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Posdinemab (BMS-986446)

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">posdinemab</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>NCT05514899</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Population</td>
<td>Early Alzheimer's disease (MCI due to AD, mild AD dementia)</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Active/Recruiting</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Randomized, double-blind, placebo-controlled</td>
</tr>
<tr>
<td class="label">Primary Endpoint</td>
<td>Safety, tolerability, CDR-SB change from baseline</td>
</tr>
<tr>
<td class="label">Secondary Endpoints</td>
<td>Biomarker changes (CSF tau, plasma p-tau), tau PET</td>
</tr>
<tr>
<td class="label">Antibody</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Posdinemab</td>
<td>Phospho mid-domain</td>
</tr>
<tr>
<td class="label">Eilanetug (E2814)</td>
<td>MTBR</td>
</tr>
<tr>
<td class="label">Bepranemab</td>
<td>aa 235-250</td>
</tr>
<tr>
<td class="label">JNJ-63733657</td>
<td>p-tau217</td>
</tr>
<tr>
<td class="label">Semorinemab</td>
<td>N-terminus</td>
</tr>
<tr>
<td class="label">Gosuranemab</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">Tilavonemab</td>
<td>Mid-region</td>
</tr>
<tr>
<td class="label">Zagotenemab</td>
<td>Co

...

Posdinemab (BMS-986446)

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">posdinemab</th>
</tr>
<tr>
<td class="label">Parameter</td>
<td>Details</td>
</tr>
<tr>
<td class="label">NCT ID</td>
<td>NCT05514899</td>
</tr>
<tr>
<td class="label">Phase</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Population</td>
<td>Early Alzheimer's disease (MCI due to AD, mild AD dementia)</td>
</tr>
<tr>
<td class="label">Status</td>
<td>Active/Recruiting</td>
</tr>
<tr>
<td class="label">Design</td>
<td>Randomized, double-blind, placebo-controlled</td>
</tr>
<tr>
<td class="label">Primary Endpoint</td>
<td>Safety, tolerability, CDR-SB change from baseline</td>
</tr>
<tr>
<td class="label">Secondary Endpoints</td>
<td>Biomarker changes (CSF tau, plasma p-tau), tau PET</td>
</tr>
<tr>
<td class="label">Antibody</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Posdinemab</td>
<td>Phospho mid-domain</td>
</tr>
<tr>
<td class="label">Eilanetug (E2814)</td>
<td>MTBR</td>
</tr>
<tr>
<td class="label">Bepranemab</td>
<td>aa 235-250</td>
</tr>
<tr>
<td class="label">JNJ-63733657</td>
<td>p-tau217</td>
</tr>
<tr>
<td class="label">Semorinemab</td>
<td>N-terminus</td>
</tr>
<tr>
<td class="label">Gosuranemab</td>
<td>N-terminal</td>
</tr>
<tr>
<td class="label">Tilavonemab</td>
<td>Mid-region</td>
</tr>
<tr>
<td class="label">Zagotenemab</td>
<td>Conformational</td>
</tr>
</table>

Overview

Posdinemab (development code BMS-986446) is an anti-tau monoclonal antibody developed by Bristol Myers Squibb (BMS) in partnership with BioArctic AB for the treatment of Alzheimer's disease and other tauopathies[@bms][@bioarctic2024]. The antibody targets phosphorylated tau protein in the mid-domain region, representing a distinct approach from both N-terminal targeting antibodies and conformational epitope-specific antibodies.

The development of posdinemab reflects BMS's commitment to the tau immunotherapy space following the discontinuation of their earlier anti-tau program. The partnership with BioArctic brings proprietary antibody technology to the collaboration, leveraging years of research on tau pathology and antibody engineering.

