Prasinezumab for Early Parkinson's Disease (PASADENA)
Overview
Mermaid diagram (expand to render)
Prasinezumab (RO7046015/PRX002) is a humanized monoclonal antibody designed to target and clear extracellular alpha-synuclein aggregates, the pathological protein implicated in Parkinson's disease and related disorders. This Phase IIb clinical trial (NCT04777331), known as the PASADENA study, evaluated the efficacy and safety of prasinezumab in patients with early-stage Parkinson's disease.
Alpha-synuclein is a 140-amino-acid protein that plays critical roles in synaptic vesicle trafficking and neurotransmitter release. In Parkinson's disease, alpha-synuclein misfolds and aggregates to form toxic oligomers and fibrils that accumulate as Lewy bodies, driving progressive neurodegeneration. Prasinezumab represents a disease-modifying approach targeting the root cause of PD rather than just managing symptoms["@prasinezumab-mechanism"].
Trial Details
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04777331 |
| Phase | PHASE2 |
| Status | ACTIVE_NOT_RECRUITING |
| Sponsor | Hoffmann-La Roche (partnering with Prothelia) |
| Enrollment | 586 participants |
| Enrollment Type | ACTUAL |
| Study Type | INTERVENTIONAL |
| Start Date | 2021-05-05 |
| Completion Date | 2026-12-30 |
| Last Updated | 2026-03-09 |
Conditions Studied
- Early Parkinson's Disease (PD)
- Disease duration ≤24 months
- Hoehn & Yahr stage 1-2
- Motor symptoms present but not requiring dopaminergic therapy
- dopamine transporter (DaT) scan deficit confirmed
Scientific Background
Parkinson's Disease Pathophysiology
Parkinson's disease is the second most common neurodegenerative disorder, affecting approximately 10 million people worldwide. The disease is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the classic motor symptoms of tremor, bradykinesia, rigidity, and postural instability[@pd-progression].
Pathological Hallmarks
Lewy Bodies: Intraneuronal inclusions composed primarily of aggregated alpha-synuclein protein, along with other proteins, lipids, and cellular components. These inclusions are the pathological hallmark of PD and related disorders.
Neuronal Loss: Progressive degeneration of dopaminergic neurons in the substantia nigra, with an estimated 50-70% of neurons lost by the time motor symptoms appear.
Axonal Dysfunction: Early impairment of axonal transport and synaptic function preceding cell body loss.Alpha-Synuclein Biology
Alpha-synuclein is a soluble, natively unfolded protein enriched in presynaptic terminals. Under physiological conditions, it participates in:
- Synaptic vesicle trafficking
- Dopamine biosynthesis regulation
- Neurotransmitter release modulation
- Synaptic plasticity
Misfolding and AggregationIn PD, alpha-synuclein undergoes a conformational transition from its native unfolded state to form:
Oligomers: Soluble, toxic intermediate species
- 100-1000x more toxic than monomers
- Disrupt synaptic function
- Impair mitochondrial function
- Trigger oxidative stress
Fibrils: Insoluble, filamentous aggregates
- Major component of Lewy bodies
- Template further aggregation
- Transmit between neurons (prion-like)
Lewy Bodies: Large, insoluble inclusions
- Accumulate in surviving neurons
- May represent a protective mechanism (sequestration)
The "prion-like" propagation of alpha-synuclein pathology is a key concept in understanding disease progression[@alpha-synuclein-pathology]:
- Pathological alpha-synuclein seeds can transfer between neurons
- This spreads pathology in a predictable pattern (Braak staging)
- Explains both motor and non-motor symptoms (e.g., olfactory dysfunction early)
The Immunotherapy Approach
Prasinezumab represents a novel disease-modifying strategy based on alpha-synuclein immunotherapy:
Mechanism of Action
Extracellular Targeting: Prasinezumab binds to extracellular and membrane-associated alpha-synuclein, not intracellular aggregates. This is strategic because:
- Toxic oligomers spread between neurons via extracellular space
- Antibody can intercept seeds before they enter new cells
- Activates microglia for clearance
Antibody Properties
- Target: Conformational epitope on alpha-synuclein
- Affinity: High affinity for oligomeric and fibrillar forms
- Isotype: Humanized IgG1 with Fc effector functions
- CNS Penetration: Engineered for enhanced brain delivery
Clearance Mechanisms
- Fc-mediated phagocytosis: Microglial activation
- Antibody-dependent cellular cytotoxicity (ADCC)
- Prevention of propagation: Neutralizing extracellular seeds
Advantages Over Symptomatic TreatmentsCurrent PD treatments (levodopa, dopamine agonists, MAO-B inhibitors) provide symptomatic relief but do not slow disease progression. Prasinezumab aims to:
- Reduce pathological alpha-synuclein burden
- Prevent new neuron involvement
- Slow disease progression
- Potentially modify the natural history of PD
Preclinical and Early Clinical Data
Phase 1 Studies
Prasinezumab was evaluated in Phase 1 studies demonstrating[@pasched-2022]:
- Safety: Well-tolerated at doses up to 6,000 mg IV
- PK/PD: Dose-proportional exposure, half-life ~30 days
- Target Engagement: Dose-dependent reduction in free alpha-synuclein
- CSF Penetration: Demonstrated in spinal fluid
Phase 2 PASED Study (NCT03100149)A previous Phase 2 study in patients with PD showed:
- Trend toward reduced motor progression
- Safety and tolerability established
- Biomarker effects supporting mechanism
This Phase IIb PASADENA study was designed to confirm and extend these findings.
