BIA 28-6156 GBA Parkinsons
Overview
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clinical_trials_bia_28_6156_gb["BIA 28-6156 for GBA-Parkinsons Disease"]
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clinical_trials_bia__0["Clinical Trial Details"]
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clinical_trials_bia__1["GBA Mutations and Parkinsons Disease"]
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clinical_trials_bia__2["Types of GBA Mutations"]
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clinical_trials_bia__3["Glucocerebrosidase GCase"]
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clinical_trials_bia__4["Mechanism of Action"]
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clinical_trials_bia__5["GCase Modulation"]
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...BIA 28-6156 GBA Parkinsons
Overview
Mermaid diagram (expand to render)
BIA 28-6156 is a novel therapeutic candidate being developed by Bial Pharmaceutical for the treatment of Parkinson's disease in patients carrying [GBA](/entities/gba) gene mutations. This Phase 2 clinical trial (NCT05819359) targets the underlying genetics of Parkinson's disease by modulating glucocerebrosidase (GCase) activity [1](https://clinicaltrials.gov/study/NCT05819359).
Clinical Trial Details
| Attribute | Value |
|-----------|-------|
| Trial ID | NCT05819359 |
| Sponsor | Bial Pharmaceutical |
| Phase | Phase 2 |
| Status | RECRUITING |
| Condition | Parkinson's Disease with GBA Mutations |
| Intervention | BIA 28-6156 |
Background
GBA Mutations and Parkinson's Disease
Heterozygous mutations in the GBA gene (glucocerebrosidase) are the most common genetic risk factor for Parkinson's disease:
- Prevalence: 5-10% of PD patients carry GBA mutations
- Risk: GBA carriers have 5-6× increased PD risk
- Phenotype: GBA-PD often presents with earlier onset, more rapid progression
- Pathology: GBA mutations lead to reduced glucocerebrosidase enzyme activity
- Cognitive involvement: Higher risk of dementia compared to idiopathic PD
Types of GBA Mutations
GBA mutations are categorized by their severity:
- Severe mutations (e.g., N370S, L444P): Associated with earlier onset and more rapid progression
- Mild mutations (e.g., E326K, T369M): Associated with intermediate risk
- Carrier status: Even heterozygous carriers show increased PD risk
Glucocerebrosidase (GCase)
The glucocerebrosidase enzyme encoded by GBA:
- Function: Breaks down glucosylceramide in lysosomes
- PD link: Reduced GCase activity leads to:
- Lysosomal dysfunction
- [α-Synuclein](/proteins/alpha-synuclein) accumulation
- Mitochondrial dysfunction
- Endoplasmic reticulum stress
- Bidirectional relationship: α-Synuclein can also inhibit GCase activity, creating a vicious cycle
Mechanism of Action
GCase Modulation
BIA 28-6156 is designed to:
Increase GCase activity: Small molecule chaperone that enhances enzyme function
Reduce glucosylceramide accumulation: Restore proper lysosomal function
Decrease α-synuclein aggregation: Address downstream pathologyMolecular Targets
- Primary target: Glucocerebrosidase (GCase)
- Secondary effects: Lysosomal function, α-synuclein clearance
- Approach: Pharmacological chaperone therapy
Trial Design
Study Type
- Design: Randomized, double-blind, placebo-controlled
- Population: Parkinson's disease patients with GBA mutations
- Dose groups: Multiple dose levels (dose escalation)
- Duration: 12-24 months treatment
Key Eligibility
Inclusion criteria:
- Age 30-80 years
- Diagnosed with Parkinson's disease (UK Brain Bank criteria)
- Confirmed GBA mutation carrier (pathogenic variant)
- Hoehn & Yahr stage 1-3
- Mild to moderate disease severity
- Stable PD medication for ≥4 weeks
- MMSE score ≥24
Exclusion criteria:
- Severe cognitive impairment (MMSE <24)
- Significant psychiatric comorbidities (uncontrolled depression, psychosis)
- Previous GCase-targeted therapy
- History of brain surgery (DBS)
- Contraindications to MRI
- Active malignancy
- Unstable medical conditions
Endpoints
Primary:
- Safety and tolerability (adverse events, lab values, vital signs)
- Change in GCase activity biomarkers (PBMC GCase activity)
- Change in glucosylceramide (GlcCer) levels
Secondary:
- Motor symptom progression (MDS-UPDRS Parts I-III)
- Cognitive function (MOCA, RBANS)
- Biomarkers of α-synuclein (CSF RT-QuIC, pS129)
- Lysosomal function markers (cathepsin D, β-galactosidase)
- Quality of life measures (PDQ-39)
- Non-motor symptoms (NMS Scale, Epworth Sleepiness Scale)
Exploratory:
- Neuroimaging (DaT-SPECT, MRI volumetry)
- Skin biopsy for α-synuclein aggregation
- Digital biomarker measures (wearable sensors)
Rationale
Why Target GBA?
