Prasinezumab (PRX002)

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Prasinezumab (PRX002)

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Prasinezumab (PRX002)</th>
</tr>
<tr>
<td class="label">Category</td>
<td>Immunotherapy</td>
</tr>
<tr>
<td class="label">Target</td>
<td>[Alpha-Synuclein](/mechanisms/alpha-synuclein) (aggregated, oligomeric forms)</td>
</tr>
<tr>
<td class="label">Route</td>
<td>IV Infusion</td>
</tr>
<tr>
<td class="label">Company</td>
<td>Prothelia/Roche</td>
</tr>
<tr>
<td class="label">Clinical Phase</td>
<td>Phase 2b</td>
</tr>
<tr>
<td class="label">Epitope</td>
<td>C-terminal residues 109-132</td>
</tr>
<tr>
<td class="label">Affinity</td>
<td>pM range for aggregated α-syn</td>
</tr>
<tr>
<td class="label">Biomarker</td>
<td>Purpose</td>
</tr>
<tr>
<td class="label">Total α-syn in CSF</td>
<td>Target engagement</td>
</tr>
<tr>
<td class="label">Oligomeric α-syn</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Phosphorylated α-syn</td>
<td>Pathology</td>
</tr>
<tr>
<td class="label">[NfL](/proteins/nfl-protein)</td>
<td>Neurodegeneration</td>
</tr>
<tr>
<td class="label">DAT imaging</td>
<td>Dopaminergic integrity</td>
</tr>
<tr>
<td class="label">Motor symptoms</td>
<td>Clinical efficacy</td>
</tr>
<tr>
<td class="label">Antibody</td>
<td>Company</td>
</tr>
<tr>
<td class="label">Prasinezumab</td>
<td>Roche/Prothelia</td>
</tr>
<tr>
<td class="label

...

Prasinezumab (PRX002)

Introduction

Prasinezumab (Prx002) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Prasinezumab (PRX002) is a humanized monoclonal antibody designed to target and clear pathological [alpha-synuclein](/proteins/alpha-synuclein) aggregates in Parkinson's disease and other synucleinopathies. Developed by Prothelia in partnership with Roche, it represents one of the most advanced immunotherapeutic approaches targeting alpha-synuclein pathology. [@pagano2024]

Overview

Mechanism of Action

Prasinezumab is a humanized IgG1 monoclonal antibody that specifically binds to the C-terminus of alpha-synuclein:

1. Target Selection

Binds to aggregated and oligomeric alpha-synuclein with high affinity (picomolar range)
Epitope chosen to specifically target pathogenic forms while sparing normal monomeric alpha-synuclein
Recognizes conformational epitopes unique to aggregated species

2. Peripheral Sequestration

Captures extracellular alpha-synuclein in the bloodstream
Reduces free serum alpha-synuclein by up to 97%
Acts as a "sink" to draw alpha-synuclein from the CNS

3. Fc-Mediated Clearance

Activates [microglia](/entities/microglia) via Fcγ receptors to clear antibody-opsonized aggregates
Enhances phagocytosis of toxic species
Promotes antigen presentation and adaptive immune response

4. Prion-Like Propagation Blockade

Prevents uptake of toxic seeds by healthy [neurons](/entities/neurons)
Blocks intercellular transmission of alpha-synuclein pathology
May protect previously unaffected brain regions

Rationale for C-Terminal Targeting

The C-terminal region of alpha-synuclein (residues 109-132) was chosen as the antibody epitope because:

It is exposed in aggregated and oligomeric forms
It is relatively protected in monomeric alpha-synuclein
It is involved in membrane binding and aggregation nucleation
Antibodies targeting this region show good blood-brain barrier penetration

Clinical Development

Phase 1 Studies (PRX002-001)

Design: Single and multiple ascending dose studies in healthy volunteers and PD patients
Key Results:
Demonstrated significant reduction in free serum alpha-synuclein (up to 97%)
Good safety and tolerability profile at all doses tested
Dose-dependent pharmacokinetics
Dose selection for Phase 2 based on PK/PD modeling
Publication: Schenk et al., Lancet Neurology 2021

Phase 2 Study (PASADENA)

Design: 12-month randomized, double-blind, placebo-controlled trial
Population: Patients with early Parkinson's disease (Hoehn & Yahr stage 1-2)
Sample Size: 316 patients randomized
Co-primary Endpoints:
MDS-UPDRS parts II/III (motor and activities of daily living)
DAT imaging (dopaminergic neuronal integrity)
Results:
Primary analysis showed numerical but not statistically significant improvement
Pre-specified subgroup analyses suggested benefit in patients with faster progression
Biomarker results showed target engagement (reduced CSF oligomeric alpha-synuclein)
Publication: Pagano et al., NEJM 2024

