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 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.
| 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 |
¶ 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:
- 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 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
The development of prasinezumab rests on strong scientific evidence:
- 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
The Phase 2 PADOVA study provided critical insights for Phase 3 design:
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)
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
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
- Prasinezumab Arm: Active treatment with RO7087494
- Placebo Arm: Matching placebo infusions
- 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
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
- 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
- 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
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.
-
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
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
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 |
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
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
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
Optional imaging substudies may include:
- DAT-PET: Dopamine transporter imaging
- MRI: Volumetric and connectivity analysis
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
The trial includes comprehensive safety monitoring:
- Regular vital signs and physical examinations
- Laboratory assessments
- Immunogenicity testing
- MRI if neurological symptoms develop
The Phase 1 study established:
- 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
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