Overview
Mermaid diagram (expand to render)
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
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.
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
Passive Immunization:
- Direct administration of monoclonal antibodies
- Predictable dosing and pharmacokinetics
- Immediate effect
- Requires repeated infusions
- Higher cost
- No dependence on patient immune response
ACI-35 represents the leading active immunization approach, while cinumercept and prasinezumab represent passive immunization strategies.
Mechanism of Action
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
2. Enhanced Clearance:
- Antibody-opsonized aggregates are phagocytosed by microglia
- Fc receptor-mediated clearance through peripheral immune cells
- Complement activation may enhance aggregate removal
3. Prevention of Spread:
- Antibodies in extracellular space intercept secreted alpha-synuclein
- Block uptake by neurons and glia
- Prevent templated conversion of endogenous protein
4. Neutralization of Toxic Species:
- 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:
Slow Neurodegeneration: May slow loss of dopaminergic neurons in substantia nigra
Preserve Function: Maintain dopamine production and release capacity
Delay Progression: Potentially delays motor and non-motor progression
Protect Multiple Systems: May protect autonomic and cognitive systemsClinical 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
Dose Levels:
- Multiple dose levels tested (3-100 μg)
- Two injection schedule (Day 0, Day 28)
Primary Endpoints:
- Safety and tolerability
- Adverse event frequency and severity
Secondary Endpoints:
- Immunogenicity: anti-pS129 antibody titers
- Specificity: binding to pS129 vs. unmodified alpha-synuclein
- CSF antibody levels (subset)
Key Results[@lundbeck2024]:
- 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
Patient Population:
- Early PD (diagnosed within 2 years)
- Age 50-80 years
- Hoehn & Yahr stage 1-2.5
- MMSE ≥26
Treatment:
- 12-month treatment period
- Optional 12-month open-label extension
Primary Endpoints:
- Safety and tolerability
- Incidence of adverse events
Secondary Endpoints:
- 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
Vaccination Studies:
- 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
Cost-effective: No need for repeated antibody production
Sustained Effect: Antibody production can persist long-term
Scalable: Easier to manufacture and distribute
Patient Convenience: Fewer clinic visits requiredChallenges
Variable Response: Immune response varies between individuals
Booster Dependency: May require periodic boosters
Autoimmunity Risk: Theoretical risk of autoimmune responsesCompetitive 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
Small Molecule Approaches:
- Alpha-synuclein aggregation inhibitors
- RNA-based approaches (ASOs)
- Gene therapy approaches
Other Immunotherapies:
- Affitope-based vaccines
- DNA vaccines
Challenges and Considerations
Scientific Challenges
Brain Penetration: Ensuring adequate antibody levels reach the CNS
Target Engagement: Demonstrating antibody reaches pathological alpha-synuclein
Efficacy Signals: Detecting clinical benefit in early-stage patients
Biomarkers: Need for biomarkers of target engagementDevelopment Challenges
Patient Selection: Identifying optimal patient population
Trial Duration: 12 months may be insufficient for disease modification
Endpoint Sensitivity: Detecting slowing of progression requires sensitive measures
Regulatory Pathway: No precedent for alpha-synuclein immunotherapy approvalSafety Considerations
Infusion Reactions: Potential for immune reactions
Autoimmunity: Theoretical risk of autoimmune responses
AAI: Amyloid-related imaging abnormalities (observed in anti-amyloid antibodies)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
Long-term Vision:
- 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)
- [Cinumercept MSA Trial](/clinical-trials/cinumercept-msa-nct04449485)
- [Prasinezumab Trial](/clinical-trials/prasinezumab-pd)
- [ABBV-951 Trial](/clinical-trials/abbv-951-foslevodopa-foscarbidopa-pd)
- [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
[Alpha-Synuclein Immunotherapy for Parkinson's Disease (2022)](https://doi.org/10.1002/mds.25273)
[ACI-35 Vaccine: Liposome-Based Immunotherapy Targeting pS129 (2021)](https://doi.org/10.1186/s13195-021-00870-z)
[ACI-35 Phase 1b Results (2024)](https://doi.org/10.1038/s41591-024-01892-2)
[Masliah et al., Alpha-synuclein immunotherapy in models (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)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:
Mermaid diagram (expand to render)