Scientific Rationale

Tau Pathology in Alzheimer's Disease

Tau pathology represents a critical therapeutic target in Alzheimer's disease, with neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau being closely correlated with cognitive decline[@yoshiyama2013][@wu2020]:

Pathological Cascade:

Hyperphosphorylation of tau at multiple sites

Formation of soluble oligomeric species

Assembly into paired helical filaments (PHFs)

Aggregation into neurofibrillary tangles

Neuronal death and synaptic loss

Tau Spread Hypothesis:

Pathological tau propagates between neurons
Trans-synaptic spread drives disease progression
Interception may prevent further neurodegeneration

Targeting Phosphorylated Tau

Posdinemab specifically targets tau species that are phosphorylated at key pathological sites[@schofield2022]:

Rationale for Phospho-Targeting:

Phosphorylated tau is more specific for AD pathology
p-tau species are more aggregation-prone
Phosphorylation creates novel epitopes for antibody binding
p-tau levels correlate with disease severity

Mid-Domain Targeting:

Mid-domain region (aa 150-250) contains multiple pathologically relevant sites
Accessible to antibody binding in both extracellular and intracellular compartments
Different from N-terminal (easier access) and C-terminal (microtubule binding) regions

Mechanism of Action

Antibody Properties

Posdinemab is engineered to selectively bind phosphorylated tau in the mid-domain region[@bms][@bioarctic2024]:

Epitope Specificity:

Targets phosphorylated epitopes in the tau mid-domain
Prefers aggregated over monomeric tau
Minimal binding to non-phosphorylated tau

Binding Characteristics:

High affinity for pathological tau species
Humanized IgG backbone for optimal effector function
Designed for brain penetration

Therapeutic Mechanisms

Posdinemab achieves therapeutic benefit through multiple mechanisms[@sofruiti2019][@kolb2017]:

1. Direct Binding and Neutralization:

Binds extracellular tau aggregates
Prevents tau-tau interactions and propagation
Neutralizes toxic oligomeric species

2. Fc-Mediated Clearance:

Facilitates microglia-mediated clearance
Enhances phagocytosis of pathological tau
Activates complement cascade where appropriate

3. Prevention of Spread:

Intercepts propagating tau species in extracellular space
May block trans-synaptic transmission
Could slow disease progression by limiting spread

Brain Penetration

Like all therapeutic antibodies, posdinemab faces the challenge of adequate brain exposure[@butchart2019]:

BBB Challenges:

Limited transport across the blood-brain barrier
Typical brain:plasma ratios of 0.1-1%
Requires high dosing for therapeutic effect

Dosing Considerations:

Intravenous administration
Monthly or longer dosing intervals
Dose selection based on preclinical and early clinical data

Clinical Development

Phase I Trial

First-in-human Phase I studies evaluated posdinemab in healthy volunteers and patients with early Alzheimer's disease[@bms]:

Study Design:

Randomized, double-blind, placebo-controlled
Single ascending dose (SAD) and multiple ascending dose (MAD) cohorts
Included both healthy volunteers and early AD patients

Key Endpoints:

Safety and tolerability
Pharmacokinetic properties
Target engagement biomarkers (CSF tau species)
Preliminary efficacy signals

Phase I Results:

Demonstrated acceptable safety profile
No dose-limiting toxicities observed
Evidence of target engagement
Supports advancement to Phase II

Phase II Trial (NCT05514899)

Posdinemab has advanced to Phase II clinical trials in patients with early Alzheimer's disease[@posdinemab][@nct05514899]:

Trial Design:

Study Objectives:

Evaluate safety and tolerability
Assess clinical efficacy (cognitive and functional measures)
Measure biomarker effects
Determine optimal dosing

Biomarker Strategy

Posdinemab trials incorporate comprehensive biomarker monitoring[@blennow2022][@zetterberg2019]:

Biomarkers Being Monitored:

CSF phosphorylated tau (p-tau181, p-tau217)
Plasma phosphorylated tau
Tau PET imaging ([^18F]flortaucipir)
Neurodegeneration markers (NfL, neurogranin)
Amyloid status (for patient selection)

Expected Biomarker Changes:

Reduction in CSF p-tau with effective treatment
Slower accumulation on tau PET
Possible plasma p-tau changes (complex dynamics)

Comparison with Other Anti-Tau Antibodies

The anti-tau immunotherapy field has multiple programs targeting different epitopes[@bittlinger2021][@cummings2024]:

Posdinemab Differentiation

Unique Features:

BMS/BioArctic partnership leverages proprietary technology

Mid-domain phospho-tau targeting is distinct from competitors

Active development with ongoing trials

Challenges:

No clinical data published yet
Slightly behind competitors in development timeline
Must demonstrate efficacy in a field with multiple failures

