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[1].
| 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 |
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[2].
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 is a soluble, natively unfolded protein enriched in presynaptic terminals. Under physiological conditions, it participates in:
Misfolding and Aggregation
In PD, alpha-synuclein undergoes a conformational transition from its native unfolded state to form:
Oligomers: Soluble, toxic intermediate species
Fibrils: Insoluble, filamentous aggregates
Lewy Bodies: Large, insoluble inclusions
The "prion-like" propagation of alpha-synuclein pathology is a key concept in understanding disease progression[3]:
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:
Antibody Properties
Clearance Mechanisms
Advantages Over Symptomatic Treatments
Current PD treatments (levodopa, dopamine agonists, MAO-B inhibitors) provide symptomatic relief but do not slow disease progression. Prasinezumab aims to:
Phase 1 Studies
Prasinezumab was evaluated in Phase 1 studies demonstrating[4]:
Phase 2 PASED Study (NCT03100149)
A previous Phase 2 study in patients with PD showed:
This Phase IIb PASADENA study was designed to confirm and extend these findings.
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.
Primary Objective
Evaluate the effect of prasinezumab on motor progression in early PD patients.
Key Design Features
Randomization: 1:1:1 to three arms
Treatment Regimen
Blinding
Time to Confirmed Motor Progression
The primary endpoint measures time from randomization to:
This endpoint was designed to capture clinically meaningful progression while minimizing noise from temporary fluctuations.
Motor Symptoms
Non-Motor Symptoms
Functional Measures
Biomarkers
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.
The trial contributes to understanding PD pathophysiology:
The trial includes extensive biomarker collection to understand:
Alpha-Synuclein Species
Neurodegeneration Markers
Inflammatory Markers
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.
The trial was conducted at approximately 60 sites globally:
Based on Phase 1 data and class effects:
Infusion-Related Reactions
Amyloid-Related Imaging Abnormalities (ARIA)
Infections
Geriatric Patients: Age >75 may have increased infection risk
GBA Carriers: May have faster progression, potential subgroup analysis
APOE4 Carriers: May have different response
The primary endpoint (time to confirmed motor progression) requires careful interpretation:
What constitutes progression?
Challenges in PD trials:
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 |
Planned subgroup analyses include:
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 |