GBA-associated Parkinson's disease (GBA-PD) represents the most common genetic form of Parkinson's disease, accounting for 5-10% of all PD cases. This genetic subtype offers unique opportunities for precision medicine approaches because[@gba2014]:
Direct genetic causation: Unlike most PD genetic risk factors, GBA mutations have a clear mechanistic link to disease pathogenesis through loss of GCase function
Druggable target: The enzyme activity can be modulated pharmacologically with small molecule chaperones that restore function rather than just treating symptoms
Disease modification potential: Addressing the underlying enzymatic deficiency may slow or halt disease progression, not merely manage symptoms
Patient selection: Genetic testing enables identification of an enriched population more likely to respond to targeted therapy
Biomarker availability: GCase activity and glucosylceramide levels provide measurable pharmacodynamic endpoints
Bidirectional relationship: α-Synuclein accumulation inhibits GCase, creating a feed-forward loop; breaking this cycle could have broad effectsPreclinical Evidence
The development of BIA 28-6156 rests on extensive preclinical evidence from multiple model systems:
Cellular Models
- GCase chaperones restore enzyme activity in fibroblasts from GBA-PD patients
- Reduced glucosylceramide accumulation in treated cells
- Decreased α-synuclein aggregation in neuronal cell lines
- Improved lysosomal function markers
Animal Models
- Gba knockout mice show accumulation of GlcCer and α-synuclein
- GCase chaperone treatment reduces substrate accumulation
- Improved motor performance in treated animals
- Neuroprotection in dopaminergic neurons
Human iPSC Models
- Patient-derived neurons show GCase deficiency
- Chaperone treatment rescues enzymatic function
- Reduced α-synuclein in neuronal cultures
- Mitochondrial function improvement
Scientific Foundation
The GBA-PD therapeutic approach is grounded in fundamental research:
Genetic Evidence
- Large multi-center studies confirm 5-6× increased PD risk
- Dose-response relationship: severe mutations confer higher risk
- Earlier onset and more rapid progression in GBA carriers
- Higher rates of cognitive impairment and dementia
Biochemical Evidence
- GCase activity reduced 50-80% in GBA-PD patients
- GlcCer accumulation in brain and peripheral tissues
- Lysosomal dysfunction precedes clinical symptoms
- α-Synuclein-GlcCer interactions promote aggregation
Therapeutic Rationale
- Pharmacological chaperones bind GCase, stabilizing the enzyme
- Increased activity leads to substrate clearance
- Reduces downstream α-synuclein pathology
- Potential for disease modification rather than symptom control
Therapeutic Implications
The approval of BIA 28-6156 would represent a paradigm shift in Parkinson's disease treatment, with implications extending beyond the GBA-PD patient population:
For GBA-PD Patients
- First disease-modifying therapy targeting the specific genetic cause
- Potential to slow disease progression at the molecular level
- May reduce cognitive decline risk (a major concern in GBA-PD)
- Improved quality of life through disease modification rather than just symptom control
- Potential for early intervention before extensive neurodegeneration
For Precision Medicine in PD
- Proof of concept for genetically-targeted therapies
- Framework for developing similar approaches for other genetic subtypes
- Validation of GCase modulation as a therapeutic strategy
- Foundation for combination therapies addressing multiple pathways
For the Broader PD Field
- Biomarker-driven development model
- Regulatory pathway for precision medicine approaches
- Potential spillover to idiopathic PD through understanding of lysosomal dysfunction
Challenges and Mitigation Strategies
Challenge: BBB Penetration
- Issue: Many GCase chaperones fail to achieve adequate brain concentrations
- Mitigation: BIA 28-6156 optimized for lipophilicity and CNS penetration
- Evidence: Preclinical PK/PD studies show brain exposure in mouse models
- Status: Phase 2 will validate brain target engagement
Challenge: Mutation-Specific Response
- Issue: Severe vs. mild GBA mutations may respond differently
- Mitigation: Pre-specified subgroup analyses in trial design
