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Omalizumab for chronic spontaneous urticaria – second line

Source agency:
NIHR-HSC
Date of Submission:
03/10/2012
Date of Printing:
21/04/2014
Disclaimer:
This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:
Omalizumab (Xolair)
Technology - description:
Omalizumab is a recombinant, human monoclonal antibody that selectively binds to human immunoglobulin E (IgE) preventing it’s binding to high affinity receptors (FcεRI) on the surface of mast cells and basophils, thus reducing receptor expression and the release of inflammatory mediators. It is intended for the treatment of chronic spontaneous urticaria (CSU) that is refractory to H1 antihistamines. In phase III clinical trials, omalizumab is administered by subcutaneous (SC) injection at 75, 150 or 300mg once every four weeks.

Omalizumab is licensed as add-on therapy to improve asthma control in patients with severe, persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen (1).

The most common adverse events (AEs) associated with omalizumab for its licensed indications include headache, upper abdominal pain, pyrexia and injection site reactions (i.e. swelling, erythema, pain, and pruritus) (1).
Company or developer:
Novartis General Medicines.
Reason for database entry:
Symptoms of urticaria are mediated primarily by the actions of histamine on H1-receptors located on endothelial cells (the wheal) and on sensory nerves (neurogenic flare and pruritus). However, in chronic urticaria a pronounced cellular infiltrate can occur which may be refractory to antihistamines (2). If licensed, omalizumab may provide an alternative treatment option beyond antihistamines, currently the only licensed treatment for CSU.
Technology - stage in early warning process:
Assessment complete
Technology - stage of development:
Investigational - phase III
Licensing, reimbursement and other approval:
In phase III clinical trials.
Technology - type(s):
Drug
Technology - use(s):
Therapeutic

Patient Indication & Setting

Patient indications:
Chronic spontaneous urticaria (CSU) in patients refractory to H1 antihistamines.
Disease description and associated mortality and morbidity:
Urticaria, also known as hives or nettle rash, presents as a raised, itchy rash on the skin that can be localised or spread across large areas of the body (3). Urticaria with a nonspecific cause characterized by the spontaneous emergence of wheals, angioedema, or both without external physical stimuli is classified as CSU if symptoms occur daily or almost daily for more than 6 weeks (4).

CSU symptoms may be short-lived, resolving completely after a few months; however in about 50% of cases symptoms persist for 3-5 years, and in 20% of cases symptoms can persist for more than 10 years (5). Patients with chronic urticaria often have a severely impaired quality of life, with negative effects on sleep, daily activities, school or work life, and social interactions (6). CSU may carry a high burden for patients, high direct and indirect healthcare costs, and large socio-economic implications (7).
Number of Patients:
In Europe, it is estimated that more than 5 million patients have persisting urticaria symptoms (8). In the UK, approximately 15% of people experience urticaria at some time in their lives, with a chronic urticaria point prevalence of 1-5 per 1,000 (9). The lifetime prevalence of chronic urticaria is 0.5-1%, and it is twice as common in women as in men (5,10). Around 60% of cases of CSU can be ascribed to autoimmune urticaria, autoreactivity, food intolerance or underlying chronic infection, the remaining 40-50% are idiopathic (a). More than half of the patients with chronic urticaria do not respond completely to antihistamines at licensed doses (a).
Technology - specialities(s):
Immunology & allergy, Skin disease, burns and wound care
Technology - setting(s):
Community and primary care
Setting - further information:
 

