Overview
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Biogen_Alzheimer_s_Disease_Pha["Biogen Alzheimers Disease Phase 2 Trial NCT05399"]
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This Phase 2 clinical trial conducted by Biogen targets Alzheimer's disease (AD) with 416 participants. The trial is currently active but not recruiting, representing Biogen's continued investment in novel AD therapeutics beyond their approved therapies [1].
Trial Details
| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05399888 |
| Phase | Phase 2 |
| Status | Active, not recruiting |
| Participants | 416 |
| Sponsor | Biogen |
| Indication | Alzheimer's Disease |
| Study Type | Interventional |
| Allocation | Randomized |
Background and Rationale
...Overview
Mermaid diagram (expand to render)
This Phase 2 clinical trial conducted by Biogen targets Alzheimer's disease (AD) with 416 participants. The trial is currently active but not recruiting, representing Biogen's continued investment in novel AD therapeutics beyond their approved therapies [1].
Trial Details
| Parameter | Value |
|-----------|-------|
| Trial ID | NCT05399888 |
| Phase | Phase 2 |
| Status | Active, not recruiting |
| Participants | 416 |
| Sponsor | Biogen |
| Indication | Alzheimer's Disease |
| Study Type | Interventional |
| Allocation | Randomized |
Background and Rationale
Biogen has been a major player in Alzheimer's disease therapeutics, with a portfolio spanning amyloid-targeting antibodies, tau-targeting therapies, and novel mechanisms. Following the approval of [Aduhelm (aducanumab)](https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-as-aduhelm) and [Leqembi (lecanemab)](https://www.fda.gov/drugs/fda-approves-leqembi-treatment-alzheimers-disease) in collaboration with Eisai, Biogen continues to advance additional therapeutic candidates [2].
This Phase 2 trial represents Biogen's broader strategy to develop next-generation AD treatments targeting multiple pathological pathways. While amyloid reduction remains a key approach, the trial may evaluate novel mechanisms including:
- Tau-targeting therapies: Following positive Phase 1 results with [BIIB080 (MAPTRx)](https://clinicaltrials.gov/study/NCT05458162), Biogen is developing multiple tau-directed approaches
- Neuroprotection: Small molecules and biologics targeting neuronal survival pathways
- Neuroinflammation modulation: Addressing the inflammatory component of AD pathophysiology
- Synaptic protection: Preserving neuronal connectivity and function
Trial Design
Study Type
- Interventional: Active treatment administration
- Randomized: Participants assigned to treatment or control groups
- Placebo-controlled: Double-blind design to minimize bias
- Double-blind: Neither participants nor investigators know assignment
Treatment Arms
The trial includes multiple treatment arms evaluating different doses or mechanisms, alongside a placebo control arm. The specific intervention details are available on ClinicalTrials.gov [1].