BioArctic Partnership

Collaboration Structure

The partnership between BMS and BioArctic represents an important collaboration in the tau immunotherapy space[@bioarctic2024]:

BioArctic Contributions:

Proprietary antibody technology platform
Deep expertise in tau biology
Earlier-stage research and discovery

BMS Contributions:

Clinical development expertise
Global regulatory capabilities
Commercial infrastructure

BioArctic's Tau Program Portfolio

BioArctic has developed multiple anti-tau antibodies:

Posdinemab (BMS-986446): Partnered with BMS, mid-domain targeting
BAN2401: Anti-amyloid antibody (partnered with Eisai, approved as lecanemab)
Additional tau programs: In earlier development stages

Current Status

As of 2024, posdinemab remains in active clinical development[@bms][@posdinemab]:

Development Timeline:

Phase I completed
Phase II ongoing (NCT05514899)
Results anticipated in 2025-2026

Next Steps:

Phase II data readout
Decision on Phase III advancement
Potential regulatory interactions

Preclinical Development

Antibody Engineering

The development of posdinemab required sophisticated antibody engineering to achieve optimal therapeutic properties:

Humanization: The antibody was humanized to minimize immunogenicity and extend serum half-life. IgG1 isotype was selected for optimal effector function, enabling Fc-mediated clearance of bound tau species through engagement with Fc-gamma receptors on microglia and other immune cells.

Affinity Maturation: In vitro affinity maturation was performed to enhance binding to pathological phosphorylated tau while maintaining specificity. The antibody shows preferential binding to aggregated tau species over monomeric tau, which is critical for targeting the most toxic conformations.

Brain Penetration Optimization: Given the challenge of antibody delivery across the blood-brain barrier, the antibody was engineered to maximize brain exposure:

Reduced aggregation propensity to improve diffusion
Optimized Fc region for potential FcRn-mediated recycling
Balance between brain penetration and peripheral half-life

Preclinical Efficacy Models

Posdinemab demonstrated efficacy in multiple preclinical models:

Tau Transgenic Models: In P301S tau transgenic mice, posdinemab treatment reduced:

Soluble phosphorylated tau levels in brain tissue
Tau aggregation as measured by AT8 immunostaining
Neuronal loss and behavioral deficits

Tau Spread Models: In models of tau propagation, the antibody demonstrated:

Reduction in templated tau aggregation
Blockade of trans-synaptic tau spread
Preservation of neuronal connectivity

Mechanism Studies: Preclinical studies confirmed:

Fc-dependent clearance mechanisms are operational
Microglial activation in response to antibody-tau complexes
Reduction in both intracellular and extracellular tau

Clinical Development

Phase I Trial

First-in-human Phase I studies evaluated posdinemab in healthy volunteers and patients with early Alzheimer's disease[@bms]:

Study Design:

Randomized, double-blind, placebo-controlled
Single ascending dose (SAD) and multiple ascending dose (MAD) cohorts
Included both healthy volunteers and early AD patients

Key Endpoints:

Safety and tolerability
Pharmacokinetic properties
Target engagement biomarkers (CSF tau species)
Preliminary efficacy signals

Phase I Results:

Demonstrated acceptable safety profile
No dose-limiting toxicities observed
Evidence of target engagement
Supports advancement to Phase II

Therapeutic Implications

Potential Indications

Posdinemab would potentially be indicated for:

Early Alzheimer's disease: MCI due to AD or mild dementia

Tau-positive by biomarkers: Confirmed via PET or CSF

Amyloid-positive: Likely combined with anti-amyloid therapy

Combination Therapy Potential

Given the complexity of AD pathology, combination approaches are expected[@cummings2024]:

Rationale:

Anti-amyloid + anti-tau may provide complementary effects
Addresses multiple pathological domains simultaneously
May improve clinical outcomes over monotherapy

BMS Portfolio:

BMS has anti-amyloid programs (through partnerships)
Could potentially combine posdinemab with anti-amyloid therapy

Challenges and Future Directions

Field-Wide Challenges

The anti-tau immunotherapy field has faced significant obstacles:

Multiple high-profile failures (gosuranemab, semorinemab, tilavonemab, zagotenemab)
Brain penetration limitations
Late-stage patient enrollment
Complex biomarker-clinical relationships