Phase 2b Study (BLAZE)

Status: Currently recruiting
Focus: Patients with early Parkinson's disease with greater likelihood of progression
Enrichment Strategy: Biomarker-driven patient selection using CSF alpha-synuclein
Primary Endpoint: Change in MDS-UPDRS at 52 weeks

Future Development Plans

Subcutaneous administration formulation for convenience
Earlier intervention in prodromal PD (REM sleep behavior disorder)
Combination therapy with small molecule aggregation inhibitors
Prevention trials in high-risk populations (LRRK2 G2019S carriers)

Therapeutic Potential

Parkinson's Disease

Disease-modifying potential by targeting alpha-synuclein pathology
May slow progression when used early in disease course
May reduce non-motor symptoms:
Autonomic dysfunction (orthostatic hypotension, constipation)
REM sleep behavior disorder
Cognitive impairment

Multiple System Atrophy (MSA)

Primary alpha-synucleinopathy with oligodendrocyte involvement
More aggressive treatment may be needed due to rapid progression
Currently being evaluated in MSA-specific trials
Challenges: [Blood-brain barrier](/entities/blood-brain-barrier) penetration, antigen sink

Dementia with Lewy Bodies (DLB)

Targets cortical Lewy bodies containing alpha-synuclein
May improve cognitive fluctuations and visual hallucinations
May address both motor and non-motor symptoms

Prodromal Parkinson's Disease

Highest potential for disease modification
Before substantial dopaminergic neuron loss
Bypasses need for symptomatic treatment

Biomarker Strategy

A key innovation in the prasinezumab program is the biomarker-driven approach:

Adverse Effects and Safety

Generally Well-Tolerated

Most adverse events mild to moderate in severity
No significant difference from placebo in Phase 2
Low rates of infusion reactions
No evidence of immune complex deposition

Potential Concerns

ARIA (Amyloid-Related Imaging Abnormalities): Not observed (unlike anti-[Aβ](/proteins/amyloid-beta) antibodies)
Immunogenicity: Low rates of anti-drug antibodies
Peripheral sink effect: Theoretical concern about peripheral alpha-synuclein deposition

Long-term Safety

Open-label extension studies ongoing
No major safety signals in 2-year follow-up

Comparison to Other Alpha-Synuclein Antibodies

Research Directions

Earlier intervention: Prodromal PD, RBD patients

Combination therapy: With small molecule aggregation inhibitors (e.g., Buntanetap)

Biomarker-driven selection: Enrich for rapid progressors

Alternative delivery: Subcutaneous administration

Prevention trials: High-risk populations

External Links

[Roche Pipeline Information](https://www.roche.com)
[Prothelia Therapeutics](https://www.prothelia.com)
[ClinicalTrials.gov: Prasinezumab](https://clinicaltrials.gov)
[ClinicalTrials.gov: BLAZE Study](https://clinicaltrials.gov)

Background

The study of Prasinezumab (Prx002) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Allen Brain Atlas Resources

[Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
[Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
[Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury

References

[Schenk DB, et al, (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34793802/)

[Pagano G, et al, (2024) (2024)](https://pubmed.ncbi.nlm.nih.gov/38953743/)

[Zhang X, et al, (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/36170428/)

[Bridi JC, et al, (2023) (2023)](https://pubmed.ncbi.nlm.nih.gov/36912091/)

[Mahapatra A, et al, (2024) (2024)](https://pubmed.ncbi.nlm.nih.gov/38234234/)

[Volc D, et al, (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35725927/)

[Jankovic J, et al, (2024) (2024)](https://pubmed.ncbi.nlm.nih.gov/38476291/)

[Kalia LV, et al, (2023) (2023)](https://pubmed.ncbi.nlm.nih.gov/37127049/)

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Prasinezumab (PRX002)

Prasinezumab (PRX002)

Introduction

Prasinezumab (PRX002)

Introduction

Overview

Mechanism of Action

1. Target Selection

2. Peripheral Sequestration

3. Fc-Mediated Clearance

4. Prion-Like Propagation Blockade

Rationale for C-Terminal Targeting

Clinical Development

Phase 1 Studies (PRX002-001)

Phase 2 Study (PASADENA)

Phase 2b Study (BLAZE)

Future Development Plans

Therapeutic Potential

Parkinson's Disease

Multiple System Atrophy (MSA)

Dementia with Lewy Bodies (DLB)

Prodromal Parkinson's Disease

Biomarker Strategy

Adverse Effects and Safety

Generally Well-Tolerated

Potential Concerns

Long-term Safety

Comparison to Other Alpha-Synuclein Antibodies

Research Directions

See Also

External Links

Background

Allen Brain Atlas Resources

References