ACI-7104.056 Alpha-Synuclein Vaccine for Parkinson's Disease

Overview

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

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

Mechanism of Action

Vaccine Design

ACI-7104.056 is designed to elicit antibodies that specifically recognize and bind to phosphorylated alpha-synuclein (pS129):

• 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

• 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

• 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

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: