BIA 28-6156 is a novel therapeutic candidate being developed by Bial Pharmaceutical for the treatment of Parkinson's disease in patients carrying GBA gene mutations. This Phase 2 clinical trial (NCT05819359) targets the underlying genetics of Parkinson's disease by modulating glucocerebrosidase (GCase) activity 1.
| Attribute |
Value |
| Trial ID |
NCT05819359 |
| Sponsor |
Bial Pharmaceutical |
| Phase |
Phase 2 |
| Status |
RECRUITING |
| Condition |
Parkinson's Disease with GBA Mutations |
| Intervention |
BIA 28-6156 |
¶ 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
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
The glucocerebrosidase enzyme encoded by GBA:
- Function: Breaks down glucosylceramide in lysosomes
- PD link: Reduced GCase activity leads to:
- Lysosomal dysfunction
- α-Synuclein accumulation
- Mitochondrial dysfunction
- Endoplasmic reticulum stress
- Bidirectional relationship: α-Synuclein can also inhibit GCase activity, creating a vicious cycle
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 pathology
- Primary target: Glucocerebrosidase (GCase)
- Secondary effects: Lysosomal function, α-synuclein clearance
- Approach: Pharmacological chaperone therapy
- 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
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
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)
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:
-
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 effects
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
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
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
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 modifications
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
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
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
¶ 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:
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
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
The regulatory pathway for GCase-targeted therapies has several considerations:
- 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 treatments
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:
| 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
Bial Pharmaceutical 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