Impact

Alternative and/or complementary technology:
Additive and substitution
Current Technology:
Guidelines recommend the use of non-sedating, second generation H1-antihistamines (e.g. cetirizine, levocetirizine, fexofenadine, loratadine, bilastine, desloratadine) for the first line treatment of CSU (2,11). Other treatment options for recurrent or persistent urticaria include (2,10,11,12,13,14):
First line
• Sedating H1-antihistamine (first generation)– chlorpheniramine, diphenhydramine (unlicensed for this indication), hydroxyzine (unlicensed for this indication) – for nocturnal use or if refractory to non-sedating H1-antihistamines.
• Topical 1% menthol in emollient cream.
Second line
• Leukotriene receptor antagonists – montelukast, zafirlukast (both unlicensed for this indication) – in conjunction with H1-antihistamine.
• Histamine H2-receptor antagonists – ranitidine, cimetidine (both unlicensed for this indication) – in conjunction with H1-antihistamine. Recommended by guidelines as third line treatment (2,10).
• UV-A and UV-B treatment – in conjunction with H1-antihistamine.
• Tetrahydrofolate dehydrogenase inhibitors – dapsone (especially for delayed pressure urticaria) (a).
Severe recalcitrant disease (a)
• Immunomodulatory medication – cyclosporin A, sulfasalazine, dapsone, hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil intravenous immunoglobulin, and short courses of systemic corticosteroids (acute flares of CSU only).
• Coumarin anticoagulants – warfarin and nicoumalone.
Health Impact:
Information not available.
Diffusion:
Information not available.
Cost, infrastructure and economic consequences:
Omalizumab is already marketed in the UK [as a treatment for severe, persistent allergic asthma]; a 1mL prefilled syringe (150mg/mL) costs £256, and treatment with 300mg would cost £512 (11).
Ethical, social, legal, political and cultural impact:
Information not available.

Evidence & Policy

Clinical evidence and safety:
Trial: NCT00866788 (includes NCT00130234, the USA subset), Q4577g; omalizumab or placebo; phase II.
Sponsor: Genentech.
Status: Published.
Source of information: Publication (4), Trial registry (15), manufacturer.
Location: Germany and USA.
Design: Randomised, placebo-controlled.
Participants: n=90; aged 12-75 years; CSU; refractory to H1 antihistamine treatment; receiving cetirizine 10mg daily, levocetirizine dihydrochloride 5mg daily, fexofenadine 60mg twice daily, fexofenadine 180mg daily, loratadine 10mg daily or desloratadine 5mg daily; diphenhydramine 25mg on an as-needed basis.
Schedule: Randomised to omalizumab 75mg, 300mg, 600mg or placebo, single dose. All SC.
Follow-up: Active treatment period 4 weeks; then 12 weeks follow up.
Primary outcome: Change in UAS7.
Secondary outcomes: Change in weekly pruritus score, change in weekly score for number of hives, change in weekly score for sleep interference, change in weekly score for the amount of rescue medication, number of patients with AEs by severity, number of participants with immunogenicity.
Key results: Omalizumab 75mg (n=23), 300mg (n=25), 600mg (n=21) vs placebo (n=21), respectively (p values vs placebo): mean change in UAS7, -9.79 (p=0.16), -19.93 (p<0.001), -14.56 (p=0.047) vs -6.91; mean change in weekly pruritus score, -4.50 (p=0.16), -9.22 (p<0.001), -6.46 (p=0.056) vs -3.45; mean change in weekly score for number of hives, -5.28 (p=0.14), -10.71 (p<0.001), -8.10 (p=0.02) vs -3.46; change in weekly score for sleep interference, -3.90 (p=0.551), -5.81 (p=0.153), -6.85 (p<0.05) vs -3.23; change in weekly score for the amount of rescue medication, -1.10 , -3.00 , -2.05 vs -1.72 (p>0.05 for all doses).
Adverse effects (AEs): Omalizumab 75mg, 300mg, 600mg vs placebo, respectively:
patients with >1 AE during treatment period, 34.8%, 48.0%, 47.6% vs 47.6; treatment-emergent AEs included upper respiratory tract infection, headache, nasopharyngitis, and dysmenorrhea. No SAEs reported.