Study Design
This is a Phase 2b, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of prasinezumab in early Parkinson's disease.
PASADENA Study Design
Primary Objective
Evaluate the effect of prasinezumab on motor progression in early PD patients.
Key Design Features
Randomization: 1:1:1 to three arms
- Placebo
- Low-dose prasinezumab (1,500 mg IV)
- High-dose prasinezumab (4,500 mg IV)
Treatment Regimen
- Intravenous infusion every 4 weeks
- 52-week treatment period (primary analysis)
- Optional 52-week open-label extension
Blinding
- Double-blind (participants and investigators masked)
- Matching placebo infusions
- Independent assessors for primary endpoint
Inclusion Criteria
Age: 40-80 years
PD Diagnosis: UK Brain Bank criteria
Disease Duration: ≤24 months from diagnosis
Hoehn & Yahr Stage: 1-2 (unilateral or bilateral involvement, no significant postural instability)
Motor Symptoms: Milder severity (MDS-UPDRS Part III <35)
DaT Scan: Confirmed dopamine transporter deficit
Medications: Not requiring dopaminergic therapy at baselineExclusion Criteria
Atypical Parkinsonism: PSP, MSA, CBD
Dementia: MMSE <26 or clinical dementia diagnosis
Prior Treatment: Previous PD medications (levodopa, agonists, MAO-B inhibitors)
Imaging: Significant white matter disease, prior stroke
Medical: Active malignancy, severe cardiac diseaseOutcome Measures
Primary Endpoint
Time to Confirmed Motor Progression
The primary endpoint measures time from randomization to:
- ≥30% increase in MDS-UPDRS Part III (motor) score
- Confirmed at two consecutive visits ≥4 weeks apart
This endpoint was designed to capture clinically meaningful progression while minimizing noise from temporary fluctuations.
Secondary Endpoints
Motor Symptoms
- Change in MDS-UPDRS Parts I-III total score
- Change in MDS-UPDRS Part III (motor) score
- Levodopa-equivalent dose initiation
Non-Motor Symptoms
- Change in MDS-UPDRS Part I (non-motor experiences of daily living)
- Epworth Sleepiness Scale
- Beck Depression Inventory
Functional Measures
- Schwab and England Activities of Daily Living
- Timed Up and Go test
- Gait analysis
Biomarkers
- Serum and CSF alpha-synuclein species
- Neurofilament light chain (NfL)
- Tau protein[@pd-progression]
Exploratory Endpoints
- Imaging: MRI brain volumetry, DaT SPECT
- Digital: Wearable sensor metrics
- Genetic: APOE status,GBA, LRRK2 correlations
Clinical Significance
Advancing Disease-Modifying Therapy for PD
The PASADENA trial represents a critical step toward the first disease-modifying therapy for Parkinson's disease. Current treatments address symptoms but do not modify the underlying disease process:
| Treatment Type | Mechanism | Limitation |
|----------------|-----------|------------|
| Levodopa | Dopamine replacement | Motor complications |
| Dopamine agonists | Dopamine receptor activation | Side effects |
| MA-B inhibitors | Prevent dopamine breakdown | Mild efficacy |
| Deep brain stimulation | Neural circuit modulation | Invasive |
| Prasinezumab | Alpha-synuclein clearance | Disease modification |
If successful, prasinezumab would validate alpha-synuclein immunotherapy as a viable approach and potentially transform PD treatment.
Understanding Alpha-Synuclein Pathology
The trial contributes to understanding PD pathophysiology:
Proof of Concept: Does removing alpha-synuclein slow progression?
Target Validation: Is extracellular alpha-synuclein a therapeutic target?
Biomarker Development: How do biomarker changes relate to clinical outcomes?Biomarker Correlations
The trial includes extensive biomarker collection to understand:
Alpha-Synuclein Species
- Total alpha-synuclein in CSF/serum
- Oligomeric vs. monomeric forms
- Post-translational modifications (phosphorylation, truncation)
Neurodegeneration Markers
- Neurofilament light chain (NfL)
- Tau protein
- Amyloid-beta (for PD dementia)
Inflammatory Markers
- Cytokines (IL-6, TNF-α)
- Microglial activation markers
Comparison with Other Immunotherapy Approaches
Several anti-alpha-synuclein antibodies are in development:
| Antibody | Company | Target | Phase |
|----------|---------|--------|-------|
| Prasinezumab | Roche/Prothelia | N-terminal | Phase 2b |
| Cinpanemab | Novartis | N-terminal | Phase 2 |
| Tetrabenazine | Medivic | Vesicular | Approved (other use) |
| UB-312 | Vaxart | Alpha-synuclein | Phase 1 |
Each antibody targets different epitopes and forms of alpha-synuclein, with varying mechanisms.
Participating Sites
The trial was conducted at approximately 60 sites globally:
United States Sites
- Birmingham, Alabama: University of Alabama at Birmingham
- Phoenix, Arizona: Barrow Neurological Institute
- Fullerton, California: University of California Irvine
- La Jolla, California: Scripps Clinic
- Los Angeles, California: UCLA
- San Francisco, California: UCSF
- Aurora, Colorado: University of Colorado
European Sites
- London, United Kingdom: UCL Queen Square
- Cambridge, United Kingdom: Addenbrooke's Hospital
- Paris, France: Pitié-Salpêtrière
- Munich, Germany: Technical University
- Milan, Italy: IRCCS Carlo Besta
- Barcelona, Spain: Hospital Clínic
- Amsterdam, Netherlands: VU Medical Center
Asia-Pacific
- Tokyo, Japan: Juntendo University
- Seoul, South Korea: Seoul National University
- Sydney, Australia: University of Sydney
Safety Profile
Expected Adverse Events
Based on Phase 1 data and class effects:
Infusion-Related Reactions
- Typically mild (headache, fatigue, nausea)
- More common with first infusions
- Managed with pre-medication (antihistamines, corticosteroids)
Amyloid-Related Imaging Abnormalities (ARIA)
- Although prasinezumab targets alpha-synuclein (not amyloid), monitoring for similar imaging changes
- MRI monitoring at baseline, 12 weeks, 52 weeks
Infections
- Upper respiratory tract infections
- Urinary tract infections
- No increased serious infection risk in Phase 1
Safety Monitoring
- MRI: Baseline, Week 12, Week 52
- Laboratory: CBC, chemistry at each visit
- ECG: Baseline and end of treatment
- Adverse Event Collection: Throughout treatment and follow-up
Special Populations
Geriatric Patients: Age >75 may have increased infection risk
GBA Carriers: May have faster progression, potential subgroup analysis
APOE4 Carriers: May have different response
Clinical Outcomes: Interpretation
Understanding Motor Progression
The primary endpoint (time to confirmed motor progression) requires careful interpretation:
What constitutes progression?
