Background

PRX005 is Prothena’s anti-tau IgG1 humanized antibody. It recognizes an epitope in the R1, R2, and R3 repeats in the microtubule binding region MTBR. This part of tau's middle section drives tau aggregation, and antibodies to it prevent the spread of misfolded protein in preclinical models (e.g., see Apr 2018 news). The rationale underlying PRX005 is that mid-region antibodies will block the spread of tau pathology more effectively than do N- or C-terminal antibodies, which thus far have been unsuccessful at slowing disease progression in clinical trials. The PRX005 epitope is present in both 3R and 4R tau splice isoforms.

No preclinical work is published on this antibody. According to a conference presentation, PRX005 was chosen from a panel of tau antibodies screened for their ability to block internalization of tau aggregates in cell culture. The antibody binds phosphorylated or unphosphorylated tau, and recognized neurofibrillary tangles and dystrophic neurites in AD brain tissue. It inhibited tau binding to its heparan sulfate proteoglycan target on the cell surface, and protected rat cortical neurons from tau toxicity. In the PS19 mouse tauopathy model, animals treated with PRX005 treatment starting at 6 months old had less phospho-tau accumulation in the brainstem four months later than untreated mice, and improved grip strength. In a mouse model of amyloidosis, weekly antibody injections prevented accumulation of tau aggregates (Mar 2021 conference news and company slides).

Prothena was developing PRX005 in collaboration with Bristol Myers Squibb. In July 2023, Prothena announced that BMS would take over the program, under the drug name BMS-986446 (press release).

Findings

On January 31, 2023, Prothena announced top-line results from a Phase 1, single-ascending-dose study. It tested intravenous infusions at three dose levels against placebo in 19 healthy volunteers. The company reported dose-proportional plasma concentrations and CNS penetration to 0.2 percent of plasma levels. All doses were claimed to be safe and well-tolerated, with no serious adverse events or clinically relevant changes in safety assessments. According to Prothena, a Phase 1 multiple-ascending-dose study is ongoing in healthy volunteers and patients with AD, with results expected by the end of 2023 (press release). This trial was not found in registries.

In October 2023, Bristol Myers Squibb began a Phase 1 trial testing single intravenous doses in 24 healthy volunteers, including some with Japanese ethnicity. The study assessed safety, tolerability, pharmacokinetics, and immunogenicity. It finished in March 2024.

In March 2024, a Phase 2 study began enrolling 475 participants with early Alzheimer’s disease for a 72-week course of treatment with one of two doses of BMS-986446 or placebo. Entry criteria include a Clinical Dementia Rating of 0.5 or 1, episodic memory impairment, and evidence of amyloid pathology. The primary outcome is change from baseline in the CDR-SB. Secondary outcomes include brain tau deposition as per PET, the iADRS, ADASCog14, and ADCS-iADL measures of cognition and function, plus the MMSE. The trial, at 199 sites in North America, Australia, and countries in Asia and Europe, is expected to be complete in 2027.

For details on BMS-986446 trials, see clinicaltrials.gov.