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 1), Alzheimer's Disease (Phase 2)
Company: AbbVie, C2N Diagnostics, LLC
C2N 8E12 is a humanized 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, the FDA 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).
Between July 2015 and October 2016, a single-ascending-dose study was conducted at 12 centers in the United States. It compared four doses of 8E12 to placebo in successive, three-to-one randomization groups. A total of 30 people were 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.
In October 2016, AbbVie and C2N 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 infused over a period of two years to placebo. 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 in the United States, Australia, and New Zealand, and is set to run until October 2020.
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