BMS-986446 Phase 2 Trial for Early Alzheimer's Disease

Overview

BMS-986446 (also known as ruvaprisutide or BOS-986) is a monoclonal antibody targeting the microtubule binding region (MTBR) of tau protein. This Phase 2 clinical trial (NCT06268886) evaluates the safety, tolerability, and efficacy of BMS-986446 in patients with early Alzheimer's disease (AD). The trial is sponsored by Bristol Myers Squibb (BMS) and represents a key component of their tau-targeted therapeutic program for AD.

Trial Details

Overview

BMS-986446 (also known as ruvaprisutide or BOS-986) is a monoclonal antibody targeting the microtubule binding region (MTBR) of tau protein. This Phase 2 clinical trial (NCT06268886) evaluates the safety, tolerability, and efficacy of BMS-986446 in patients with early Alzheimer's disease (AD). The trial is sponsored by Bristol Myers Squibb (BMS) and represents a key component of their tau-targeted therapeutic program for AD.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06268886 |
| Official Title | A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BMS-986446 in Subjects With Early Alzheimer's Disease |
| Sponsor | Bristol Myers Squibb |
| Phase | Phase 2 |
| Status | Recruiting |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Masking | Double Blind (Participant, Investigator) |
| Enrollment | 475 participants (planned) |

Study Population

Inclusion Criteria

• Age 55-85 years
• Clinical diagnosis of early Alzheimer's disease (MCI due to AD or mild AD dementia)
• MMSE score ≥ 20
• Positive amyloid biomarker (CSF or PET)
• Tau biomarker positivity (elevated p-tau in CSF)
• Stable AD medications (if applicable)

Exclusion Criteria

• History of other neurodegenerative diseases
• Significant cerebrovascular disease
• Active psychiatric disorders
• Contraindications to MRI or PET imaging

Mechanism of Action

BMS-986446 is an anti-MTBR tau antibody that specifically binds to the microtubule binding region of tau protein, which is the core domain involved in tau aggregation. Unlike N-terminal or mid-domain tau antibodies, anti-MTBR antibodies are designed to:

The MTBR-targeting approach is supported by evidence that this region is critical for tau aggregation and is present in multiple tau species including monomers, oligomers, and fibrils.

Study Design

Randomization (1:1:1:1)
├── Placebo (n=~118)
├── BMS-986446 Low Dose (n=~119)
├── BMS-986446 Medium Dose (n=~119)
└── BMS-986446 High Dose (n=~119)

Treatment Duration: 76 weeks (18 months) Follow-up: 52 weeks post-treatment

Primary Endpoints

• Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13)
• Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)

Secondary Endpoints

• Change in CSF biomarkers (p-tau181, p-tau217, total tau)
• Change in tau PET SUVr
• Change in amyloid PET
• Safety and tolerability
• Immunogenicity (anti-drug antibodies)

Rationale for MTBR Targeting

The choice of MTBR as the antibody target is based on several key findings:

Competitive Landscape

BMS-986446 joins other tau-targeting antibodies in clinical development:

| Agent | Company | Target | Phase | Trial |
|-------|---------|--------|-------|-------|
| Lecanemab | Eisai/Biogen | N-terminus/pN/A | Approved | Clarity AD |
| Donanemab | Lilly | N-terminus/pN3 | Approved | TRAILBLAZER-ALZ 2 |
| Tilavonemab | AbbVie | Mid-domain | Phase 2 | TANGO |
| Gosuranemab | Biogen | N-terminus | Phase 2 | Failed |
| Semorinemab | Roche | Mid-domain | Phase 2 | Failed |
| BMS-986446 | BMS | MTBR | Phase 2 | NCT06268886 |

Expected Outcomes

This trial will determine:

• Whether anti-MTBR tau antibodies can slow cognitive decline in early AD
• Optimal dosing regimen for efficacy and safety
• Biomarker changes correlating with clinical response
• Population characteristics predicting treatment response

Cross-Links

• [Tau Pathology in Alzheimer's Disease](/mechanisms/tau-pathology-alzheimers)
• [Tau Immunotherapy](/mechanisms/tau-immunotherapy-alzheimers)
• [Anti-Tau Antibody Clinical Trials](/clinical-trials/anti-tau-antibody-clinical-trials)
• [Biomarkers in Alzheimer's Disease](/mechanisms/alzheimers-biomarkers)
• [Early Alzheimer's Disease](/diseases/alzheimers-disease-early-stage)

References