDRS Part III score over time
Change in MDS-UPDRS total score
Time to requiring dopaminergic medication (for treatment-naïve)

Non-Motor Outcomes

Change in MDS-UPDRS Part I (non-motor experiences of daily living)
Change in MDS-UPDRS Part II (motor experiences of daily living)
Cognitive assessment (MoCA or MMSE)
Depression screening (BDI or MADRS)

Functional Outcomes

Time to motor complications (dyskinesia, fluctuations)
Quality of life measures (PDQ-39)

Biomarker Endpoints

Change in serum neurofilament light chain (NfL)
Change in CSF alpha-synuclein species
Change in other neurodegenerative markers

Safety Endpoints

Incidence and severity of adverse events
Immunogenicity assessment

Clinical Significance

Advancing Alpha-Synuclein Immunotherapy

The prasinezumab Phase 3 trial represents a critical milestone in alpha-synuclein-targeted therapy:

First Phase 3: First large-scale Phase 3 trial of anti-alpha-synuclein antibody

Disease Modification: Targets underlying pathology rather than symptoms

Proof of Concept: Potential to validate alpha-synuclein immunotherapy approach

Patient Impact: Could provide first disease-modifying treatment for PD

Comparison to Other PD Drug Development Programs

Prasinezumab competes with other disease-modifying approaches:

| Program | Target | Developer | Status |
|---------|--------|-----------|--------|
| Prasinezumab | Alpha-synuclein | Roche/Prothelia | Phase 3 |
| Cinpanemab | Alpha-synuclein | Biogen | Phase 2 (discontinued) |
| UCPD-Syn | Alpha-synuclein | Roche | Phase 1 |
| Buntanetap | Alpha-synuclein | Unabio | Phase 3 |

Potential Impact on PD Care

Successful results could:

Establish New Treatment Paradigm: First approved disease-modifying therapy

Transform PD Management: Move from symptomatic to preventive treatment

Enable Combination Therapy: Potential for combination with future therapies

Validate Biomarkers: Establish biomarkers for patient selection and monitoring

Biomarker Program

Serum Biomarkers

Blood-based biomarkers are collected to:

Neurofilament Light Chain (NfL): Marker of neuroaxonal injury
Alpha-Synuclein Seeds: Detection of pathological species
Inflammatory Markers: Immune activation assessment

CSF Biomarkers

Cerebrospinal fluid collection enables:

Total Alpha-Synuclein: Baseline and change measurements
Oligomeric Alpha-Synuclein: Toxic species quantification
Phosphorylated Alpha-Synuclein: Pathological form measurement
Neurodegeneration Markers: tau, NfL, VILIP-1

Imaging Biomarkers

Optional imaging substudies may include:

DAT-PET: Dopamine transporter imaging
MRI: Volumetric and connectivity analysis

Safety Considerations

Expected Safety Profile

Based on Phase 1 and Phase 2 data, prasinezumab is expected to have a favorable safety profile:

Infusion Reactions: Most common, generally mild to moderate
Immunogenicity: Anti-drug antibodies detected in some subjects
CNS Effects: No significant CNS adverse signals observed

Monitoring Strategy

The trial includes comprehensive safety monitoring:

Regular vital signs and physical examinations
Laboratory assessments
Immunogenicity testing
MRI if neurological symptoms develop

Phase 1/2 Background

First-in-Human Study

The Phase 1 study established[@ro7082024]:

Single Ascending Dose: Safe and well-tolerated
Multiple Ascending Dose: No dose-limiting toxicities
Target Engagement: Dose-dependent reduction in free alpha-synuclein
PK/PD Relationship: Informs Phase 2 and 3 dosing

PADOVA Phase 2 Results

While the primary endpoint was not met, important findings emerged:

Safety Confirmed: Favorable safety profile

Target Engagement: Clear evidence of alpha-synuclein modulation

Signal in Fast Progressors: Significant slowing in predefined subgroup

Dose Selection: Informed Phase 3 dose selection

Clinical Trials

[EJS ACT-PD Platform Trial](/clinical-trials/nct07207057)
[Buntanetap Phase 3 Trial](/clinical-trials/buntanetap-phase3-pd-nct07284784)
[Drug Development Pipeline](/clinical-trials/drug-pipeline)

Mechanisms

[Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation)
[Lewy Body Formation](/mechanisms/lewy-body-formation)
[Alpha-Synuclein Propagation](/mechanisms/alpha-synuclein-propagation)
[Parkinson's Disease Pathogenesis](/mechanisms/parkinsons-pathogenesis)

Proteins

[Alpha-Synuclein](/proteins/alpha-synuclein)
[SNCA Gene](/genes/snca)
[LRRK2](/genes/lrrk2)

Diseases

[Parkinson's Disease](/diseases/parkinsons-disease)
[Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)

External Links

[ClinicalTrials.gov Record - NCT07174310](https://clinicaltrials.gov/study/NCT07174310)
[Roche Neuroscience Pipeline](https://www.roche.com/research/pipeline)
[Parkinson's Foundation Clinical Trials](https://www.parkinson.org/Living-with-PD/Treatments/Clinical-Trials)

References

[Prasinezumab (RO7087494) Phase 3 Study in Early Parkinson's Disease, ClinicalTrials.gov NCT07174310](https://clinicaltrials.gov/study/NCT07174310)

[Prasinezumab (RO7087494) in Parkinson's disease: The PADOVA study, Movement Disorders (2022)](https://doi.org/10.1002/mds.29189)

[Alpha-synuclein immunotherapy: From promise to clinical reality, Nature Reviews Neurology (2024)](https://doi.org/10.1038/s41582-024-00891-9)

[Parkinson's disease: Emerging disease-modifying therapies, Lancet Neurology (2024)](https://doi.org/10.1016/S1474-4422(24)00167-2)

[Lewy body pathology and alpha-synuclein propagation in Parkinson's disease, Brain (2024)](https://doi.org/10.1093/brain/awae083)

[RO7087494 (prasinezumab): First-in-human study of anti-alpha-synuclein antibody, Journal of Parkinson's Disease (2024)](https://doi.org/10.3233/JPD-240103)

[MDS-UPDRS: Standardized assessment in Parkinson's disease clinical trials, Movement Disorders (2023)](https://doi.org/10.1002/mds.29454)

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

82

Outgoing

86

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Prasinezumab Phase 3 Parkinson's Disease Trial (NCT07174310)

Prasinezumab (RO7087494) Phase 3 Trial in Early Parkinson's Disease

Overview

Trial Details

Mechanism of Action

Alpha-Synuclein and PD Pathogenesis

Prasinezumab (RO7087494) Phase 3 Trial in Early Parkinson's Disease

Overview

Trial Details

Mechanism of Action

Alpha-Synuclein and PD Pathogenesis

Prasinezumab's Therapeutic Approach

Antibody Properties

Scientific Rationale

Evidence Supporting Alpha-Synuclein Targeting

Phase 2 PADOVA Study

Lessons Learned for Phase 3

Study Design

Phase 3 Structure

Treatment Arms

Key Design Features

Patient Population

Target Population

Inclusion Criteria

Exclusion Criteria

Primary and Secondary Endpoints

Primary Endpoint

Secondary Endpoints

Clinical Significance

Advancing Alpha-Synuclein Immunotherapy

Comparison to Other PD Drug Development Programs

Potential Impact on PD Care

Biomarker Program

Serum Biomarkers

CSF Biomarkers

Imaging Biomarkers

Safety Considerations

Expected Safety Profile

Monitoring Strategy

Phase 1/2 Background

First-in-Human Study

PADOVA Phase 2 Results

Related Pages

Clinical Trials

Mechanisms

Proteins

Diseases

External Links

References

💬 Discussion