Background

This humanized IgG1 monoclonal antibody recognizes the microtubule-binding region (MTBR) of tau, on the rationale that such antibodies will more potently interfere with cell-to-cell propagation of pathogenic, aggregated tau than do antibodies targeting the tau N-terminus. It has high affinity for tau phosphorylated at residue 217. JNJ-63733657 was reported to eliminate pathogenic tau "seeds" in a cell-based assay and inhibit spread of tau pathology in a mouse model (see Apr 2018 conference news). The antibody was used to develop a sensitive assay for p217Tau in cerebrospinal fluid from Alzheimer’s disease patients (Bijttebier et al., 2021).

Findings

From December 2017 to January 2020, Janssen Research and Development ran a Phase 1 trial at seven sites in Europe, evaluating JNJ-63733657's safety and tolerability in 72 participants. Part 1 of this trial administered a single, ascending dose by intravenous infusion to healthy volunteers; based on data from part 1, part 2, then infused multiple ascending doses to participants with prodromal or mild Alzheimer's disease. Outcomes include adverse events, JNJ-63733657 exposure in blood and CSF, pharmacokinetic parameters of antibody accumulation, distribution, and clearance, as well as presence of anti-JNJ-63733657 host antibodies. Results of the single-dose study were presented in July 2019 (see AAIC abstract). No safety issues were noted. Serum pharmacokinetics were linear with dose, and 0.2 percent ended up in CSF. In November 2020, the multiple dosing results were presented at CTAD. Pharmacokinetics were similar in healthy or AD volunteers receiving three monthly doses. The drug was deemed tolerable, most frequent complaints being back pain and headache. Single or multiple administration led to dose-dependent reductions in free p217 tau in CSF.

From September 2018 to July 2019, Janssen ran a single-ascending dose safety and pharmacokinetics study in 24 healthy volunteers in Japan.

In January 2021, a Phase 2 study began for 420 people with early AD symptoms and a positive tau PET scan. Enrollees must have a Clinical Dementia Rating of 0.5 and report subjective cognitive decline in the previous six months. They are to receive low- or high-dose antibody or matching placebo every four weeks for up to 4.5 years. The primary outcome is cognition measured on the ADAS-Cog 13; secondary outcomes include other standard measures of cognition and function, plus tauopathy burden as per PET and CSF tau, safety, and pharmacokinetics. Later in 2021, the primary endpoint was changed to the integrated Alzheimer Disease Rating Scale, a composite of cognition and function. In December 2022, the company reported that using plasma ptau217 to screen participants before PET scanning helped the trial to more efficiently achieve the goal of enrolling equal numbers with high or low tangle burden (Dec 2022 conference news). The trial is fully enrolled with 523 participants at 141 sites in North America, Europe, Australia, and Japan, and will run until 2026. In an optional long-term extension, participants randomized to high or low dose will continue the same treatment; those on placebo will be randomized to high or low dose.

In 2022, Janssen conducted a Phase 1, single-dose study in Beijing to ascertain pharmacokinetics and safety in 10 healthy Chinese adults.

For all registered trials on this antibody, see clinicaltrials.gov