Biodrugs 2004; 18 (6): 415-418ADIS SPOTLIGHT 1173-8804/04/0006-0415/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Spotlight on Omalizumab in Allergic Asthma1

Lynne M. Bang and Greg L. Plosker

Adis International Limited, Yardley, Pennsylvania, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4151. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4162. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4163. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4164. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4175. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

Omalizumab (Xolair®) is a humanized monoclonal antibody used in the treatment of adolescent and adultAbstractpatients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). Itselectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells andother effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventingcellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases freeserum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantlyimproves airway inflammation parameters.

Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days,thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight andpretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received adosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or300mg every 4 weeks, or 225, 300, or 375mg every 2 weeks.

In adults and adolescents (≥12 years of age) with moderate to severe allergic asthma, subcutaneousadministration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescuemedication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receivingomalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completelywithdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studiesshowed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks.

Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Commonadverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection,sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar tothat with placebo.

In conclusion, omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for thetreatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic andQOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients.

1 This Spotlight is derived from abstract and summary text of an Adis Drug Evaluation originally published in full in Treatments in RespiratoryMedicine 2004; 3 (3): 182-198. Reviewers of the original full text article are listed in the Acknowledgments section.

416 Bang & Plosker

Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacyand tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.

1. Pharmacodynamic Properties Mean absolute bioavailability of omalizumab is 62%[14] and thedrug demonstrates linear pharmacokinetics at doses >0.5 mg/

Omalizumab (Xolair®)2 is a humanized recombinant immu- kg.[15] The distribution volume of omalizumab is 78 mL/kg.[14]

noglobulin G (IgG) monoclonal antibody that selectively binds to In patients with allergic asthma, the terminal elimination half-the Cε3 domain of free IgE at the FcεR1 binding site.[1,2] This, in life averaged 26 days, with an apparent clearance of 2.4 mL/kg/turn, prevents IgE binding to mast cells and other effector cells, day.[14] On the basis of data from animal studies, urinary excretionrendering them unable to detect allergens and, thereby, preventing appears to be the major route of elimination.[16]

the cellular activation by antigen and the associated allergic/asthmatic symptoms.[1,3,4] 3. Therapeutic Efficacy

In patients with allergic asthma, omalizumab rapidly decreasedSubcutaneous omalizumab ≥0.016 mg/kg/IgE (IU/mL) per 4serum free IgE levels in a dose-dependent manner. In clinical trials

weeks, as add-on therapy with inhaled corticosteroids (ICS), sig-of 28 weeks’ duration, subcutaneous treatment with omalizumabnificantly reduced the mean number of asthma exacerbations perresulted in median reductions in serum free IgE levels ofpatient and the percentage of patients experiencing an acute exac-89–99%.[5,6] After discontinuation of omalizumab therapy, serumerbation during 28 or 32 weeks of therapy.[5,6,17] In the two largest,free IgE levels slowly increased to the original level over a numberdouble-blind, randomized studies, 14.6%[5] and 12.8%[6] of omal-of weeks to months.[7]

izumab recipients experienced an asthma exacerbation during theIn patients with allergic asthma, omalizumab decreased high-16-week stable-corticosteroid period compared with 23.3% andaffinity IgE receptor expression by 2 log increments.[8] Further-30.5% of those in the placebo group. Corresponding values for themore, median basophil FcεR1 density was decreased by ≈97%12-week corticosteroid-reduction phase were 21.3% and 15.7%after 3 months of treatment with omalizumab in a study in patientsfor omalizumab compared with 32.3% and 29.8% with placebo.with allergic rhinitis, with or without allergic asthma.[9]