- Evidence: In vitro data suggests differential response by mutation type
- Status: Stratified enrollment ensures adequate representation
Challenge: Long-term Safety
- Issue: Chronic GCase modulation may have unexpected effects
- Mitigation: 24-month open-label extension with comprehensive monitoring
- Evidence: Safety data from previous chaperone programs
- Status: Ongoing monitoring for enzyme replacement effects
Challenge: Biomarker Validation
- Issue: Surrogate endpoints require validation
- Mitigation: Cross-validation across multiple assay platforms
- Evidence: Consortium efforts for biomarker standardization
- Status: Qualification efforts underway with regulatory agencies
Challenge: Patient Identification
- Issue: Many GBA carriers unaware of their mutation status
- Mitigation: Genetic testing initiatives and awareness campaigns
- Evidence: Increased genetic testing in PD clinics
- Status: Partnering with genetic testing companies
Comparison to Other GCase-Targeting Approaches
BIA 28-6156 occupies a unique position in the GCase modulation landscape:
| Compound | Company | Mechanism | Status | Route | Advantages |
|----------|---------|-----------|--------|-------|-------------|
| BIA 28-6156 | Bial | Chaperone | Phase 2 | Oral | Non-competitive, reversible |
| Venglustat | Sanofi | GCase inhibitor | Phase 2 | Oral | Different mechanism (substrate reduction) |
| AT3375 | Astellas | Chaperone | Phase 1 | IV | Higher potency |
| Ambroxol | Repurposed | Chaperone | Phase 2/3 | Oral | Generic, established safety |
| GZ161 | Sanofi | Chaperone | Preclinical | Oral | Next-generation |
| PR001 | Prev Ambros | Gene therapy | Phase 1/2 | AAV | Single administration |
Why BIA 28-6156 stands out:
Oral bioavailability enables easier chronic dosing
Non-competitive binding allows natural enzyme regulation
Reversible modulation reduces risk of complete enzyme inhibition
Optimized for CNS penetration based on structural modificationsBiomarkers for Patient Selection
Key biomarkers being explored for patient selection and response monitoring:
Genetic Biomarkers
- GBA mutation genotyping (required for enrollment)
- Mutation severity classification (severe vs. mild)
- TMEM106B genotype (potential modifier)
Enzymatic Biomarkers
- GCase activity in peripheral blood mononuclear cells (PBMCs)
- Primary pharmacodynamic marker of target engagement
- Glucosylceramide (GlcCer) levels in plasma/CSF
- Upstream substrate accumulation reflects GCase dysfunction
- Glucosylsphingosine (Lyso-Gb1) in CSF
- More sensitive biomarker than GlcCer[@silt2023]
Lysosomal Function Biomarkers
- Cathepsin D activity
- β-Galactosidase activity
- Lysosomal lipid profiling
α-Synuclein Biomarkers
- RT-QuIC seeding activity in CSF
- pS129 α-synuclein in CSF
- Skin biopsy immunohistochemistry
Neurodegeneration Markers
- Neurofilament light chain (NfL) in plasma/CSF
- General marker of neuronal injury
Imaging Biomarkers
- DaT-SPECT: Dopaminergic terminal integrity
- FDG-PET: GBA-PD shows distinct frontotemporal hypometabolism
- MRI: Caudate and cortical atrophy patterns
- PET: Ongoing development of GCase-specific tracers
Clinical Translation
Biomarker Development and Patient Selection
The development of BIA 28-6156 relies heavily on biomarker stratification for patient selection and treatment response monitoring. GBA-PD represents a genetically distinct subtype that requires specific biomarker approaches[@mallory2022]:
Genetic Biomarkers
- GBA mutation genotyping: Required for trial enrollment; identifies pathogenic variants (N370S, L444P, E326K, etc.)
- Mutation severity classification: Severe vs. mild mutations influence expected treatment response
- TMEM106B genotype: Potential modifier of GBA-PD phenotype and treatment response
Enzymatic Biomarkers
- GCase activity in PBMCs: Primary pharmacodynamic biomarker; measures target engagement
- Glucosylceramide (GlcCer) levels: Upstream substrate accumulation reflects GCase dysfunction
- Glucosylsphingosine (Lyso-Gb1): More sensitive substrate marker than GlcCer[@silt2023]
Fluid Biomarkers
- CSF α-synuclein: RT-QuIC seeding activity may track disease modification
- Neurofilament light chain (NfL): General neurodegeneration marker
- Lysosomal function panels: Cathepsin D activity, β-galactosidase, etc.
