Name:	Etanercept
Other Names:	Enbrel™
Therapeutic Applications:	Alzheimer's Disease
Therapy Types:	Protein: fusion of a TNF receptor fused to the Fc portion of IgG1
Mechanisms:	Anti-inflammatory, lowering TNF-alpha in CNS.
Development Status:	investigational outside U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	Etanercept is a fusion protein engineered to link the extracellular ligand-binding portion of human p75 TNFα receptor 2 to the Fc component of human immunoglobulin G1 (IgG1). The soluble dimeric TNFR2 acts as a decoy receptor and inhibits TNFα by blocking its interaction with cell surface TNF receptors, thus reducing inflammatory responses involved in autoimmune diseases, but also contributing to general immunosuppression. Licensed indications of etanercept include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis. Efficacy in these autoimmune clinical applications is based on etanercept mimicking soluble TNFα receptor inhibitory effects. The fusion to IgG Fc prolongs biological effect by extending the circulating half-life of the protein.
Role in Alzheimer's Disease:	Aβ peptide and oligomers inhibit LTP in a TNFα-mediated mechanism, preventable by TNFα-neutralizing ligands (Rowan et al., 2007). TNFα levels are 25x elevated in CSF of AD patients compared with controls (Tarkowski et al., 1999) whereas lowered TNFα in plasma is a diagnostic marker for AD (Ray et al 2007). Microglial cells produce TNFα and Aβ-activated microglia increase TNF production (Combs et al., 2001). TNFα is associated with increased amyloidogenesis (Blasko et al., 1999) and glutamate excitotoxicity (De et al., 2005; Taylor et al., 2005; Zou et al., 2005). Efficacy of etanercept in Alzheimer Disease was initially reported in results from a open-label, uncontrolled, pilot study of 12 mild to severe AD patients, treated for 6 months, administering 25-50 mg etanercept via once weekly perispinal infusion (Tobinick et al, 2006; Tobinick and Gross, 2008). In all measures of cognitive function including MMSE, ADAS-Cog, and SIB, the treatment demonstrated improvement over baseline scores. No control patients were included. In a single case study, one patient improved significantly within minutes of etanercept injection (Tobinick and Gross, 2008; comment Griffin, 2008). The mechanisms responsible for rapid improvement have not been defined, but may include interference with glial TNFα functions as a regulator of synaptic transmission (Beattie et al 2002), or TNFα involvement of Abeta peptide inhibition of LTP (Wang et al 2005). See Alzforum news 'Breakthrough or False Hope? Etanercept Case Report Draws Scrutiny' and comments.
Side Effects:	Because etanercept is an injected biologic, the most common side effect of treatment is injection site reaction, including erythema, itching, pain, swelling, bleeding, bruising, occurring in 37% of treated patients in placebo-controlled trials in rheumatologic indications. All TNF-blocking agents, including etanercept, affect host defenses against infections as systemic immunosuppressants. Adverse effects associated with etanercept therapy include serious or life-threatening opportunistic infections such as tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. An increased rate of lymphoma up to several-fold has been reported in the rheumatoid arthritis patient population, and may be further increased in patients with more severe disease activity. For further details, see Enbrel Prescribing Information.
Companies:	Amgen, Pfizer, Inc., Wyeth
Notes:	Wyeth, University of Southampton and Hampshire Partnership NHS Foundation Trust have initiated a Phase 2 double-blind, placebo-controlled clinical trial to assess safety and tolerability of etanercept in AD, administering etanercept 50 mg given as a once weekly subcutaneous injection. This study is currently recruiting participants and is located at the Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, Hampshire, United Kingdom. For further details, see STEADI-09. This entry was updated January 19, 2011.

References

Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol. 2008 Jul 21;8:27. Alzforum POW Link

Griffin WS. Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5:3. Abstract

Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008 Jan 9;5:2. Alzforum POW Link and Comments

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Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25. Alzforum POW Link

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De A, Krueger JM, Simasko SM. Glutamate induces the expression and release of tumor necrosis factor-alpha in cultured hypothalamic cells. Brain Res. 2005 Aug 16;1053(1-2):54-61. Alzforum POW Link

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Zou JY, Crews FT. TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res. 2005 Feb 9;1034(1-2):11-24. Alzforum POW Link

Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. Alzforum POW Link

Combs CK, Karlo JC, Kao SC, Landreth GE. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci. 2001 Feb 15;21(4):1179-88. Alzforum POW Link

Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol. 1999 Jul;19(4):223-30. Alzforum POW Link

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