All comparisons between omalizumab and placebo were statisti-In patients with allergic asthma, treatment with omalizumab,cally significant (p < 0.01).[5,6]

but not placebo, significantly improved various mediators of air-In the two largest, double-blind, randomized trials, subcutane-way inflammation. Sputum eosinophils were significantly reduced

ous omalizumab significantly improved asthma scores and de-in patients treated with omalizumab when compared with placebocreased rescue β2-agonist use when compared with placebo.[5,6] Inin a double-blind trial.[10] In other studies, treatment with omal-one of the trials, for example, mean asthma scores improved fromizumab decreased antigen-induced histamine release by4.31 at baseline to 2.51 and 2.36 after 16 and 28 weeks of65–90%[8,11] and cellular inflammatory late-asthmatic response byomalizumab therapy, and rescue medication use decreased by80%.[8] Statistically significant reductions were also observed in≈30% at endpoint (28 weeks).[5] Morning peak expiratory flowblood eosinophil counts, interleukin-13 levels, and skin-prick testrate and/or FEV1 values were improved at various time points inreactivity with omalizumab versus placebo.[11]

patients receiving omalizumab, but not in those receiving placebo,In well designed trials, treatment with omalizumab significant-during the stable-corticosteroid and corticosteroid-reductionly attenuated the early- and late-phase asthmatic airway responsesphases of the two well designed studies.[5,6] However, these resultsto an allergen challenge.[12,13] Compared with baseline values inshould be interpreted with caution, as absolute improvements inone study, the median concentration of allergen required to cause athese parameters were small and may not have been clinicallyfall in forced expiratory volume in 1 second (FEV1) of 15% (PC15)meaningful.was increased by 2.7 doubling doses after 77 days of treatment

During the 12-week corticosteroid-reduction phase in the twowith omalizumab.[13]

large trials, the dosage of ICS was significantly reduced in patientsreceiving omalizumab compared with placebo, without a loss of2. Pharmacokinetic Propertiesasthma control.[5,6] More than 50% of omalizumab recipients

Subcutaneous omalizumab is slowly absorbed, with peak se- achieved a ≥50% reduction in ICS dosage. Median reductions inrum concentrations observed after an average of 7–8 days.[14] beclomethasone dipropionate (BDP) dosages of 75%[5] and 80%[6]

2 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2004 Adis Data Information BV. All rights reserved. Biodrugs 2004; 18 (6)

Spotlight on Omalizumab 417

were reported for omalizumab-treated patients compared with attempted gradually over the course of several weeks under the50% and 47% in placebo recipients (all p < 0.001). In addition, direction of a physician.[14]

approximately 40% of omalizumab recipients completely with- Pretreatment rather than current serum total IgE levels shoulddrew from ICS treatment during this period.[5,6] be used to determine dosage requirements if treatment has lapsed

In several well designed studies evaluating patient quality of for a period of <12 months.[14] Serum total IgE levels may belife (QOL), subcutaneous omalizumab for 28–32 weeks increased retested for dose determination if treatment has been stopped foroverall Asthma QOL Questionnaire (AQLQ) scores from baseline ≥1 year. There is currently no commercially available test toby 0.47–0.93 points and by 0.61–1.05 points during the stable- monitor serum free IgE levels during omalizumab therapy.corticosteroid and corticosteroid-reduction phases, respective- Subcutaneous omalizumab has not been evaluated in patientsly.[18-20] In comparison, increases of 0.26–0.66 and 0.24–0.7 points with pretreatment serum total IgE levels above 700 IU/mL.[14]

were reported for placebo recipients during the same time periods Because of a lack of data in this patient population there arein these trials (p < 0.05 for all comparisons). In general, improved concerns regarding both efficacy and tolerability of omalizumab.QOL scores were maintained throughout the corticosteroid-reduc- Consequently, there are no dosage recommendations for omal-tion phase of study in all trials, and, in some studies, a greater izumab in patients with pretreatment serum total IgE levels >700proportion of patients receiving omalizumab than placebo IU/mL,[14] thus precluding its use in a proportion of patients withachieved clinically significant improvements of ≥0.5 points from asthma that is difficult to treat.baseline in AQLQ scores.[18,21] Omalizumab is contraindicated in patients who have previously

In general, extensions of double-blind randomized trials with experienced a severe hypersensitivity reaction to the drug.[14]

omalizumab showed that the beneficial effects of the drug are Patients should be monitored after injection of omalizumab formaintained during therapy for 1 year.[22,23] possible anaphylaxis and medications for the treatment of hyper-

sensitivity reactions, including anaphylaxis, should be available.4. Tolerability The use of omalizumab in pregnant women has not been adequate-

ly evaluated and, as such, the drug should be used with caution inOmalizumab was generally well tolerated in adolescents and

these patients.[14]

adults with allergic asthma in clinical trials. Adverse effects fol-lowing omalizumab administration for up to 52 weeks were most- Acknowledgmentsly mild to moderate in severity and occurred at a similar frequencyto those in placebo recipients.[5,6,17,22,23] Common adverse events The full text article in Treatments in Respiratory Medicine 2004; 3 (3):

182-198 was reviewed by: W.E. Berger, Mission Viejo Medical Center,reported in adult and adolescent patients with allergic asthma whoMission Viejo, California, USA; R. Buhl, Pulmonary Department, Universityreceived omalizumab in controlled clinical trials were injectionHospital, Mainz, Germany; R.E. Jonkers, Pulmonology Department, AMC,

site reaction (45%), viral infection (23%), upper respiratory tractAmsterdam, Netherlands; O. Noga, Allergy and Asthma Clinic, Charite,

infection (20%), sinusitis (16%), headache (15%), and pharyngitis Humboldt University, Berlin, Germany; M. Soler, Pulmonary Division, St.(11%).[14] The most common local reactions with subcutaneous Claraspital, Basel, Switzerland; W.W. Storms, Asthma and Allergy Associ-

ates, Colorado Springs, Colorado, USA; S. Walker, National Respiratoryomalizumab include bruising, redness, warmth, and itching. MostTraining Centre, Warwick, England.injection site reactions occur within 1 hour of administration of

omalizumab, and their frequency usually decreases with continueduse of the drug.[14] References

1. Gilbey SC, Weissler JC. Anti-IgE monoclonal antibody therapy for the treatmentof asthma. Clinical Pulmonary Medicine 2002; 9 (2): 69-745. Dosage and Administration 2. Shields RL, Whether WR, Zioncheck K, et al. Inhibition of allergic reactions withantibodies to IgE. Int Arch Allergy Immunol 1995; 107: 308-12

Omalizumab is indicated in the US for the treatment of moder- 3. Storms W. Allergens in the pathogenesis of asthma: potential role of anti-immu-noglobulin E therapy. Am J Respir Med 2002; 1 (5): 361-8ate to severe persistent asthma in adults and adolescents (aged ≥12

4. Presta LG, Lahr SJ, Shields RL, et al. Humanization of an antibody directed againstyears) who have a positive skin-prick test or in vitro reaction to a IgE. J Immunol 1993; 151 (5): 2623-32

5. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant human-perennial aeroallergen and whose asthma is inadequately con-ized monoclonal antibody, for the treatment of severe allergic asthma. J Allergytrolled with ICS.[14] The drug is administered by subcutaneousClin Immunol 2001 Aug; 108 (2): 184-90

injection at a dosage of 150 or 300mg every 4 weeks, or 225, 300, 6. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reducesexacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001or 375mg every 2 weeks based on patient bodyweight and pretreat-Aug; 18 (2): 254-61

ment serum total IgE levels. Multiple delivery sites should be used 7. Saini SS, MacGlashan Jr DW, Sterbinsky SA, et al. Down-regulation of humanbasophil IgE and FC epsilon RI alpha surface densities and mediator release byfor doses of >150mg. Corticosteroid dosage reduction should be

© 2004 Adis Data Information BV. All rights reserved. Biodrugs 2004; 18 (6)

