Foralumab Phase 2 Trial for Alzheimer's Disease

Overview

Foralumab (also known as TZLS-401) is a human monoclonal antibody targeting CD3 epsilon (CD3ε), a subunit of the T-cell receptor complex. This Phase 2a clinical trial (NCT06489548) evaluates the safety, tolerability, and ability of Foralumab to modulate microglial activation in patients with Alzheimer's disease (AD). The trial is conducted at Brigham and Women's Hospital in Boston, Massachusetts.

Foralumab represents a novel immunomodulatory approach to AD that targets the peripheral immune system to indirectly modulate neuroinflammation — a key pathological feature of neurodegeneration.

Background and Rationale

CD3 Targeting and Neuroinflammation

The CD3 complex is essential for T-cell receptor signaling and T-cell activation. While historically explored in autoimmune diseases and organ transplantation, CD3-targeted antibodies have emerged as potential modulators of neuroinflammation through immune tolerance mechanisms:

Foralumab Specifics

Overview

Foralumab (also known as TZLS-401) is a human monoclonal antibody targeting CD3 epsilon (CD3ε), a subunit of the T-cell receptor complex. This Phase 2a clinical trial (NCT06489548) evaluates the safety, tolerability, and ability of Foralumab to modulate microglial activation in patients with Alzheimer's disease (AD). The trial is conducted at Brigham and Women's Hospital in Boston, Massachusetts.

Foralumab represents a novel immunomodulatory approach to AD that targets the peripheral immune system to indirectly modulate neuroinflammation — a key pathological feature of neurodegeneration.

Background and Rationale

CD3 Targeting and Neuroinflammation

The CD3 complex is essential for T-cell receptor signaling and T-cell activation. While historically explored in autoimmune diseases and organ transplantation, CD3-targeted antibodies have emerged as potential modulators of neuroinflammation through immune tolerance mechanisms:

Foralumab Specifics

Foralumab is a fully human IgG1 monoclonal antibody that binds to the CD3ε subunit. Unlike earlier mouse-derived anti-CD3 antibodies, Foralumab's fully human structure reduces immunogenicity and may enable repeated dosing.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06489548 |
| Official Title | Phase 2a Study of Foralumab (TZLS-401) in Alzheimer's Disease: Safety, Tolerability, and Microglial Modulation |
| Sponsor | Brigham and Women's Hospital |
| Phase | Phase 2a |
| Status | Recruiting |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Masking | Double Blind (Participant, Investigator) |
| Enrollment | ~60 participants (planned) |

Study Design

Arms

• Low-dose arm: Foralumab 50 µg
• High-dose arm: Foralumab 100 µg
• Placebo arm: Matching vehicle control

Duration

• Screening period: 4 weeks
• Treatment period: 24 weeks
• Follow-up period: 12 weeks
• Total study duration: ~40 weeks

Study Population

Inclusion Criteria

• Age 55-85 years
• Clinical diagnosis of mild-to-moderate Alzheimer's disease (MMSE 16-26)
• PET or CSF evidence of amyloid pathology
• Stable on baseline AD medications (if applicable) for ≥8 weeks
• Able to undergo repeated IV infusions

Exclusion Criteria

• History of autoimmune disease
• Active infection or recent serious infection (<4 weeks)
• Immunosuppressive therapy within 6 months
• Significant psychiatric comorbidity
• Active malignancy or history of malignancy within 5 years

Endpoints

Primary Endpoints

Secondary Endpoints

Mechanism of Action

Clinical Significance

This trial addresses a critical gap in AD therapeutics — the role of peripheral immune system modulation in reducing neuroinflammation. Key aspects:

Related Mechanisms

• [Neuroinflammation in AD](/mechanisms/neuroinflammation-ad)
• [Microglial activation pathways](/mechanisms/microglial-activation-pathways)
• [TREM2 and microglial function](/proteins/trem2)
• [Peripheral immune-CNS crosstalk in neurodegeneration](/mechanisms/peripheral-immune-cns-crosstalk)

Related Therapeutics

• [AL002 TREM2 Agonist](/clinical-trials/al002-trem2-agonist-alzheimers) — direct microglial activation approach
• [Anti-tau immunotherapies](/therapeutics/tau-immunotherapy) — disease-modifying approach
• [Microglial modulation therapies](/therapeutics/microglial-modulation-therapy) — broader category

References