Trennette R. Gilbert, Pharm. D CandidateSamira Msalka Macon, Pharm. D CandidateClass of 2010University of Southern Nevada – College of Pharmacy

Understand the pathophysiology and prevalence of asthma

Discuss the role of TNF-α in the inflammatory response

Understand the role of TNF-α in asthma

Review the mechanism anti-TNF-α therapy

Discuss the adverse reactions and indications of etanercept

Evaluate current literature investigating the use of etanercept to treat asthma

Affects an estimated 20 million AmericansMore common in children than adults

Occurs in about 5 million American children Most common childhood disease

GenderAdults = Women > Men

Children = Boys > Girls

Chronic inflammatory disorder of the airways

Characterized by Episodic wheezing/breathlessness

Chest tightness

Airflow obstruction

Bronchial hyperresponsiveness

Multiple stimuli Ragweed, dander, pollution

Exposure to bacteria or viruses

Manifests in 3 distinct phases

Phase 1 (early acute):Allergen activates IgE-bearing cells [macrophages, mast cells, Th-2 cells] which will then secrete proinflammatory mediators

Bronchoconstriction

Mucus secretion

Vasodilation of the airway

Phase 2 (late acute):Additional inflammatory mediators are released

Cytokines (including TNF-α) also released Submucosal edema

Airway hyperresponsiveness

Phase 3 (chronic):Epithelial cell damage

Mucus hypersecretion

Enhanced hyperresponsiveness

It is this phase that represents an unmet need for therapy

Associated with high morbidity/mortality

Usually refractory to mainstay therapyBeta-agonists

Corticosteroids

TNF-α is an inflammatory cytokine secreted by inflammatory cells1

Secreted as membrane-bound protein3

Cleaved by TNF-α converting enzyme to trimeric soluble form

Soluble form stimulates TNFR1 and TNFR2Leads to activation of nuclear factor κB (NFκB)

Promotes transcription of proinflammatory factors including TNF-α

Patients with severe refractory asthma have increased levels of membrane-bound TNF-α, TNF-α receptor 1, and TNF-α-converting enzyme4

In chronic asthma it has been postulated that there is an altered inflammatory response

Mild asthma is associated with Th-2Activate eosinophils and promote antibody formation

Responsive to corticosteroids

Chronic and severe asthma is associated with Th-1

Promote inflammation, activate macrophages, and stimulate cytotoxic T cell differentiation

Partially responsive to corticosteroids

http://www.bio.davidson.edu/COURSES/Immunology/Students/spring2000/wolf/tnfpathway.gif

Etanercept (Enbrel®)Ligand-binding portion of the p75 TNF receptor bound to the Fc portion of human IgG subclass 15

Binds 2 TNF molecules

IndicationsRA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

ADRsAbdominal pain, edema, local injection site reactions, rhinitis, infection [BBW]

ANA and anti-dsDNA antibodiesLupus-like syndrome

Black box

http://img.medscape.com/slide/migrated/editorial/cmecircle/2001/285/maini/slide04.gif

MonitoringCBC

ESR/CRP

TB testing

Pregnancy Category B

Safety not established in pregnant women

Pregnancy registry 1-877-311-8972

Morjaria et al

Rouhani et al

Primary endpointsEfficacy of etanercept in controlling severe refractory asthma (ACQ) and its ability to improve asthma-related quality of life (AQLQ)

Inclusion criteria≥ 12% ↑ in FEV1 after inhalation of 400 µg of salbutamol

Less than 8 mg/ml of methacholine caused a 20% ↓ in FEV1 (PC20)

Global Initiative for Asthma criteria for severe refractory asthma. 6

Study design Lung function assessed at baseline and at weekly clinic visits

Participants randomized to receive treatment or placebo

19 treatment = 50mg SQ once weekly x 12 weeks

20 placebo

Results No significant improvement in AQLQ scores (p > 0.05)6

Improvement in ACQ scores (p = 0.030, 95% CI)6

LimitationsMany patients also had depression/poor health status

Compliance assessed by review of prescription records and clinic visit attendance

Many patients using leukotriene antagonists or nebulized albuterol

Dose and length of trial based on studies done for rheumatoid arthritis

Primary endpointsAbility of etanercept to reach its receptors in the lungs and inhibit TNF activity

Inclusion criteriaMild to moderate persistent asthma or mild intermittent asthma

Skin allergy response to cat dander, short ragweed, Timothy grass, and Dermatophagoides farinae

Allergic asthma (reversible airflow obstruction and FEV1 ≥ 70% of predicted)

Early and late phase responses to inhaled allergen challenge

Study designAllergen challenge and BAL at baseline

13 patients in treatment and placebo groupTreatment = 4 doses of 25mg SQ twice weekly x 2 weeks

BAL 24 hr after 4th dose

Methacholine (or saline) challengeFEV1 evaluated

BAL 5 mins & 24 hrs post-allergen challenge

Results No difference in airflow obstruction (p = 0.9, 95% CI)7

Significant elevation in TNFR2 in treatment group (p < 0.001, 95% CI)7

LimitationsTNF activity in the lungs could not be accurately assessed

No method of assessing compliance

Length of trial was only 2 weeks

Significant increase in IL-4 (p = 0.033, 95% CI)7

IL-4 activates macrophages and promotes IgE production

TNF necessary to control allergic response in asthma??

Etanercept has shown benefits in the treatment of other inflammatory disorders

TNF-α plays a role in asthma

Both trials evaluated were of high scientific rigor

Randomized, double-blind, placebo controlled

No definitive conclusions may be drawn

Additional trials are warranted before recommending etanercept for asthma

1. http://www.lungusa.org/site/c.dvLUK9O0E/b.22691/k.A12D/Asthma__Children.htm

2. Kelly, William A; Sorkness, Christine A. Pharmacotherapy: a pathophysiological approach. 7th ed. New York: McGraw Hill; c2008. Chapter 28, Asthma; p. 463-66.

3. Brightling C, Berry M, Amrani Y. Targeting TNF-α: A novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008 Jan;121(1):5-10; quiz 11-2. Epub 2007 Nov 26.

4. Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor α in refractory asthma. N Engl J Med. 2006 Feb 16;354(7):754-8.

5. Enbrel [package insert]. Thousand Oaks, CA: Immunex Corp; June 2008. http://enbrel.com/pdf/enbrel_pi.pdf. Accessed October 7, 2008.

6. Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomized, placebo controlled, trial. Thorax. 2008 Jul;63(7):584-91. Epub 2008 Feb 1.

7. Rouhani FN, Meitin CA, Kaler M, Miskinis-Hilligoss D, Stylianou M, Levine SJ. Effect of TNF antagonism on asthmatic airway inflammation. Respir Med. 2005 Sep;99(9):1175-82. Epub 2005 Mar 23.