Duration
- Treatment period: Protocol-defined duration based on dose-escalation design
- Follow-up period: Extended monitoring for safety and efficacy endpoints
- Total study duration: Approximately 18-24 months including follow-up
Inclusion Criteria
Key Eligibility Requirements
- Age: 50-85 years (typical AD trial range)
- Diagnosis: Clinical diagnosis of Alzheimer's disease
- Amyloid confirmation: Positive amyloid PET scan or CSF biomarker
- Cognitive status: MMSE score within specified range (typically 16-26)
- Stable medications: No changes to AD medications for specified period
- Capacity: Ability to provide informed consent or have surrogate consent
Exclusion Criteria
- Significant neurological disorders other than AD
- Psychiatric conditions that could affect participation
- Medical conditions contraindicating study participation
- Prior exposure to certain experimental AD therapies
Outcome Measures
Primary Endpoints
- Safety and tolerability: Adverse event monitoring, laboratory values, vital signs
- Cognitive endpoints: Standardized measures of memory, executive function, and global cognition
Secondary Endpoints
- Biomarker endpoints: CSF and plasma biomarkers including amyloid, tau, and neurodegeneration markers
- PET imaging: Amyloid and tau PET to assess pathological changes
- Functional outcomes: Activities of daily living and functional capacity measures
- Pharmacokinetics: Drug exposure and relationship to response
Exploratory Endpoints
- Digital biomarkers and wearable device data
- Remote cognitive assessments
- Quality of life measures
Biogen AD Pipeline Overview
Biogen maintains a comprehensive Alzheimer's disease pipeline with multiple programs at various stages [2]:
Approved Therapies
| Drug | Mechanism | Status |
|------|-----------|--------|
|
Leqembi (lecanemab) | Anti-amyloid (Aβ protofibrils) | FDA approved (2023) |
|
Aduhelm (aducanumab) | Anti-amyloid (Aβ plaques) | FDA approved (2021) |
Clinical Development
| Drug | Mechanism | Phase | NCT |
|------|-----------|-------|-----|
|
BIIB080 (MAPTRx) | Tau ASO | Phase 2 | NCT05458162 |
|
BIIB017 | Tau antibody | Phase 1 | NCT04619576 |
|
BIIB076 | Anti-amyloid | Phase 1 | NCT03294867 |
Research Programs
- Tau gene silencing: Collaboration with Ionis Pharmaceuticals using antisense technology
- Neuroprotective agents: Small molecules targeting multiple pathways
- Combination approaches: Evaluating synergistic mechanisms
- Diagnostic biomarkers: Enhancing early detection and patient selection
Amyloid-Targeting Field Context
This trial operates in the context of the evolving amyloid-targeting field:
Positive Results:
- [Leqembi Phase 3 CLARITY-AD](/clinical-trials/lecanemab-trailblazer-alz2) showed 27% slowing of cognitive decline
- [Donanemab Phase 3 TRAILBLAZER-ALZ 2](/clinical-trials/donanemab-trailblazer-alz2) demonstrated 35% slowing in low/medium tau population
Challenges:
- ARIA (amyloid-related imaging abnormalities) monitoring required
- Early intervention may be critical for maximum benefit
- Biomarker-based patient selection improves outcomes
Scientific Rationale
The trial design reflects current understanding of AD pathophysiology:
Amyloid cascade hypothesis: Amyloid plaques initiate a cascade leading to tau pathology and neurodegeneration
Multi-target approach: Targeting multiple pathological mechanisms may provide additive benefits
Biomarker-driven design: Using CSF and PET biomarkers for patient selection and endpoint assessment
Disease modification: Aiming to slow progression rather than just symptomatic improvementRegulatory Context
This Phase 2 trial may serve multiple purposes:
- Dose-finding: Identify optimal dose for Phase 3
- Proof-of-concept: Demonstrate biological activity and clinical signal
- Regulatory feedback: Generate data for FDA breakthrough therapy designation
- Strategic positioning: Differentiate from competitor programs
Biomarker Considerations in AD Trials