418 Bang & Plosker

anti-IgE-infusions is reversible in vitro and in vivo. J Immunol 1999; 162 (9): 17. Holgate ST, Chuchalin AG, Hebert J, et al. Efficacy and safety of a recombinant5624-30 anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin

8. Fick RB, Rohane PW, Gupta N, et al. Anti-inflammatory effects of a recombinant Exp Allergy 2004; 34: 632-8monoclonal anti-IgE (E25) in asthma [abstract]. Am J Respir Crit Care Med

18. Finn A, Gross G, van Bavel J, et al. Omalizumab improves asthma-related quality2000; 161 (3 Pt 2): 199of life in patients with severe allergic asthma. J Allergy Clin Immunol 20039. MacGlashan Jr DW, Bochner BS, Adelman DC, et al. Down-regulation of FceeR1Feb; 111 (2): 278-84expression on human basophils during in vivo treatment of atopic patients with

anti-IgE antibody. J Immunol 1997; 158: 1438-45 19. Buhl R, Hanf G, Soler M, et al. The anti-IgE antibody omalizumab improves10. Djukanovic R, Wilson SJ, Kraft M, et al. Effect of treatment with anti-IgE antibody asthma-related quality of life in patients with allergic asthma. Eur Respir J 2002

(omalizumab) on airway inflammation in mild atopic asthma [abstract no.Nov; 20 (5): 1088-94C082]. 99th International Conference of the American Thoracic Society; 2003

16 May: 703 20. Holgate S, Chuchalin A, Herbert J, et al. Omalizumab (rhumab-E25) improves

asthma-specific quality of life in patients with severe allergic asthma [abstract].11. Noga O, Hanf G, Kunkel G. Immunological and clinical changes in allergicasthmatics following treatment with omalizumab. Int Arch Allergy Immunol Am J Respir Crit Care Med 2001 Apr; 163 (5 Pt 2): 8582003; 131 (1): 46-52

21. Higgins B, Britton M, Carrillo T, et al. Anti-IgE therapy with omalizumab12. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal

improves asthma-related quality of life of patients with poorly controlledantibody on the early- and late-phase responses to allergen inhalation inallergic asthma [abstract no. 299]. J Allergy Clin Immunol 2003 Feb; 111asthmatic subjects [see comments]. Am J Respir Crit Care Med 1997; 155:

1828-34 Suppl. 2: 144

13. Boulet LP, Chapman KR, Cote J, et al. Inhibitory effects of an anti-IgE antibody 22. Lanier BQ, Corren J, Lumry W, et al. Omalizumab is effective in the long-termE25 on allergen-induced early asthmatic response [see comments]. Am J Respir

control of severe allergic asthma. Ann Allergy Asthma Immunol 2003; 91: 154-Crit Care Med 1997; 155: 1835-409

14. Genentech Inc. Xolair® (omalizumab) for subcutaneous use (US prescribing23. Buhl R, Soler M, Matz J, et al. Omalizumab provides long-term control in patientsinformation) [online]. Available from URL: http://www.gene.com/gene/com-

mon/inc/pi/xolair.jsp [Accessed 2003 Sep 25] with moderate-to-severe allergic asthma. Eur Respir J 2002 Jul; 20 (1): 73-8

15. Marian M, Sun Y-N, Sinclair D, et al. Clinical pharmacokinetics (PK) and IgEpharmacodynamics (PD) of omalizumab, a recombinant humanized monoclon-al antibody to IgE [abstract PI-23]. Clin Pharmacol Ther 2001; 69 (2): 7 Correspondence: Greg L. Plosker, Adis International Limited, 770 Township

16. Fox JA, Hotaling TE, Struble C, et al. Tissue distribution and complex formation Line Road, Suite 300, Yardley, PA 19047, USA.with IgE of an anti-IgE antibody after intravenous administration in cy-nomolgus monkeys. J Pharmacol Exp Ther 1996; 279 (2): 1000-8 E-mail: demail@adis.com

© 2004 Adis Data Information BV. All rights reserved. Biodrugs 2004; 18 (6)