Johnson & Johnson Submits Clinical Application in China for Tau Antibody JNJ-63733657 Targeting Alzheimer's Disease

On August 17, 2021, the official website of the Center for Drug Evaluation (CDE) indicated that Johnson & Johnson's anti-tau antibody drug JNJ63733657 submitted a clinical trial application for the treatment of patients with Alzheimer's disease. Alzheimer's disease is the most common neurodegenerative disease among the elderly population and has become a major threat to the health of older adults as well as a significant economic burden on society.

Screenshot from: CDE Official Website

It is reported that in December 2017, Johnson & Johnson’s JNJ63733657 was first publicly registered for clinical trials. To date, a total of three clinical trials have been initiated, with two currently in Phase I and one underway in Phase II.

Data source: Insight Database

Tau protein is a microtubule-associated protein. In the brains of patients with Alzheimer's disease, pathological neurofibrillary tangles resulting from the aggregation and hyperphosphorylation of Tau protein are one of the hallmark features. Tau pathology is strongly correlated with neurodegeneration and cognitive impairment in patients with Alzheimer's disease. It is also a key target for Alzheimer's disease drug development.

Selected Tau-Targeted Therapies for Alzheimer's Disease

Image source: PharmaCube

Most drug targets for Alzheimer's disease therapeutics fall into two categories: those targeting beta-amyloid and those targeting tau protein. Due to the high complexity, substantial costs, and elevated failure rates associated with research and development, this field continues to face significant challenges, despite numerous companies having invested in the R&D of Alzheimer's drugs. Current data indicate that there are currently no tau antibody drugs under development in China.

First Tau Antibody Clinical Trial Fails

On September 23, 2020, Genentech, a member of the Roche Group, and its partner AC Immune jointly announced that their investigational anti-Tau antibody semorinemab missed the primary endpoint and two secondary endpoints in a Phase II trial named TAURIEL.

TAURIEL was a Phase II, double-blind, placebo-controlled clinical trial targeting patients with prodromal to mild Alzheimer’s disease, which enrolled 457 patients with early Alzheimer’s disease to compare the improvement in cognitive function over 79 weeks of treatment with semorinemab versus placebo. The primary endpoint was the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. The two secondary endpoints included the cognitive subscale of the 13-item version of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI).

In November 2020, it was reported at the 13th Clinical Trials on Alzheimer's Disease (CTAD) Conference that semorinemab failed to improve clinical outcomes in patients with prodromal or mild Alzheimer's disease in the Phase II TAURIEL trial. To date, these data have not demonstrated any difference in the rate of cognitive decline across any subgroup analysis. Biomarker analyses are ongoing, but preliminary data have provided little encouragement.

Bristol-Myers Squibb Acquires U.S. Development Rights to PRX005 for $2.2 Billion

On June 24, 2021, Bristol Myers Squibb announced it had secured an exclusive U.S. license for Prothena’s PRX005 for $80 million. PRX005 is a potential best-in-class anti-tau antibody for the treatment of Alzheimer’s disease, designed to specifically target a region within the microtubule-binding region (MTBR).

In addition, under the collaboration, Prothena will receive a total of $230 million in upfront payments and is eligible for an additional $160 million for U.S. rights and $165 million for global rights, as well as up to $1.7 billion in regulatory and commercial milestone payments, totaling up to $2.2 billion, plus potential tiered royalties on commercial sales across multiple programs.

Multiple preclinical studies have demonstrated that, compared with other anti-tau antibodies, PRX005 exhibits superior capability in binding, intercepting, and blocking the cellular internalization of pathological tau, as well as in mitigating downstream neurotoxicity.

Biogen/Ionis Antisense Oligonucleotide Therapy Significantly Reduces Tau Protein Levels

On July 26, 2021, Biogen and Ionis Pharmaceuticals announced that BIIB080/IONIS-MAPTRx, an antisense oligonucleotide therapy jointly developed by the two companies, met the primary endpoints of safety and tolerability in a Phase 1 clinical trial conducted in patients with mild Alzheimer's disease. The therapy functions by binding to the mRNA encoding the tau protein, thereby inducing mRNA degradation and reducing tau protein levels.

Trial data demonstrated that in patients treated with BIIB080, total tau protein concentrations in cerebrospinal fluid (CSF) exhibited a dose-dependent reduction at 8 weeks (Day 141) after the last dose, with decreases of 30%, 40%, and 49% from baseline in the low-, medium-, and high-dose groups administered once every 4 weeks, respectively. Total tau protein levels in CSF continued to decline at 16 weeks after the last dose in BIIB080-treated patients, showing average reductions from baseline of 55% and 49% in the high-dose groups administered once every 4 weeks and once every 12 weeks, respectively. Phosphorylated tau protein levels demonstrated a similar dose-dependent reduction.

Just last month, the Alzheimer's Association International Conference convened. Prothena, Alector, AB Science, Cassava Sciences, and numerous R&D teams presented updates on their respective Alzheimer's disease therapies at the event. While the development of anti-amyloid drugs for Alzheimer's disease has faced repeated setbacks, the tau protein, as another critical biomarker of neurodegenerative diseases, has gradually emerged as a research focus. Looking ahead, the path to Alzheimer's drug development remains long and arduous.