Johnson & Johnson's Tau Monoclonal Antibody Receives FDA Fast Track Designation on January 8

The U.S. Food and Drug Administration (FDA) has granted Johnson & Johnson fast track designation for its developing Tau monoclonal antibody Posdinemab for the treatment of early Alzheimer's disease (AD) patients. This decision was announced on January 8. Previously, Johnson & Johnson's other active immunotherapy targeting phosphorylated Tau protein, JNJ-2056, also received FDA fast track designation.

Posdinemab is a monoclonal antibody that targets specific hyperphosphorylated epitopes in the intermediate region of the Tau protein, aiming to delay or prevent the progression of Alzheimer's disease by inhibiting the deposition and spread of pathological Tau protein. The drug is currently undergoing a Phase IIb AuTonomy clinical study (NCT04619420).

In November 2021, Posdinemab received its first clinical approval in China to delay cognitive decline in patients diagnosed with prodromal AD and mild AD dementia stages. According to official information from the drug clinical trial registration and information disclosure platform, Johnson & Johnson has completed a Phase I, open-label, single-dose study assessing the pharmacokinetics, safety, and tolerability of Posdinemab in healthy subjects in China.

In the brains of Alzheimer's patients, two main proteins—Tau protein and beta-amyloid (Aβ)—misfold and accumulate into aggregates. For decades, the primary treatment strategies for AD have focused on the Aβ cascade hypothesis. Among the seven Aβ monoclonal antibodies that are currently under rapid development, three have already been approved for market release: Aducanumab (by Eisai/Biogen), Lecanemab, and Donanemab (by Eli Lilly). However, Aducanumab has been abandoned by Eisai and Biogen due to ongoing controversies, while Lecanemab is expected to achieve annual sales of $2 billion in the 2024 fiscal year. Donanemab has been on the market for less than six months, and its market performance is promising.

Tau protein is a low molecular weight microtubule-associated protein whose physiological function is to enhance the stability of cellular microtubules. However, pathological Tau accumulation is one of the causes of neurofibrillary tangles (NFT) formation and neuronal loss. Due to various factors, including Aβ deposition, cyclin-dependent kinase-5 is excessively activated, leading to the hyperphosphorylation of Tau protein. This hyperphosphorylation disrupts the Tau-microtubule interaction, reducing Tau protein affinity for microtubules, causing NFT accumulation in the cytoplasm, and resulting in transport defects along microtubules and neuronal death.

As our understanding of Tau-dependent neurotoxicity deepens, and as Tau immunotherapy has shown promising results in several preclinical studies, Tau-based therapeutic strategies offer new insights for Alzheimer's drug development. Current drug development strategies mainly focus on inhibiting Tau protein hyperphosphorylation, controlling the aggregation and spread of pathological Tau, as well as active and passive immunotherapy.