Therapeutics

Etanercept

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Overview

Name: Etanercept
Synonyms: Enbrel™
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Amgen, Inc., Pfizer
Approved for: Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondilysis

Background

Etanercept inhibits the function of a pro-inflammatory cytokine called tumor necrosis factor alpha (TNF-α). Etanercept is a fusion protein consisting of two copies of the TNF-α receptor and the Fc end of the immunoglobulin G (IgG) antibody. Also called a decoy receptor, etanercept binds both the soluble and the membrane-bound forms of TNF-α, counteracting its signaling.

Etanercept is administered by injection under the skin, and in this form is FDA-approved for the treatment of various rheumatological and inflammatory skin conditions. Etanercept is effective and widely prescribed for these conditions. Its side effects include, among others, increased risk for serious infections including tuberculosis, invasive fungal infections, and bacterial infections such as listeria (see Enbrel.com).

The rationale of evaluating peripheral administration of etanercept as a treatment for Alzheimer's disease derives from studies suggesting that low-grade, chronic, systemic inflammation releases TNF-α, which reportedly can communicate from the periphery to the brain to induce a central immune response involving adverse microglial activation. In Alzheimer's disease patients, elevated serum TNF-α has been linked to faster decline and worse psychiatric symptoms (Perry et al., 2007; Drake et al., 2001; Holmes et al., 2009; Holmes et al., 2011).

In mouse models of neurodegenerative disease, several studies have shown that microglia are primed to activation in response to systemic inflammatory stimuli (Mar 2015 conference news; Perry and Hughes, 2014; Cunningham et al., 2005).

Findings

As of spring 2015, one double-blind, randomized, placebo-controlled trial of subcutaneous etanercept in Alzheimer's disease has been conducted, at the University of Southampton, U.K. In 2011, this investigator-initiated trial began enrolling 41 people with mild to moderate Alzheimer's disease whose MMSE fell between 10 and 27 and who had no evidence of prior exposure to tuberculosis. They were randomized to 50 mg of enbrel or matching placebo injected under the skin once a week for six months. Primary outcomes were tolerability as measured by compliance, and safety as measured by the number of and type of adverse events. Secondary outcomes were cognitive, functional, and behavioral measures, as well as cytokine measures in blood.

This trial has been published in the peer-reviewed literature (Butchart et al., 2015). In brief, etanercept was reported to be well tolerated, with 18 of 20 patients in the etanercept group completing the study compared to 15 of 21 in the placebo group. No new side effects appeared in this small AD population. As expected, infections were more common in the etanercept group. They included gastroenteritis, respiratory and urinary-tract infections, pharyngitis, and cellulitis. Eleven reports of infection were captured in nine people on etanercept compared to seven infections in six people on placebo. Of 97 side effects recorded in this study, one was serious but occurred in the placebo group. 

The secondary clinical outcomes showed no statistically significant differences, but did show trends favoring the peripheral etanercept group. Of note, decline on the ADAS-cog in the placebo group was twice what had been anticipated, and the randomization results indicated slightly worse neuropsychiatric symptoms in the placebo group at baseline. Analysis of serum inflammatory markers showed no differences between the groups at baseline, but higher serum TNF-α levels at weeks 12 and 24 weeks of treatment, as well as four weeks later after washout. This is consistent with the increased half-life of the dimeric fusion protein after binding TNF-α. 

According to the authors, this study calls for independent validation in a larger, more heterogeneous AD patient population. It does not by itself support off-label use of subcutaneous etanercept for the treatment of AD dementia (Butchart et al., 2015). It also, according to the authors, is different in concept from a hypothesized rapid change of central TNF-α through a perispinal etanercept injection. This approach has not been evaluated in RCTs and remains controversial (Novella S, Science-based Medicine, accessed 11 May 2015).

Last Updated: 12 May 2015

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References

News Citations

  1. Systemic Inflammation: A Driver of Neurodegenerative Disease?

Paper Citations

  1. Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, Sharples R, Sharif S, McFarlane B, Raybould R, Thomas R, Passmore P, Perry VH, Holmes C. Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015 May 26;84(21):2161-8. Epub 2015 May 1 PubMed.
  2. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007 Feb;7(2):161-7. PubMed.
  3. Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, Hulme S, Georgiou RF, Hinz R, Gerhard A, Vail A, Prenant C, Julyan P, Maroy R, Brown G, Smigova A, Herholz K, Kassiou M, Crossman D, Francis S, Proctor SD, Russell JC, Hopkins SJ, Tyrrell PJ, Rothwell NJ, Allan SM. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun. 2011 Aug;25(6):1113-22. Epub 2011 Feb 26 PubMed.
  4. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768-74. PubMed.
  5. Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology. 2011 Jul 19;77(3):212-8. PubMed.
  6. Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014 Apr;10(4):217-24. Epub 2014 Mar 18 PubMed.
  7. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 2005 Oct 5;25(40):9275-84. PubMed.

External Citations

  1. Science-based Medicine
  2. Enbrel.com

Further Reading

Papers

  1. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T. Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007 Feb;170(2):680-92. PubMed.
  2. Brambilla R, Ashbaugh JJ, Magliozzi R, Dellarole A, Karmally S, Szymkowski DE, Bethea JR. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain. 2011 Sep;134(Pt 9):2736-54. PubMed.
  3. Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007 Sep;4(4):378-85. PubMed.
  4. Barnum CJ, Chen X, Chung J, Chang J, Williams M, Grigoryan N, Tesi RJ, Tansey MG. Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. J Parkinsons Dis. 2014;4(3):349-60. PubMed.
  5. McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, Laferla FM, Oddo S, Blesch A, Tansey MG. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis. 2009 Apr;34(1):163-77. PubMed.