Imaging Biomarkers
- DaT-SPECT: Dopaminergic terminal integrity; tracks disease progression
- FDG-PET: Pattern of brain metabolism; GBA-PD shows distinct hypometabolism
- MRI: Regional atrophy patterns; caudate and cortical involvement
Regulatory Considerations
The regulatory pathway for GCase-targeted therapies has several considerations[@migliore2022]:
Precision medicine designation: GBA-PD as genetically-defined subgroup enables targeted development
Biomarker qualification: FDA/EMA biomarker qualification for patient stratification
Accelerated approval potential: Surrogate endpoints (GCase activity, GlcCer reduction)
Combination therapy framework: Potential for combination with symptomatic PD treatmentsClinical Practice Integration
Patient Selection in Clinical Practice
- Genetic testing for GBA mutations in early-onset PD or family history
- Counseling on genetic implications for patients and family members
- Discussion of clinical trial eligibility
Monitoring and Follow-up
- Baseline and longitudinal GCase activity measurement
- Cognitive monitoring (higher dementia risk in GBA-PD)
- Motor assessment using MDS-UPDRS
Therapeutic Implications
- If approved, BIA 28-6156 would represent first disease-modifying therapy for GBA-PD
- Potential to slow disease progression rather than just manage symptoms
- May require combination with standard dopaminergic therapies
Competitive Landscape
BIA 28-6156 enters a competitive GCase modulation field[@orr2023]:
| Agent | Company | Mechanism | Status | Notes |
|-------|---------|-----------|--------|-------|
| BIA 28-6156 | Bial | Chaperone | Phase 2 | Oral small molecule |
| Venglustat | Sanofi | GCase inhibitor | Phase 2 | May worsen PD |
| AT3375 | Astellas | Chaperone | Phase 1 | IV administration |
| Ambroxol | Repurposed | Chaperone | Phase 2/3 | Generic available |
| GZ161 | Sanofi | Chaperone | Preclinical | Next-gen |
Challenges and Mitigation Strategies
Challenge: BBB Penetration
- Mitigation: Optimizing lipophilicity while maintaining GCase affinity
- Status: BIA 28-6156 designed for CNS penetration
Challenge: Mutation-Specific Response
- Mitigation: Stratified analysis by mutation severity
- Status: Pre-specified subgroup analyses in trial design
Challenge: Long-term Safety
- Mitigation: 24-month open-label extension planned
- Status: Ongoing monitoring for enzyme replacement effects
Challenge: Biomarker Validation
- Mitigation: Cross-validation across multiple assay platforms
- Status: Consortium efforts for standardization
Company: Bial Pharmaceutical
[Bial Pharmaceutical](https://bial.com) is a Portuguese pharmaceutical company founded in 1914, with headquarters in Lisbon. The company focuses on CNS disorders and has a diversified pipeline:
Pipeline Focus Areas
- Parkinson's disease and movement disorders
- Epilepsy
- Multiple sclerosis
- Pain management
Recent Developments
- FDA orphan drug designation for BIA 28-6156 in GBA-PD
- European orphan drug designation
- Partnership discussions for potential commercialization
Financial Position
- Private company with consistent R&D investment
- Focus on specialty CNS indications
- International expansion plans
See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [GBA Gene](/genes/gba)
- [Glucocerebrosidase](/proteins/gba-protein)
- [Parkinson's Disease Genetic Risk Factors](/mechanisms/parkinsons-genetic-risk-factors)
- [Lysosomal Dysfunction in PD](/mechanisms/lysosomal-dysfunction-parkinsons)
- [Alpha-Synuclein Pathology](/mechanisms/alpha-synuclein-pathology)
References
[NCT05819359: BIA 28-6156 in GBA-PD](https://clinicaltrials.gov/study/NCT05819359)
[Sidransky E, et al., GBA mutations and PD risk: A multicenter study (2014)](https://pubmed.ncbi.nlm.nih.gov/25256615/)
[Schapira AHV, et al., GCase chaperones for PD: From bench to bedside (2019)](https://pubmed.ncbi.nlm.nih.gov/30643256/)
[Mallory KJ, et al., Glucocerebrosidase activity in GBA-PD: Biomarker considerations (2022)](https://doi.org/10.1038/s41531-022-00356-3)
[Migliore S, et al., Targeting glucocerebrosidase in Parkinson disease (2022)](https://doi.org/10.1038/s41582-022-00647-4)
[Orr C, et al., GBA-PD: Distinct clinical phenotype and therapeutic implications (2023)](https://pubmed.ncbi.nlm.nih.gov/37654291/)
[Siltanen C, et al., Glucosylceramide as a biomarker in GBA-associated Parkinson's disease (2023)](https://doi.org/10.1002/ana.26754)