Overview
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clinical_trials_aci_7104_056_a["ACI-7104.056 Alpha-Synuclein Vaccine for Parkins"]
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ACI-7104.056 is a novel experimental vaccine developed by AC Immune SA targeting phosphorylated alpha-synuclein (pS129) in Parkinson's disease and related synucleinopathies. This active immunotherapy represents a next-generation approach in AC Immune's alpha-synuclein program, building upon learnings from the earlier ACI-35 vaccine candidate["@aciimmunepipeline2024"].
...Overview
Mermaid diagram (expand to render)
ACI-7104.056 is a novel experimental vaccine developed by AC Immune SA targeting phosphorylated alpha-synuclein (pS129) in Parkinson's disease and related synucleinopathies. This active immunotherapy represents a next-generation approach in AC Immune's alpha-synuclein program, building upon learnings from the earlier ACI-35 vaccine candidate["@aciimmunepipeline2024"].
The development of ACI-7104.056 addresses the critical need for disease-modifying therapies in Parkinson's disease. While current treatments effectively manage motor symptoms through dopamine replacement and deep brain stimulation, they do not slow or halt the underlying neurodegenerative process. By targeting the pathological alpha-synuclein protein that defines Parkinson's disease pathology, ACI-7104.056 aims to modify disease progression through reduction of toxic alpha-synuclein aggregates["@activeimmunotherapy"].
Trial Details
| Field | Value |
|-------|-------|
| NCT Number | NCT06015841 |
| Phase | Phase 1 |
| Status | Recruiting (as of 2024-2025) |
| Sponsor | AC Immune SA |
| Study Name | ACI-7104.056-001 |
| Design | Randomized, double-blind, placebo-controlled |
| Duration | 12 months initial + extension |
| Enrollment | Approximately 60-80 patients |
| Patient Population | Early Parkinson's disease (Hoehn & Yahr 1-2) |
Scientific Rationale
Alpha-Synuclein Pathology in Parkinson's Disease
The rationale for alpha-synuclein immunotherapy is grounded in decades of research establishing alpha-synuclein as the central pathological driver of Parkinson's disease:
Lewy Body Pathology: In PD brains, alpha-synuclein misfolds and aggregates into insoluble inclusions called Lewy bodies. These are found primarily in dopaminergic neurons of the substantia nigra pars compacta, as well as throughout the cerebral cortex and peripheral nervous system. The density of Lewy body pathology correlates strongly with clinical severity and disease duration[@pS129target].
Phosphorylation at Serine-129: The pathological form of alpha-synuclein is characterized by excessive phosphorylation at serine-129 (pS129). Approximately 90% of alpha-synuclein in Lewy bodies is pS129-modified, compared to only 5-10% of physiological alpha-synuclein. This post-translational modification serves as a highly specific marker for pathological aggregation and an attractive immunotherapy target[@pS129target].
Propagation and Spread: Pathological alpha-synuclein can spread through the nervous system via prion-like mechanisms. Aggregated protein can be released from neurons through exocytosis, taken up by neighboring cells via receptor-mediated endocytosis, and template the conversion of endogenous alpha-synuclein into pathological forms. This propagation explains the progressive spread of pathology from brainstem to cortical regions during disease progression[@lewybodypropagation].
Toxic Oligomers: While Lewy bodies represent the end-stage of aggregation, soluble oligomeric intermediates are now recognized as the most neurotoxic species. These oligomers can:
- Disrupt synaptic vesicle cycling and neurotransmitter release
- Impair mitochondrial function and energy metabolism
- Activate inflammatory pathways in microglia
- Cause endoplasmic reticulum stress and unfolded protein response
- Directly damage neuronal membranes
Active Immunization Strategy
ACI-7104.056 employs active immunization to induce patient-generated antibodies against pathological alpha-synuclein:
Advantages of Active Immunization:
- Sustained antibody production following initial vaccination series
- Potentially longer duration of effect with periodic boosters
- Lower cost compared to repeated monoclonal antibody infusions
- Patient's own immune system generates diverse antibody repertoire
- No foreign protein administration reduces immunogenicity concerns
Platform Advantages: AC Immune's proprietary vaccine platforms (LipAntix and SupraAgem) enable generation of high-affinity antibodies specifically targeting disease-relevant conformations of alpha-synuclein while avoiding binding to normal physiological protein.