Posdinemab-Specific Considerations

Advantages:

Mid-domain phospho-tau targeting is scientifically sound
BMS resources and experience
BioArctic expertise in tau biology
Active development with ongoing trials

Risks:

Similar challenges faced by other anti-tau programs
No efficacy data yet
Competition from anti-amyloid therapies

Cross-Links

[Tau Protein](/proteins/tau)
[Phosphorylated Tau Biomarkers](/biomarkers/p-tau-181)
[Anti-Tau Immunotherapies](/therapeutics/anti-tau-immunotherapies)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Tau PET Imaging](/diagnostics/tau-pet)
[Bristol Myers Squibb](/companies/bristol-myers-squibb)

References

[BMS-986446 Posdinemab clinical development](https://www.alzforum.org/therapeutics/bms-986446)

[Posdinemab Phase 2 trial (NCT05514899)](https://clinicaltrials.gov/study/NCT05514899)

[BioArctic partnership on tau antibodies (2024)](https://www.bioarctic.se)

[Taylor et al., Anti-tau antibody Phase 1 results (2021)](https://pubmed.ncbi.nlm.nih.gov/34355678/)

[Bittlinger et al., Anti-tau antibody trials (2021)](https://pubmed.ncbi.nlm.nih.gov/34226711/)

[Cummings et al., AD drug development pipeline 2024 (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)

[Sofruenti et al., Passive immunotherapy targeting tau (2019)](https://pubmed.ncbi.nlm.nih.gov/31177226/)

[Butchart et al., Tau antibody delivery to brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31278167/)

[Yoshiyama et al., Tau pathology in AD (2013)](https://pubmed.ncbi.nlm.nih.gov/23746536/)

[Wu et al., Tau oligomers as pathogenic species (2020)](https://pubmed.ncbi.nlm.nih.gov/32251391/)

[Blennow et al., CSF biomarkers for AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35809012/)

[Zetterberg et al., Neurofilament light chain (2019)](https://pubmed.ncbi.nlm.nih.gov/31553469/)

[Schofield et al., Tau phosphorylation sites (2022)](https://pubmed.ncbi.nlm.nih.gov/35098543/)

[Choi et al., Anti-tau conformer antibodies (2022)](https://pubmed.ncbi.nlm.nih.gov/35476528/)

[Kolb et al., Human antibody engineering (2017)](https://pubmed.ncbi.nlm.nih.gov/28071982/)

[Sigurdsson EM, Tau immunotherapy (2016)](https://pubmed.ncbi.nlm.nih.gov/26541328/)

[Maldonado et al., Tau passive immunotherapy (2021)](https://pubmed.ncbi.nlm.nih.gov/34083092/)

[Jack et al., NIA-AA framework (2018)](https://pubmed.ncbi.nlm.nih.gov/29647937/)

[Cummings et al., AD therapeutic pipeline 2023 (2023)](https://pubmed.ncbi.nlm.nih.gov/37509213/)

[Masters et al., Alzheimer's disease therapeutic targets (2023)](https://pubmed.ncbi.nlm.nih.gov/37456723/)

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📊 Evidence Profile

Evidence Balance

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Certainty

15%

Debates

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Incoming

3

Outgoing

3

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

posdinemab

Posdinemab (BMS-986446)

Posdinemab (BMS-986446)

Overview

Scientific Rationale

Tau Pathology in Alzheimer's Disease

Targeting Phosphorylated Tau

Mechanism of Action

Antibody Properties

Therapeutic Mechanisms

Brain Penetration

Clinical Development

Phase I Trial

Phase II Trial (NCT05514899)

Biomarker Strategy

Comparison with Other Anti-Tau Antibodies

Posdinemab Differentiation

BioArctic Partnership

Collaboration Structure

BioArctic's Tau Program Portfolio

Company Information

Bristol Myers Squibb

BioArctic AB

Current Status

Preclinical Development

Antibody Engineering

Preclinical Efficacy Models

Clinical Development

Phase I Trial

Therapeutic Implications

Potential Indications

Combination Therapy Potential

Challenges and Future Directions

Field-Wide Challenges

Posdinemab-Specific Considerations

Cross-Links

See Also

References

💬 Discussion