Trial: NCT00481676; CIGE025ADE05; omalizumab or placebo; phase II.
Sponsor: Novartis.
Status: Published.
Source of information: Publication (16), trial registry (17), manufacturer.
Location: Germany.
Design: Randomised, placebo-controlled.
Participants: n=49; aged 18-70 years; chronic urticaria; moderate to severe; specific serum IgE anti-thyroperoxidase level ≥8.0IU/mL (international units per millilitre); receiving loratadine 10mg daily and clemastine 1mg (maximum 3 tablets daily) as rescue medication; not responded to antihistamine for ≥2 weeks; UAS ≥0 during first 7 days of screening period; UAS7 ≥10 at randomization.
Schedule: Randomised to omalizumab 75-375mg (based on baseline IgE and body weight) or placebo every 2 or 4 weeks. All SC.
Follow-up: Active treatment period 24 weeks.
Primary outcome: Change in UAS7.
Secondary outcomes: Number of patients with wheals, erythemas, pruritus, and angioedemas; standardised (with respect to length of time) Area under the curve (AUC) for UAS; use of concomitant and rescue medications; change in DLQI; change in Skindex Score; change in Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL); patient's global assessment of symptoms; investigator's global assessment of symptoms.
Key results: Omalizumab (n=27) vs placebo (n=22): change in UAS, -17.8 vs -7.9 (p<0.01); protection from wheal development, 70.4% vs 4.5%; absence of pruritus, 59.3% vs 9.1%; absence of erythemas, 66.7% vs 18.2%; absence of angioedemas, 77.8% vs 36.4%; patient’s global assessment of being symptom free, 59% vs 14%; investigator’s global assessment of being symptom free, 67% vs 4%. Significantly lower standardised AUC over 24 weeks reported for omalizumab group (p<0.001). Significantly greater improvement of QoL in omalizumab group measured by DLQI, Skindex and CU-Q2oL questionnaires (p<0.01).
Adverse effects (AEs): For omalizumab vs placebo, respectively, most frequent AEs: diarrhoea, 14.8% vs 9.1%; nasopharyngitis, 33.3% vs 50%; headache, 37% vs 27.3%.
Economic evaluation:
 
Ongoing research:
Trial: NCT01287117, Q4881g, GA00887; omalizumab or placebo; phase III.
Sponsor: Genentech.
Status: Ongoing.
Source of information: Trial registry (18), manufacturer.
Location: EU and USA.
Design: Randomised, placebo-controlled.
Participants: n=6; aged 12-75 years; CSU; refractory to standard-dosed H1 antihistamine treatment.
Schedule: Randomised to omalizumab 75mg, 150mg, 300mg, or placebo every 4 weeks for 24 weeks. All SC.
Follow-up: Active treatment period 24 weeks; then 16 weeks follow up. Follow up every 4 weeks.
Primary outcomes: Change in weekly itch score (a component of Urticaria Activity Score summed over a week [UAS7]) at week 12.
Secondary outcomes: Measured at week 12: change in UAS7, change in weekly hives score, time to weekly itch minimally important difference (MID) response, proportion of patients with UAS7 ≤6, change in weekly largest hive score, proportion of weekly itch score MID responders, change from baseline in health-related quality of life (QoL) (as measured by the Dermatology Life Quality Index [DLQI]), proportion of angioedema-free days from week 4 to week 12, incidence and severity of AEs and serious AEs (SAEs).
Expected reporting date: Primary completion date reported as Jun 2013.

Trial: NCT01292473, Q4882g, GA00888; omalizumab or placebo; phase III.
Sponsor: Genentech.
Status: Ongoing.
Source of information: Trial registry (19), manufacturer.
Location: EU and USA.
Design: Randomised, placebo-controlled.
Participants: n=323; aged 12-75 years; CSU; refractory to standard-dosed H1 antihistamine treatment.
Schedule: Randomised to omalizumab 75mg, 150mg, 300mg, or placebo every 4 weeks for 12 weeks. All SC.
Follow-up: Active treatment period 12 weeks; then 16 weeks follow up. Follow up every 4 weeks.
Primary outcomes: Change in weekly itch score (a component of UAS7).
Secondary outcomes: Change in UAS7, change in weekly hives score, time to weekly itch MID response, proportion of patients with UAS7 ≤6, change in weekly largest hive score, proportion of weekly itch score MID responders, change from baseline in health-related QoL (as measured by DLQI), proportion of angioedema-free days from week 4 to week 12, incidence and severity of AEs and SAEs.
Expected reporting date: Primary completion date reported as Jun 2013.

