Prasinezumab (RO7087494) Phase 3 Trial in Early Parkinson's Disease
Overview
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TREATMENT["Treatment"]
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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 deathPrasinezumab'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 neuronsAntibody 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 humansPhase 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 modelingStudy 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 infusionsKey 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 visitsExclusion 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 conditionsPrimary 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 PDComparison 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 monitoringBiomarker 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 selectionRelated Pages
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)