Background

C2N 8E12 is a humanized IgG4 antibody that was being developed by C2N Diagnostics and AbbVie to treat tauopathies. It recognizes an aggregated, extracellular form of pathological tau, binding to tau's N-terminus. This form of tau has been implicated in transneuronal propagation of tau pathology in cell-based and mouse models, and postulated to explain the stereotypical progression of tau pathology in Alzheimer's disease (Clavaguera et al., 2009; Braak and Del Tredici, 2011). 

8E12 differs from some other anti-tau antibodies in that its mechanism of action requires no uptake into neurons. The mouse version of this antibody reportedly blocked seeding in a cell-based tau sensor assay and uptake of AD-derived tau by primary neurons (Kfoury et al., 2012; Funk et al., 2015). In P301S tau-transgenic mice, it was reported to reduce brain neurofibrillary pathology, insoluble tau, microgliosis, seeding activity by the lysate of treated brain, brain atrophy, and deficits in the conditioned fear response (Yanamandra et al., 2013; Yanamandra et al., 2015).

In July 2015 and April 2016, the FDA and EMA, respectively, granted this antibody orphan-drug designation for the treatment of progressive supranuclear palsy, a tauopathy affecting about 20,000 people in the United States, and 33,000 in Europe.

Findings

Between July 2015 and August 2016, AbbVie and C2N conducted a single-ascending-dose study at 12 centers in the United States. It compared four doses from 2.5 to 50 mg/kg of 8E12 to placebo in successive, three-to-one randomization groups and followed them to 84 days after dosing. The 30 participants met modified NINDS-SPSP criteria, and their MRI scans were consistent with a PSP diagnosis. The goal was to find the maximum tolerated dose; outcomes included safety, tolerability, immunogenicity, and pharmacokinetics. At conferences in 2016 and 2017, results were presented as showing 8E12 to have been safe; a maximum tolerated dose was not determined in this trial. The antibody had a half-life of 27 to 37 days, with dose-related exposure in blood and a CSF-to-blood ratio of 0.18 to 0.38 percent (Aug 2017 conference news; West et al., 2017). In April 2018, an open-label extension study started to assess 8E12's longer-term safety and tolerability in participants in this trial who are ineligible for its Phase 2 trial below. 

In October 2016, AbbVie started a Phase 2 trial in 400 people who met diagnostic criteria for Alzheimer's disease. Their early disease stage was defined by a CDR rating of 0.5, an MMSE of 22 or higher, and an RBANS of 85 or lower; AD is ascertained by a positive amyloid PET scan. This trial compared three doses of 8E12 to placebo, to be infused over a period of 96 weeks plus 16-week followup. The primary outcomes were decline on the CDR Sum of Boxes and adverse events. Besides blood-based pharmacokinetic parameters for the 8E12 antibody, secondary outcomes included a range of clinical and functional measures such as the ADAS-Cog14, RBANS, FAQ, ADCS-MCI-ADL-24. No tau-based target engagement outcomes were listed. The trial was conducted at 68 sites in North America, six European countries, Australia, and New Zealand, and was set to run until 2021. In March 2019, the trial stopped enrolling at 453 participants, and ended in July 2021. People who completed the study were offered a long-term safety extension of up to 5.5 years of dosing. This extension also ended in July 2021. According to results presented at the 2021 CTAD conference, tilavonemab did not change the decline on the CDR-SB, or any of the cognitive for functional secondary outcomes, nor did it lower brain atrophy or levels of plasma neurofilament light (Nov 2021 conference news). Results were published after peer review (Florian et al., 2023). An autopsy of one patient who had received 2,000 mg antibody per month for 14 months revealed typical PSP pathology, with no pathological modifications attributed to treatment (Beck et al., 2023).

In December 2016, AbbVie started a Phase 2 PSP efficacy study comparing 2,000 or 4,000 mg of tilavonemab to placebo infused for one year. It enrolled 378 people aged 40 or older who had had PSP symptoms for fewer than five years. Primary outcomes were decline on the PSP Rating Scale (PSPRS) Total Score and adverse events; secondary outcomes included pharmacokinetic, MRI, as well as global and Parkinson’s clinical measures. The trial was conducted at 66 sites in North America, Australia, France, Germany, Italy, Spain, and Japan; it was set to run until June 2020. In January 2018, AbbVie and C2N started a four-year extension in people who completed the placebo-controlled phase; they were to receive ABBV-8E12 but stay randomized to dose. Primary outcomes were decline on the PSPRS Total Score for up to five years; secondary outcomes included change on Parkinson’s and global clinical measures.

In July 2019, an interim analysis of the Phase 2 PSP trial data found no benefit of antibody over placebo, and AbbVie stopped the study and the ongoing open-label extension (Jul 2019 news). The company also discontinued preapproval access for people with primary tauopathies. Trial results were subsequently published. Target engagement was confirmed by a decrease in CSF free tau and higher plasma total tau in treated groups, but the antibody showed no efficacy. No treatment-related adverse events were reported (Höglinger et al., 2021; Koga et al., 2021; Höglinger, 2021; Grossmann, 2021). More negative results of N-terminal anti-tau antibodies have been reported, as well (Mar 2021 conference news).

In July, 2021, AbbVie announced it would stop development of tilavonemab and delisted it from its pipeline.

For details, see clinicaltrials.gov.

Clinical Trial Timeline