ACI-35 Alpha-Synuclein Vaccine for Parkinson's Disease

Overview

Overview

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["@alphasynuclein2022"][@aci2021].

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.

Trial Details

| 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) |

Scientific Rationale

Alpha-Synuclein Pathology in PD

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:

• Disrupt synaptic function
• Impair mitochondrial integrity
• Activate inflammatory pathways
• Cause cellular stress and death

Active vs. Passive Immunization

Immunotherapy approaches for alpha-synuclein divide into active and passive strategies:

Active Immunization (ACI-35):

• Vaccination induces patient to produce their own antibodies
• Potentially longer duration of effect after initial series
• May require booster shots
• Dependent on patient's immune response capability
• Lower cost and easier administration
• More sustained antibody levels possible

• Direct administration of monoclonal antibodies
• Predictable dosing and pharmacokinetics
• Immediate effect
• Requires repeated infusions
• Higher cost
• No dependence on patient immune response

Mechanism of Action

Liposome-Based Vaccine Platform

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.

Antibody-Mediated Clearance

The anti-alpha-synuclein antibodies induced by ACI-35 function through multiple mechanisms:

1. Binding to Pathological Aggregates:

• High affinity for pS129 alpha-synuclein
• Recognition of oligomers and fibrils
• Minimal binding to physiological monomeric alpha-synuclein

• Antibody-opsonized aggregates are phagocytosed by microglia
• Fc receptor-mediated clearance through peripheral immune cells
• Complement activation may enhance aggregate removal

• Antibodies in extracellular space intercept secreted alpha-synuclein
• Block uptake by neurons and glia
• Prevent templated conversion of endogenous protein

• Bind oligomers before they interact with synapses
• Prevent oligomer-induced membrane disruption
• Protect mitochondrial function

Disease-Modifying Potential

By reducing the burden of pathological alpha-synuclein:

Clinical Trial Design

Phase 1b Study (Completed)

The initial Phase 1b study established safety and immunogenicity:

Design:

• Randomized, double-blind, placebo-controlled
• Single and multiple ascending dose cohorts
• Healthy volunteers and early PD patients

• Multiple dose levels tested (3-100 μg)
• Two injection schedule (Day 0, Day 28)

• Safety and tolerability
• Adverse event frequency and severity

• Immunogenicity: anti-pS129 antibody titers
• Specificity: binding to pS129 vs. unmodified alpha-synuclein
• CSF antibody levels (subset)

• Good safety and tolerability profile
• Dose-dependent antibody responses
• Antibodies showed specificity for pS129 alpha-synuclein
• Detectable antibodies in CSF

Phase 2a Study (Ongoing)

The current Phase 2a study evaluates efficacy:

Design:

• Randomized, double-blind, placebo-controlled
• 1:1 randomization

• Early PD (diagnosed within 2 years)
• Age 50-80 years
• Hoehn & Yahr stage 1-2.5
• MMSE ≥26

• 12-month treatment period
• Optional 12-month open-label extension

• Safety and tolerability
• Incidence of adverse events

• Antibody titer and specificity
• Clinical outcome measures (MDS-UPDRS)
• CSF biomarker changes
• Dopaminergic imaging (DAT SPECT)

Preclinical Evidence

Animal Model Studies

ACI-35 demonstrated efficacy in multiple preclinical models:

Transgenic Mouse Models:

• Reduced alpha-synuclein pathology in brain
• Decreased pS129-positive aggregates
• Improved behavioral outcomes
• No evidence of increased pathology in some models

• High antibody titers achieved
• Antibodies cross blood-brain barrier
• Clearance of pre-existing aggregates observed
• No autoimmune reactions

Mechanistic Validation

Preclinical work established:

• Antibodies recognize human pS129 alpha-synuclein
• Binding to oligomers and fibrils demonstrated
• Fc-mediated clearance mechanisms confirmed
• No significant binding to monomeric alpha-synuclein

Comparison with Other Alpha-Synuclein Immunotherapies

| 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 |

Advantages of Active Immunization

Challenges

Competitive Landscape

ACI-35 enters a competitive landscape with multiple alpha-synuclein-targeting approaches:

Passive Immunotherapy:

• Cinumercept (BNC271): Anti-aggregated alpha-synuclein antibody, Phase 2
• Prasinezumab (RO708): Anti-alpha-synuclein antibody, Phase 2
• ABBV-951: Anti-oligomer antibody, Phase 1

• Alpha-synuclein aggregation inhibitors
• RNA-based approaches (ASOs)
• Gene therapy approaches

• Affitope-based vaccines
• DNA vaccines

Challenges and Considerations

Scientific Challenges

Development Challenges

Safety Considerations

Future Directions

Based on trial results and field progress:

Next Steps:

• Phase 2b/3 trials if Phase 2a successful
• Biomarker development for patient selection
• Combination approaches with other modalities

• Preventive vaccination in at-risk populations
• Combination with symptomatic therapies
• Personalized medicine approaches

Cross-References

Related Disease Pages

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Dementia with Lewy Bodies](/diseases/dementia-lewy-bodies-parkinsons)
• [Multiple System Atrophy](/diseases/multiple-system-atrophy)
• [Synucleinopathies](/diseases/synucleinopathies)

Related Mechanism Pages

• [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway)
• [Lewy Body Formation](/mechanisms/lewy-body-formation)
• [Alpha-Synuclein Propagation](/mechanisms/alpha-synuclein-propagation)
• [Synaptic Dysfunction in PD](/mechanisms/synaptic-dysfunction-pd)

Related Clinical Trials

• [Cinumercept MSA Trial](/clinical-trials/cinumercept-msa-nct04449485)
• [Prasinezumab Trial](/clinical-trials/prasinezumab-pd)
• [ABBV-951 Trial](/clinical-trials/abbv-951-foslevodopa-foscarbidopa-pd)

Related Therapeutics

• [Alpha-Synuclein Immunotherapies](/therapeutics/alpha-synuclein-immunotherapies)
• [Disease-Modifying Therapies](/therapies/disease-modifying)
• [Active Immunization](/therapies/active-immunotherapy-alzheimers)

External Links

• [ClinicalTrials.gov: NCT04678180](https://clinicaltrials.gov/ct2/show/NCT04678180)
• [AC Immune SA](https://www.acimmune.com)
• [Lundbeck](https://www.lundbeck.com)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving ACI-35 Alpha-Synuclein Vaccine for Parkinson's Disease discovered through SciDEX knowledge graph analysis: