Prothena Corporation plc announced that its partner, Bristol Myers Squibb (BMS), has received Fast Track Designation from the U.S. Food and Drug Administration (FDA) for BMS-986446 (PRX005), an investigational anti-microtubule binding region-tau (anti-MTBR-tau) antibody currently in Phase 2 clinical development for the treatment of early Alzheimer’s disease.
The Fast Track program is designed to accelerate the development and review of drugs targeting serious medical conditions with significant unmet needs. This designation enables closer FDA interaction during development and allows for the possibility of priority review or rolling submissions of marketing applications, potentially shortening the time to approval if the therapy proves effective.
Targeting Tau Pathology in Alzheimer’s
Alzheimer’s disease (AD) is the leading cause of dementia in adults, characterized by progressive memory loss, cognitive decline, and functional impairment. At the biological level, Alzheimer’s involves several pathological changes, including the accumulation of abnormal tau protein within the brain. In healthy neurons, tau stabilizes microtubules—structures essential for intracellular transport and neuron integrity. However, in Alzheimer’s, tau becomes misfolded and forms aggregates, spreading through neural networks and disrupting brain function.
The microtubule binding region (MTBR) of tau has been identified as a critical driver of this neurodegenerative cascade. BMS-986446 (PRX005) is specifically designed to target pathological tau fragments containing the MTBR domain. By neutralizing these toxic species and facilitating their clearance, the antibody aims to slow or halt disease progression—a goal that remains largely unmet by current symptomatic treatments.
Preclinical and Early Clinical Findings
Preclinical studies of BMS-986446 have demonstrated promising disease-modifying potential. In laboratory models, the antibody significantly reduced the uptake and spread of tau pathology, provided neuroprotective effects against behavioral deficits, and co-localized with tau aggregates in Alzheimer’s brain tissue, confirming target engagement.
The therapy has also advanced successfully through Phase 1 clinical evaluation, which assessed its safety, tolerability, and pharmacokinetics in healthy volunteers. Across three dosing cohorts, BMS-986446 was found to be safe and well tolerated, with no serious adverse events reported. These favorable early results supported the transition to a larger Phase 2 trial, which is now fully enrolled.
Advancing Through Phase 2 Trials
The ongoing Phase 2 clinical study of BMS-986446 is designed to explore both biological and clinical endpoints. The trial includes multiple biomarkers related to tau and amyloid-beta, the two hallmark proteins associated with Alzheimer’s pathology, alongside cognitive and functional outcome measures. This comprehensive approach is intended to evaluate the antibody’s impact not only on molecular markers of disease but also on its potential to alter clinical progression in patients with early-stage Alzheimer’s.
Bristol Myers Squibb noted that the full enrollment of the Phase 2 trial represents an important milestone in the program’s advancement. Results from this study will help determine whether BMS-986446 can meaningfully slow neurodegeneration and preserve cognitive function—critical benchmarks in the quest for disease-modifying Alzheimer’s therapies.
Partnership and Financial Details
Under the terms of the global license agreement between Prothena and Bristol Myers Squibb, BMS holds worldwide rights to BMS-986446. Prothena is eligible to receive up to $562.5 million in additional regulatory and sales milestone payments, reflecting the program’s potential commercial and clinical significance. In addition, Prothena will earn tiered royalties on future net sales of the antibody.
Bristol Myers Squibb is responsible for all aspects of development, manufacturing, regulatory communications, and commercialization of BMS-986446. Prothena’s continued collaboration with BMS underscores its strategic focus on tau-targeting therapeutics and the broader mission of addressing neurodegenerative diseases through innovative, biology-driven drug design.
Looking Ahead
The FDA’s Fast Track designation for BMS-986446 represents a significant step forward in efforts to combat Alzheimer’s disease at its molecular roots. With no cure currently available and limited treatment options that only manage symptoms, the potential for a therapy that targets the underlying tau pathology offers hope to millions of patients and families affected by the disease.
As Bristol Myers Squibb advances its Phase 2 program and prepares for potential late-stage development, the industry will be watching closely. The success of BMS-986446 (PRX005) could mark a new chapter in the evolving landscape of Alzheimer’s research—where targeting tau, alongside amyloid, might finally deliver therapies capable of slowing or preventing the devastating cognitive decline characteristic of the disease.
About BMS-986446 (PRX005)
BMS-986446 is a humanized monoclonal antibody that targets multiple domains of the microtubule binding region of tau, a highly pathogenic tau fragment associated with neurofibrillary tangle formation and cognitive decline in Alzheimer’s disease. BMS-986446 binds to specific regions of the tau protein (R1–R3 within the microtubule-binding domain) to prevent the cell-to-cell spread of tau and tau uptake into cells. It also activates microglia—the brain’s immune cells—through its Fc receptor function, promoting the clearance of tau via phagocytosis.
About the TargetTau-1 Phase 2 Trial (NCT06268886)
TargetTau-1 is a randomized, double-blind, placebo-controlled, global Phase 2 proof-of-concept study designed to evaluate the efficacy, safety and tolerability of multiple doses of BMS-986446 in participants with early Alzheimer’s disease. The study aims to determine whether targeting MTBR-tau can modify disease progression. In addition to clinical outcome measures, the trial integrates a comprehensive biomarker strategy to assess tau and amyloid-beta biology.
About Alzheimer’s Disease
Alzheimer’s disease is a progressive, multifaceted and devastating neurodegenerative disease and the most common type of dementia in adults. Changes in the brain disrupt communication between neurons, impacting memory, cognition and behavior. As a result, Alzheimer’s disease has a significant impact on the day-to-day lives of those it directly affects, as well as on their families, caregivers and friends, resulting in considerable shifts in interpersonal relationships. T
here remains a critical need for disease-modifying therapies that can slow or delay the progression of Alzheimer’s disease as well as therapies that manage and ease neurobehavioral symptoms.
About Prothena
Prothena Corporation plc is a late-stage clinical biotechnology company with expertise in protein dysregulation and a pipeline of investigational therapeutics with the potential to change the course of devastating neurodegenerative and rare peripheral amyloid diseases. Fueled by its deep scientific expertise built over decades of research, Prothena is advancing a pipeline of therapeutic candidates for a number of indications and novel targets for which its ability to integrate scientific insights around neurological dysfunction and the biology of misfolded proteins can be leveraged.
Prothena’s pipeline includes both wholly-owned and partnered programs being developed for the potential treatment of diseases including ATTR amyloidosis with cardiomyopathy, Alzheimer’s disease, Parkinson’s disease and a number of other neurodegenerative diseases. For more information, please visit the Company’s website at www.prothena.com and follow the Company on X (formerly Twitter) @ProthenaCorp.
