BIA 28-6156 for GBA-Parkinson's Disease

BIA 28-6156 GBA Parkinsons

Overview

BIA 28-6156 GBA Parkinsons

Overview

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:

Molecular 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

• 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

• 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)

• 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]:

Preclinical 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

• 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

• 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

• 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

• 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

If Successful: Transformative Potential

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

• 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

• 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

• 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

• 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

• 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

• 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:

Biomarkers 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)

• 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]

• Cathepsin D activity
• β-Galactosidase activity
• Lysosomal lipid profiling

• RT-QuIC seeding activity in CSF
• pS129 α-synuclein in CSF
• Skin biopsy immunohistochemistry

• Neurofilament light chain (NfL) in plasma/CSF
• General marker of neuronal injury

• 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

• 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]

• 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.

• 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]:

Clinical 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

• Baseline and longitudinal GCase activity measurement
• Cognitive monitoring (higher dementia risk in GBA-PD)
• Motor assessment using MDS-UPDRS

• 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

• Mitigation: Stratified analysis by mutation severity
• Status: Pre-specified subgroup analyses in trial design

• Mitigation: 24-month open-label extension planned
• Status: Ongoing monitoring for enzyme replacement effects

• 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

• FDA orphan drug designation for BIA 28-6156 in GBA-PD
• European orphan drug designation
• Partnership discussions for potential commercialization

• 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