Amyloid Biomarkers
The confirmation of amyloid pathology is essential for patient selection in modern AD trials [1]:
PET Imaging:
- [Florbetapir (Amyvid)](https://www.fda.gov/drugs/fda-approves-first-drug-imaging-amyloid-plaque-alzheimers-disease) PET measures cortical amyloid burden
- Standardized uptake value ratio (SUVR) provides quantitative assessment
- Centiloid scale enables cross-study comparison
- Threshold values typically indicate presence (Centiloid >20-30) or absence (Centiloid <20)
Cerebrospinal Fluid Biomarkers:
- Aβ42/Aβ40 ratio: Reduced in amyloid-positive individuals
- Total tau: Elevated in neurodegeneration
- p-tau181/217/231: Specific to AD pathological process
- Neurofilament light chain (NfL): Marker of neuronal injury
Tau Biomarkers
Given Biogen's tau pipeline, this trial likely incorporates tau biomarker assessment:
CSF Tau:
- Total tau reflects overall tau pathology burden
- Phosphorylated tau (p-tau181, p-tau217) indicates AD-specific modifications
Tau PET:
- [Flortaucipir (Tauvid)](https://www.fda.gov/drugs/fda-approves-drug-imaging-tau-pathology-alzheimers-disease) binds to neurofibrillary tangles
- Braak staging correlates with regional tau accumulation
- Tau burden predicts cognitive progression
Neurodegeneration Markers
Structural MRI:
- Hippocampal volume loss indicates disease progression
- Cortical thickness measurements
- White matter hyperintensities assessment
- Atrophy rates over time
Functional Biomarkers:
- FDG-PET shows hypometabolism in AD-affected regions
- Default mode network connectivity changes
- Blood-based biomarkers (NfL, GFAP) for monitoring
Clinical Outcome Measures
Cognitive Assessments
Primary Cognitive Endpoints:
- Clinical Dementia Rating Scale (CDR): Global measure of dementia severity
- CDR-SB (sum of boxes): More sensitive to change
- Range 0-18, higher indicates worse function
- MMSE (Mini-Mental State Examination): Screening tool
- 30-point scale, lower indicates impairment
- ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive):
- Primary endpoint in many Phase 3 trials
- 70-point scale, higher indicates worse function
Functional Assessments
Activities of Daily Living:
- ADCS-ADL: Alzheimer's Disease Cooperative Study Activities of Daily Living
- FAQ (Functional Activities Questionnaire): Caregiver-reported function
- BADLS (Bristol Activities of Daily Living Scale)
Behavioral Measures
Neuropsychiatric Symptoms:
- NPI (Neuropsychiatric Inventory): Caregiver-reported behavioral changes
- CMAI (Cohen-Mansfield Agitation Inventory): Agitation assessment
- Geriatric Depression Scale: Mood assessment
Competitive Landscape
Phase 2/3 Amyloid-Targeting Programs
| Drug | Company | Mechanism | Status |
|------|---------|-----------|--------|
| Lecanemab | Biogen/Eisai | Anti-Aβ protofibrils | Approved |
| Donanemab | Lilly | Anti-Aβ plaques | Approved |
| Remternetug | Lilly | Anti-Aβ | Phase 2/3 |
| AC-003 | Apollo | Anti-Aβ | Phase 2 |
Tau-Targeting Programs
| Drug | Company | Mechanism | Status |
|------|---------|-----------|--------|
| E2814 | Eisai/WashU | Anti-tau antibody | Phase 2/3 |
| BIIB080 | Biogen/Ionis | MAPT ASO | Phase 2 |
| NIO752 | Roche | MAPT ASO | Phase 1 |
| JNJ-63742057 | Janssen | Anti-tau antibody | Phase 1 |
Neuroprotection and Disease Modification
| Drug | Company | Mechanism | Status |
|------|---------|-----------|--------|
| Suvvy-101 | SuVvie | Neuroprotection | Phase 2 |
| GV971 | Green Valley | Multi-target | Phase 3 |
Trial Site Considerations
Global Distribution
Phase 2 trials typically involve multiple regions:
North America: United States and Canada - Major academic medical centers and specialized AD research sites
Europe: UK, Germany (Charité), France (INSERM), Spain - NIHR dementia research network and specialized sites
Asia-Pacific: Japan (J-ADNI network), South Korea, Australia (AIBL), Singapore - National Neuroscience Institute
Site Selection Criteria
- Experience: Prior AD trial participation
