FDA Fast Tracks Anti-MTBR-Tau-Targeting Antibody BMS-986446 for Alzheimer Disease

According to a recent announcement, the FDA granted fast track designation to Bristol Myers Squibb’s investigational anti-microtube binding region-tau (anti-MBTR-tau) antibody, BMS-986446, for the treatment of patients with early-stage Alzheimer disease (AD). The drug is currently being studied in a phase 2 trial, dubbed TargetTau-1, which tests efficacy, safety, and tolerability of multiple doses in those with early AD.¹

Anti-MTBR-tau antibodies like BMS-986446 are designed to target the MTBR of tau protein, a critical domain that drives tau aggregation into neurofibrillary tangles in AD. Unlike full-length tau, MTBR fragments are highly aggregation-prone and appear early in disease progression, making them an attractive therapeutic target.

In preclinical models, BMS-986446 had shown an ability to reduce tau uptake and spread, while protecting against behavioral deficits in AD brain tissue. The agent binds to the R1-R3 regions of tau’s microtube-binding domain to block its spread and uptake, while activating microglia via Fc receptor signaling to enhance tau clearance through phagocytosis.

"The FDA’s Fast Track Designation for BMS-986446 underscores the urgent need for innovative therapies for Alzheimer’s disease and recognizes the potential of this investigational anti-MTBR-tau antibody to meaningfully alter the trajectory of disease progression," Laura Gault, senior vice president and head of development, Neuroscience, at BMS, said in a statement.¹

The ongoing phase 2 study is a fully enrolled trial of approximately 310 patients with early AD who are randomly assigned to either 2 different doses of BMS-986446 or placebo for a 76-week treatment period. Expected to complete in 2027, the trial used change in brain tau deposition, measured through tau PET, as the primary outcome measure. Other secondary measures include change in Clinical Dementia Rating-Sum of Boxes, integrated Alzheimer’s Disease Rating Scale (iADRS), Alzheimer’s Disease Assessment Scale-Cognitive Subscale, and Alzheimer’s Disease Cooperative Study–instrumental Activities of Daily Living scale.²

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Gault added, "Bristol Myers Squibb is taking a continuum of care approach to Alzheimer’s disease, studying investigational medicines such as those targeting tau to change the course of the disease as well as several symptomatic treatment options that can address severe shifts in behavioral symptoms, such as psychosis and agitation, that significantly impact patients and their caregivers."¹

In the phase 2 study, eligible patients are between 50 and 80 years old, with mild cognitive impairment (MCI) due to AD or mild AD dementia consistent with the National Institutes on Aging and the Alzheimer’s Association core clinical criteria. Patients must have evidence of AD pathology, in addition to CDR scores between 0.5 to 1.0, as well as Mini-Mental State Exam scores between 20 and 28.

TargetTau-1 excludes any individual who has contraindications to PET imaging or an inability to tolerate MRI. In addition, the study bars those with conditions other than AD, individuals with Geriatric Depression Scale scores greater than or equal to 8, and those with any serious medical condition that could, in the opinion of the investigator, affect the participant’s safety or interfere with study assessments.

There are a few other anti-MTBR-tau antibodies in development for AD and tauopathies, including JNJ-63733657 (Johnson & Johnson), which remains in phase 2, as well as Eisai’s E2814. UCB’s UCB0107, or bepranemab, is another anti-tau antibody also directed at MTBR epitopes, currently being studied in AD and progressive supranuclear palsy.

REFERENCES
1. Bristol Myers Squibb’s Anti-MTBR-Tau-Targeting Antibody, BMS-986446, Granted Fast Track Designation by U.S. FDA for the Treatment of Alzheimer’s Disease. News release. October 1, 2025. Accessed October 2, 2025. https://news.bms.com/news/details/2025/Bristol-Myers-Squibbs-Anti-MTBR-Tau-Targeting-Antibody-BMS-986446-Granted-Fast-Track-Designation-by-U-S--FDA-for-the-Treatment-of-Alzheimers-Disease/default.aspx
2. Study to Evaluate the Efficacy, Safety, and Tolerability of an Anti-MTBR Tau Monoclonal Antibody (BMS-986446) in Participants With Early Alzheimer's Disease (TargetTau-1). Clinicaltrials.gov. Updated July 24, 2025. Accessed October 2, 2025. https://clinicaltrials.gov/study/NCT06268886