ACI-35 is an innovative experimental vaccine developed through a collaboration between AC Immune SA and Lundbeck, designed to target alpha-synuclein pathology in Parkinson's disease and related synucleinopathies. This liposomal vaccine represents a first-in-class active immunotherapy approach that aims to induce antibodies recognizing and clearing toxic alpha-synuclein aggregates, potentially slowing or halting disease progression through disease modification rather than symptomatic relief[1][2].
The development of ACI-35 addresses one of the most pressing needs in Parkinson's disease therapeutics — the lack of treatments that can modify the underlying disease process. While current therapies effectively manage motor symptoms through dopamine replacement or stimulation, they do not slow the progressive degeneration of dopaminergic neurons. By targeting the pathological alpha-synuclein protein that defines Parkinson's disease, ACI-35 represents a fundamental shift toward disease-modifying therapy development.
Alpha-synuclein is a small presynaptic protein that normally plays critical roles in neurotransmitter release and synaptic plasticity. In Parkinson's disease and other synucleinopathies, this protein misfolds and aggregates into toxic oligomers and fibrils, forming Lewy bodies and Lewy neurites — the characteristic pathological features of the disease. The spread of these aggregates throughout the nervous system correlates with disease progression, making alpha-synuclein an attractive therapeutic target.
| Field | Value |
|---|---|
| NCT Number | NCT04678180 |
| Phase | Phase 1b/2a |
| Status | Active, recruiting (as of 2025) |
| Sponsor | AC Immune SA / Lundbeck |
| Study Name | ACI-35.001 |
| Design | Randomized, double-blind, placebo-controlled |
| Duration | 12 months + 12-month extension |
| Enrollment | Approximately 80-120 patients |
| Patient Population | Early Parkinson's disease (≤2 years from diagnosis) |
The rationale for alpha-synuclein immunotherapy rests on decades of research establishing alpha-synuclein as the central pathological driver of Parkinson's disease:
Lewy Body Pathology: In PD brains, alpha-synuclein aggregates into insoluble inclusions called Lewy bodies. These are found in dopaminergic neurons of the substantia nigra and throughout the nervous system. The burden of Lewy body pathology correlates with clinical severity.
Propagation Hypothesis: Pathological alpha-synuclein can spread from cell to cell through prion-like mechanisms. Aggregated alpha-synuclein can be released from neurons, taken up by neighboring cells, and template the conversion of endogenous alpha-synuclein into pathological forms. This propagation explains the progressive spread of pathology throughout the brain.
Toxic Oligomers: While Lewy bodies represent the end-stage of aggregation, soluble oligomeric intermediates are considered the most toxic species. These oligomers can:
pS129 as Target: Phosphorylation at serine-129 (pS129) is the predominant post-translational modification in pathological alpha-synuclein. Approximately 90% of alpha-synuclein in Lewy bodies is pS129-modified, making it a highly specific target for immunotherapy.
Immunotherapy approaches for alpha-synuclein divide into active and passive strategies:
Active Immunization (ACI-35):
Passive Immunization:
ACI-35 represents the leading active immunization approach, while cinumercept and prasinezumab represent passive immunization strategies.
ACI-35 employs a sophisticated liposomal delivery system:
Liposome Composition: Phospholipid vesicles create a particulate delivery vehicle that mimics pathogen size and structure, triggering robust immune responses. The liposomes are approximately 100 nm in diameter.
Immunogen Design: The immunogen consists of recombinant human alpha-synuclein phosphorylated at serine-129 (pS129). This specific post-translational modification ensures antibodies recognize the pathological form.
T-cell Epitopes: The formulation includes T-cell epitopes from the alpha-synuclein sequence to provide adequate T-cell help, ensuring robust and sustained antibody responses.
Adjuvant Properties: The liposome itself has inherent adjuvant properties, enhancing the immune response without requiring additional adjuvants.
The anti-alpha-synuclein antibodies induced by ACI-35 function through multiple mechanisms:
1. Binding to Pathological Aggregates:
2. Enhanced Clearance:
3. Prevention of Spread:
4. Neutralization of Toxic Species:
By reducing the burden of pathological alpha-synuclein:
The initial Phase 1b study established safety and immunogenicity:
Design:
Dose Levels:
Primary Endpoints:
Secondary Endpoints:
Key Results[3]:
The current Phase 2a study evaluates efficacy:
Design:
Patient Population:
Treatment:
Primary Endpoints:
Secondary Endpoints:
ACI-35 demonstrated efficacy in multiple preclinical models:
Transgenic Mouse Models:
Vaccination Studies:
Preclinical work established:
| Agent | Type | Company | Stage | Target |
|---|---|---|---|---|
| ACI-35 | Active vaccine | AC Immune/Lundbeck | Phase 1b/2a | pS129 α-syn |
| Cinumercept | Passive mAb | Biogen/UCB | Phase 2 | Aggregated α-syn |
| Prasinezumab | Passive mAb | Roche | Phase 2 | Aggregated α-syn |
| ABBV-951 | Passive mAb | AbbVie | Phase 1 | α-syn oligomers |
ACI-35 enters a competitive landscape with multiple alpha-synuclein-targeting approaches:
Passive Immunotherapy:
Small Molecule Approaches:
Other Immunotherapies:
Based on trial results and field progress:
Next Steps:
Long-term Vision:
Alpha-Synuclein Immunotherapy for Parkinson's Disease. Movement Disorders. 2022. ↩︎
ACI-35 Vaccine: Liposome-Based Immunotherapy Targeting pS129. Alzheimer's & Dementia. 2021. ↩︎
ACI-35 Phase 1b Results. Nat Med. 2024. ↩︎