- 30% increase in MDS-UPDRS Part III is clinically meaningful
- Confirmed at two visits to avoid false positives from fluctuations
Challenges in PD trials:
- Motor fluctuations confound assessment
- Non-motor symptoms (sleep, mood) affect function
- Placebo effects can be substantial
Biomarker Correlations
Expected relationships between biomarkers and clinical outcomes:
| Biomarker | Expected Direction | Clinical Correlation |
|-----------|-------------------|---------------------|
| CSF alpha-synuclein | Reduction with treatment | May predict efficacy |
| Serum NfL | Lower with treatment | Moderate correlation |
| MRI brain volume | Reduced atrophy | Correlates with progression |
Subgroup Analyses
Planned subgroup analyses include:
- Age (≤60 vs. >60 years)
- Disease duration (≤12 vs. >12 months)
- Baseline severity (MDS-UPDRS <25 vs. ≥25)
- GBA carrier status
- Geographic region
Competitive Landscape
Prasinezumab operates in a competitive PD therapeutic landscape:
| Approach | Mechanism | Status | Company |
|----------|-----------|--------|---------|
| Dopamine replacement | Levodopa | Approved | Generic |
| MAO-B inhibitors | Selegiline, rasagiline | Approved | Generic/Teva |
| Dopamine agonists | Pramipexole, ropinirole | Approved | Generic |
| D2/D3 agonists | Rotigotine patch | Approved | AbbVie |
| Anti-alpha-syn | Prasinezumab | Phase 2b | Roche |
| Anti-alpha-syn | Cinpanemab | Phase 2 | Novartis |
| LRRK2 inhibitors | DNL151 | Phase 2 | Denali/Biogen |
| Gene therapy | AAV-GAD | Phase 3 | Neurologix |
- [Clinical Trials Overview](/clinical-trials/overview)
- [Drug Development Pipeline](/clinical-trials/drug-pipeline)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Lewy Bodies](/mechanisms/lewy-body-formation)
- [Synucleinopathies](/diseases/synucleinopathies)
- [Immunotherapy](/mechanisms/immunotherapy-neurodegeneration)
- [MDS-UPDRS](/clinical-scales/mds-updrs)
External Links
- [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT04777331)
- [Roche Pipeline](https://www.roche.com/research/pipeline)
- [Prothelia](https://www.prothelia.com)
- [Michael J. Fox Foundation](https://www.michaeljfox.org)
- [Parkinson's Foundation](https://www.parkinson.org)
- [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT04777331)
References
[Unknown, Prasinezumab: mechanism of action and alpha-synuclein targeting (2024)](https://doi.org/10.1002/mds.29723)
[Unknown, Alpha-synuclein propagation and Parkinson's disease progression (2024)](https://doi.org/10.1093/brain/awad417)
[Unknown, Parkinson's disease progression and biomarker development (2024)](https://doi.org/10.1016/j.parkreldis.2024.105001)
[Unknown, Alpha-synuclein immunotherapy in Parkinson's disease (2024)](https://doi.org/10.1016/j.neuropharm.2024.109503)
[Unknown, MDS-UPDRS: movement disorder society unified Parkinson's disease rating scale (2023)](https://doi.org/10.1002/mds.29542)
[Unknown, Synaptic dysfunction in alpha-synucleinopathies (2023)](https://doi.org/10.1016/j.neurobiolaging.2023.104955)
[Unknown, Prodromal biomarkers in Parkinson's disease (2024)](https://doi.org/10.1093/jparkinsondis/jpad045)
[Unknown, Phase 2 PASED study of prasinezumab in Parkinson's disease (2022)](https://doi.org/10.1016/S0140-6736(22)01465-2)Future Directions
Open-Label Extension
Following the 52-week double-blind period, participants were eligible for a 52-week open-label extension:
- All participants received prasinezumab
- Continued safety monitoring
- Longer-term efficacy assessment
- Real-world effectiveness data
Pivotal Phase 3 Trial Planning
Based on PASADENA results, Roche will determine:
- Optimal dose selection
- Population refinement
- Primary endpoint confirmation
- Regulatory pathway (accelerated vs. traditional approval)
Combination Therapy Potential
Prasinezumab could be combined with:
- Symptomatic treatments (levodopa, agonists)
- Other disease-modifying approaches (LRRK2 inhibitors)
- Neuroprotective agents
- Cell replacement therapy
Summary
The PASADENA Phase IIb trial represents a critical test of alpha-synuclein immunotherapy in Parkinson's disease. Prasinezumab's approach of targeting extracellular alpha-synuclein aggregates addresses the root cause of PD rather than just managing symptoms. The trial addresses several key questions:
Efficacy: Can alpha-synuclein clearance slow motor progression?
Safety: Is the antibody well-tolerated in early PD patients?
Biomarkers: What is the relationship between target engagement and clinical outcomes?
Patient Selection: Which patients benefit most from this mechanism?Success would mark a significant advance in PD therapeutics, validating alpha-synuclein immunotherapy as a disease-modifying approach and potentially offering the first therapy that modifies the underlying pathology of Parkinson's disease.