Synonyms: ABBV-8E12, C2N 8E12, HJ9.3
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy, Alzheimer's Disease
U.S. FDA Status: Progressive Supranuclear Palsy (Discontinued), Alzheimer's Disease (Phase 2)
Company: AbbVie, C2N Diagnostics, LLC
C2N 8E12 is a humanized IgG4 antibody 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 development of progressive supranuclear palsy, a tauopathy affecting about 20,000 people in the United States (company press release, EMA release).
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 50mg/kg of 8E12 to placebo in successive, three-to-one randomization groups and followed 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 compares three doses of 8E12 to placebo, to be infused over a period of 96 weeks plus 16-week followup. The primary outcomes are decline on the CDR Sum of Boxes and adverse events. Besides blood-based pharmacokinetic parameters for the 8E12 antibody, secondary outcomes include a range of clinical and functional measures such as the ADAS-Cog14, RBANS, FAQ, ADCS-MCI-ADL-24. No tau-based target engagement outcomes are listed. The trial is being conducted at 68 sites in North America, six European countries, Australia, and New Zealand, and is set to run until 2021. In March 2019 the trial stopped enrolling at 453 participants, and people who completed the study were offered a long-term safety extension with up to 5.5 years of dosing.
In December 2016, AbbVie started a Phase 2 PSP efficacy study comparing two doses of 8E12 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 49 sites in North America, Australia, France, Germany and Italy; 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 May 2018, this trial was listed as being conducted at 26 sites in the U.S. and Italy and set to run through 2022.
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 (July 2019 news). The company also discontinued preapproval access for people with primary tauopathies.
For details, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 29 Sep 2020
- High-Dose Aβ and Tau Immunotherapies Complete Initial Safety Tests
- AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
- Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
- Braak H, Del Tredici K. Alzheimer's pathogenesis: is there neuron-to-neuron propagation?. Acta Neuropathol. 2011 May;121(5):589-95. PubMed.
- Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular Propagation of Tau Aggregation by Fibrillar Species. J Biol Chem. 2012 Jun 1;287(23):19440-51. PubMed.
- Funk KE, Mirbaha H, Jiang H, Holtzman DM, Diamond MI. Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake. J Biol Chem. 2015 Aug 28;290(35):21652-62. Epub 2015 Jun 30 PubMed.
- Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-Tau Antibodies that Block Tau Aggregate Seeding In Vitro Markedly Decrease Pathology and Improve Cognition In Vivo. Neuron. 2013 Oct 16;80(2):402-14. PubMed.
- Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015 Mar;2(3):278-88. Epub 2015 Jan 23 PubMed.
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