A Phase IIB, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study ... (NCT04777331)

Prasinezumab for Early Parkinson's Disease (PASADENA)

Overview

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 |

Prasinezumab for Early Parkinson's Disease (PASADENA)

Overview

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

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

In PD, alpha-synuclein undergoes a conformational transition from its native unfolded state to form:

• 100-1000x more toxic than monomers
• Disrupt synaptic function
• Impair mitochondrial function
• Trigger oxidative stress

• Major component of Lewy bodies
• Template further aggregation
• Transmit between neurons (prion-like)

• Accumulate in surviving neurons
• May represent a protective mechanism (sequestration)

• 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

• Toxic oligomers spread between neurons via extracellular space
• Antibody can intercept seeds before they enter new cells
• Activates microglia for clearance

• 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

• Fc-mediated phagocytosis: Microglial activation
• Antibody-dependent cellular cytotoxicity (ADCC)
• Prevention of propagation: Neutralizing extracellular seeds

Current 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

A previous Phase 2 study in patients with PD showed:

• Trend toward reduced motor progression
• Safety and tolerability established
• Biomarker effects supporting mechanism

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

• Placebo
• Low-dose prasinezumab (1,500 mg IV)
• High-dose prasinezumab (4,500 mg IV)

• Intravenous infusion every 4 weeks
• 52-week treatment period (primary analysis)
• Optional 52-week open-label extension

• Double-blind (participants and investigators masked)
• Matching placebo infusions
• Independent assessors for primary endpoint

Inclusion Criteria

Exclusion Criteria

Outcome 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

Secondary Endpoints

• Change in MDS-UPDRS Parts I-III total score
• Change in MDS-UPDRS Part III (motor) score
• Levodopa-equivalent dose initiation

• Change in MDS-UPDRS Part I (non-motor experiences of daily living)
• Epworth Sleepiness Scale
• Beck Depression Inventory

• Schwab and England Activities of Daily Living
• Timed Up and Go test
• Gait analysis

• 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:

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)

• Neurofilament light chain (NfL)
• Tau protein
• Amyloid-beta (for PD dementia)

• 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:

• Typically mild (headache, fatigue, nausea)
• More common with first infusions
• Managed with pre-medication (antihistamines, corticosteroids)

• Although prasinezumab targets alpha-synuclein (not amyloid), monitoring for similar imaging changes
• MRI monitoring at baseline, 12 weeks, 52 weeks

• 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

• 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 |

Related Resources

• [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

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:

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.