Name: C2N 8E12
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy, Alzheimer's Disease
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 2), 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. 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 (Kfoury et al., 2012). 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 (see 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. A total of 30 people enrolled who met modified NINDS-SPSP criteria and whose MRI scans were consistent with this 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 0.35 (Aug 2017 conference news, Dec 2016 company release). In February 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. This single-group extension will enroll about 10 people and run until September 2020.
In October 2016, AbbVie started a Phase 2 trial in 400 people who meet diagnostic criteria for Alzheimer's disease. Their early disease stage is defined by a CDR rating of 0.5, an MMSE of 22 or higher, and an RBANS score 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 66 sites in North America, 6 European countries, Australia, and New Zealand, and is set to run until 2021.
In December 2016, AbbVie started a Phase 2 PSP efficacy study comparing two doses of 8E12 to placebo infused for one year. It aims to enroll 330 people who are 40 or older and have had PSP symptoms for fewer than five years. Primary outcomes are decline on the PSP Rating Scale (PSPRS) Total Score and adverse events; secondary outcomes include pharmacokinetic, MRI, as well as global and Parkinson’s clinical measures. The trial is being conducted at 49 sites in North America, Australia, France, Germany and Italy; it is set to run until June 2020. In January 2018, AbbVie and C2N started a 4-year extension study to this trial in people who have completed the placebo-controlled treatment phase. All participants will be randomized to ABBV-8E12 but the trial stays randomized to dose. Primary outcomes are decline on the PSPRS Total Score for up to 5 years; secondary outcomes include 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; it is set to run through 2022.
For details, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- 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.
- 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.
No Available Further Reading