- Infrastructure: MRI, PET, CSF collection capabilities
- Patient Access: Diverse patient population
- Regulatory: Track record with local authorities
Safety Monitoring
Adverse Event Categories
Common Expected Events:
- Injection site reactions (for parenteral therapies)
- Headache
- Fatigue
- Upper respiratory infections
Special Safety Monitoring:
- ARIA-E: Amyloid-related imaging abnormalities - edema
- MRI monitoring required
- Symptomatic management when needed
- ARIA-H: Microhemorrhages or siderosis
- Gradient echo MRI monitoring
- Risk factors include anticoagulation, cerebral amyloid angiopathy
Laboratory Monitoring
- Hematology: CBC with differential
- Chemistry: Comprehensive metabolic panel
- Urinalysis: Kidney function
- CSF analysis: For intrathecal therapies
Statistical Considerations
Sample Size and Power
The 416 participants provide adequate power for:
- Detecting moderate effect sizes (0.3-0.5 SD)
- Multiple dose arms
- Subgroup analyses
Statistical Analyses
- Primary: Mixed model repeated measures (MMRM)
- Sensitivity: Multiple imputation for missing data
- Subgroup: Pre-specified demographic and biomarker subgroups
- Multiplicity: Control for multiple endpoints and doses
Future Implications
If Successful
- Advancement to Phase 3 pivotal trials
- Potential breakthrough therapy designation
- Integration with Biogen's broader AD portfolio
- Competitive positioning against Lilly and Eisai
If Unsuccessful
- Iterative study design modifications
- Biomarker refinements
- Combination approach exploration
- Portfolio prioritization decisions
Patient Perspective
Trial Experience
Participants in this trial can expect:
Screening: 4-8 weeks of assessments
Baseline: Comprehensive biomarker and cognitive testing
Treatment: Regular infusions/injections per protocol
Monitoring: Frequent safety assessments and visits
Follow-up: Post-treatment observation periodBenefits and Risks
Potential Benefits:
- Access to cutting-edge therapy
- Regular medical monitoring
- Contribution to scientific knowledge
- Potential for direct therapeutic benefit
Potential Risks:
- Treatment side effects
- Placebo assignment (50% chance)
- Time commitment
- Trial procedures burden
Summary
This Phase 2 trial represents Biogen's strategic approach to developing next-generation Alzheimer's disease therapeutics. With 416 participants and a focus on biomarker-driven patient selection, the trial incorporates modern clinical trial design principles learned from previous amyloid-targeting programs. The results will inform not only Biogen's pipeline but also the broader field's understanding of optimal AD therapeutic development [1][2].
References
[ClinicalTrials.gov - NCT05399888](https://clinicaltrials.gov/study/NCT05399888)
[Biogen Alzheimer's Disease Pipeline](https://www.biogen.com/en/science-and-pipeline/alzheimers-disease)
[Leqembi FDA Approval](https://www.fda.gov/drugs/fda-approves-leqembi-treatment-alzheimers-disease)
[BIIB080 Phase 1 Study - Nature Medicine](https://doi.org/10.1038/s41591-024-03123-y)
[CLARITY-AD Phase 3 Results - Alzheimer's Disease](https://pubmed.ncbi.nlm.nih.gov/37444252/)
[Dononemab TRAILBLAZER-ALZ 2 Results](https://pubmed.ncbi.nlm.nih.gov/37336015/)
[FDA Approves First Drug for Imaging Amyloid Plaque](https://www.fda.gov/drugs/fda-approves-first-drug-imaging-amyloid-plaque-alzheimers-disease)
[FDA Approves Drug for Imaging Tau Pathology](https://www.fda.gov/drugs/fda-approves-drug-imaging-tau-pathology-alzheimers-disease)See Also
- [Biogen BIIB080 (MAPTRx) Antisense Oligonucleotide](/clinical-trials/biib080-maptrx-aso-alzheimers)](/institutions/biogen)
- [Lecanemab Phase 3 (CLARITY-AD)](https://clinicaltrials.gov/study/NCT04437511)
- [Anti-Tau Therapeutics](/therapeutics/anti-tau-therapeutics)](/therapeutics)
- [Alzheimer's Disease Drug Pipeline](/clinical-trials/drug-pipeline)
- [Amyloid-Targeting Therapies](/therapeutics/amyloid-targeting-therapies)