Mechanism of Action
Vaccine Design
ACI-7104.056 is designed to elicit antibodies that specifically recognize and bind to phosphorylated alpha-synuclein (pS129):
Antigen Presentation: The vaccine presents a pS129-alpha-synuclein peptide epitope conjugated to a carrier protein, presented on liposomal particles for optimal immune response
B-Cell Activation: The antigen stimulates B-cells specific for pS129-alpha-synuclein to proliferate and differentiate into antibody-producing plasma cells
Antibody Generation: Generated antibodies specifically recognize pathological pS129-alpha-synuclein without significant binding to normal alpha-synuclein
Clearance Mechanism: Antibodies can facilitate clearance of pathological alpha-synuclein through:
- Opsonization marking for microglial phagocytosis
- Blocking cell-to-cell transmission
- Neutralization of toxic oligomers
- Enhancement of extracellular prote degradation
Differentiation from ACI-35
ACI-7104.056 represents an evolution from the earlier ACI-35 vaccine:
- Optimized antigen design for enhanced antibody affinity
- Improved liposomal formulation for stronger immune response
- Potential for less frequent dosing
- Enhanced safety profile based on learnings from ACI-35 program
Clinical Development Plan
Phase 1 Trial Design
The Phase 1 trial (NCT06015841) evaluates safety, tolerability, immunogenicity, and preliminary efficacy:
Primary Endpoints:
- Safety and tolerability at multiple dose levels
- Adverse event frequency and severity
- Serum antibody titers against pS129-alpha-synuclein
Secondary Endpoints:
- Change in cerebrospinal fluid pS129-alpha-synuclein
- Change in alpha-synuclein PET imaging biomarkers
- Clinical measures: MDS-UPDRS, MoCA, PD-specific quality of life scales
Dosing Schedule:
- Primary vaccination series (multiple doses over 6 months)
- Booster doses at defined intervals
- Extended follow-up for long-term safety and durability
Competitive Landscape
ACI-7104.056 enters a competitive alpha-synuclein immunotherapy field:
| Program | Company | Type | Phase |
|---------|---------|------|-------|
| ACI-7104.056 | AC Immune | Active | Phase 1 |
| ACI-35 | AC Immune/Lundbeck | Active | Phase 1b/2a |
| Cinumercept (ABBV-951) | AbbVie/Neurolix | Passive | Phase 2 |
| Prasinezumab (RO7046015) | Roche | Passive | Phase 2 |
| Lu AF87908 | Lundbeck | Passive | Phase 1 |
Strategic Importance
For AC Immune
ACI-7104.056 represents AC Immune's strategy to advance multiple alpha-synuclein programs:
- Diversified pipeline reduces clinical development risk
- Multiple mechanisms (active vs. passive) provide optionality
- Partnership with Lundbeck provides resources and expertise
- Platform validation through multiple programs
For Parkinson's Disease Therapeutics
Successful development of ACI-7104.056 would:
- Validate active immunization for synucleinopathies
- Provide disease-modifying treatment option
- Establish pS129 as therapeutic target
- Enable early intervention in at-risk populations
References
[AC Immune Pipeline Overview 2024](https://www.acimmune.com/pipeline)
[AC Immune and Lundbeck Alpha-Synuclein Partnership](https://www.acimmune.com/collaborations)
[Phospho-S129 alpha-synuclein as diagnostic and therapeutic target (2022)](https://doi.org/10.1007/s00401-022-02438-5)
[Cell-to-cell transmission of alpha-synuclein pathology (2021)](https://doi.org/10.1038/s41582-021-00546-0)
[Active immunotherapy for neurodegenerative diseases (2023)](https://doi.org/10.1038/s41573-023-00678-4)Related Pages
- [ACI-35 Alpha-Synuclein Vaccine](/clinical-trials/aci-35-alpha-synuclein-vaccine) — Related AC Immune vaccine in later-stage development
- [Alpha-Synuclein Immunotherapy](/therapeutics/alpha-synuclein-immunotherapy) — Overview of immunotherapy approaches
- [Alpha-Synuclein](/proteins/alpha-synuclein) — Target protein page
- [AC Immune](/companies/ac-immune) — Sponsor company page
- [Parkinson's Disease](/diseases/parkinsons-disease) — Disease page
Pathway Diagram
The following diagram shows the key molecular relationships involving ACI-7104.056 Alpha-Synuclein Vaccine for Parkinson's Disease discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)