Background

This humanized, monoclonal IgG4 antibody binds to the central region of tau, recognizing amino acids 235–250 near tau's microtubule-binding domain. The rationale of this approach is that mid-region antibodies will more potently interfere with the cell-to-cell propagation of pathogenic, aggregated tau than do N-terminally targeted anti-tau antibodies. UCB0107 was reported to inhibit seeding in a cellular assay and inhibit spread of tau pathology in a mouse model (Apr 2018 conference news). UCB0107 also binds tau monomers.

This antibody's activity against pathologic tau seeds has been characterized in a cell-based seeding aggregation assay, in tau transgenic mice injected with Alzheimer's disease brain extract, and in mice injected with K18 P301L tau fibrils known to propagate pathology to regions distal of the injection. Peer-reviewed data are published in open-access articles (Courade et al., 2018; Albert et al., 2019). 

Findings

In February 2018, Brussels-based UCB Biopharma started a first, single-ascending-dose study to evaluate safety and tolerability of UCB0107 intravenous infusion. The trial enrolled 52 healthy men, and planned to use up to seven dose groups depending on safety review of the previous, lower dose. Besides adverse events, the 20-week trial measured UCB0107 exposure in blood and CSF, pharmacokinetic parameters of antibody distribution and clearance, as well as presence of anti-UCB0107 host antibodies. The trial ended in December 2018. According to results presented at a 2019 movement disorders conference, all participants in the seven dose groups completed the study. No drug-related adverse events or changes in safety results were reported. Serum and CSF concentrations increased with dose, and the CSF/serum ratio held constant across doses. There was no evidence of anti-drug antibodies (see press release and late-breaking abstract 3).

In March 2019, the company completed a Phase 1 trial in 24 healthy Japanese men who received a single, unspecified dose of UCB0107 dosage or placebo. Endpoints were adverse events and pharmacokinetics.

In December 2019, a Phase 1 study began to enroll 25 patients with progressive supranuclear palsy at 14 sites in Belgium, Germany, Spain, and the United Kingdom. Participants receive a predefined dose of UCB0107 or placebo for one year, with a four-month safety follow-up. The primary outcome is incidence of treatment-emergent adverse events. The study is expected to finish in November 2021. As of March 2021, no safety concerns had been reported (see Mar 2021 conference news); the study finished in November 2021. An open-label extension began in November 2020, to run for up to five years.

In July 2020, UCB announced a licensing agreement with Roche/Genentech to develop UCB0107 for Alzheimer’s disease. In the deal, UCB received $120 million and committed to conducting a proof-of-concept study in AD (press release).

The AD study began in June 2021. The Phase 2 trial plans to randomize 450 people with mild cognitive impairment or mild AD dementia to one of two doses of bepranemab or placebo for 80 weeks. Enrollment requires clinical diagnosis and evidence of amyloid accumulation by PET or CSF markers. The primary endpoint is change from baseline in the CDR-SB. Secondary outcomes include adverse events, ADAS-Cog14, Amsterdam Instrumental Activities of Daily Living, MMSE, tau-PET, and serum drug concentrations. A 48-week open-label extension is planned. The study will run until November 2025.

For trial details on this antibody, see clinicaltrials.gov.