Trial: NCT01264939, Q4883g, GA00889; omalizumab or placebo; phase III.
Sponsor: Genentech.
Status: Ongoing.
Source of information: Trial registry (20), manufacturer.
Location: EU (inc UK), USA, Australia, New Zealand and Singapore.
Design: Randomised, placebo-controlled.
Participants: n=332; aged 12-75 years; CSU; refractory to standard-dosed H1 antihistamine treatment.
Schedule: Randomised to omalizumab 300mg, or placebo every 4 weeks for 24 weeks. All SC.
Follow-up: Active treatment period 24 weeks; then 16 weeks follow up. Follow up every 4 weeks.
Primary outcomes: Safety, serum thyroid autoantibodies (ATA) change in vital signs, clinical laboratory evaluations, incidence and severity of adverse events (AEs).
Secondary outcomes: Measured at week 12: change in weekly itch score, change in UAS7, change in weekly hives score, time to weekly itch MID response, proportion of patients with UAS7 ≤6, change in weekly largest hive score, proportion of weekly itch score MID responders, change from baseline in health-related QoL (as measured by DLQI), proportion of angioedema-free days from week 4 to week 12, incidence and severity of AEs and SAEs.
Expected reporting date: Primary completion date reported as Jun 2013.
Ongoing or planned HTA:
 
Web link:
 
References and sources:
(a) Expert personal communication.
(1)The electronic Medicines Compendium (eMC). Summary of Product Characteristics, Xolair. Novartis Pharmaceuticals UK Ltd, UK, June 2012. http://www.medicines.org.uk/EMC/medicine/ 17029/SPC/Xolair+150+mg+powder+and+solvent+for+solution+for+injection/ Accessed 26 July 2012.
(2) Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64(10):1427-43.
(3) NHS Choices. Urticaria (hives). http://www.nhs.uk/conditions/Nettle-rash/Pages/Introduction.aspx Accessed 26 July 2012.
(4) Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine–refractory chronic idiopathic urticaria. The Journal of Allergy and Clinical Immunology 2011;128(3):567-573.e1.
(5) Patient.co.uk. Chronic Urticaria. http://www.patient.co.uk/health/Chronic-Urticaria.htm Accessed 26 July 2012
(6) O'Donnell BF, Lawlor F, Simpson J et al. The impact of chronic urticaria on the quality of life. British Journal of Dermatology 1997;136(2):197-201.
(7) Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009;64(10):1417-26.
(8) Metz M and Maurer M. Omalizumab in chronic urticaria. Current Opinion in Allergy and Clinical
Immunology 2012;12(4):406-411.
(9) Patient.co.uk. Urticaria. September 2010. http://www.patient.co.uk/doctor/Urticaria.htm Accessed 26 July 2012.
(10) Powell RJ, Du Toit GL, Siddique N et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clinical and Experimental Allergy 2007;37(5):631-650.
(11) British Medical Association and Royal Pharmaceutical Company of Great Britain. British National Formulary. BNF 63. London: BMJ Group and RPS Publishing, March 2012.
(12) Grattan CE, Humphreys F and British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. British Journal of Dermatologist 2007;157(6):1116-23.
(13) Primary Care Dermatology Society. Urticaria and Angioedema. May 2010. http://www.pcds.org.uk/image-atlas/a-z-of-diagnosis/50-image-atlas-detailed-articles/153-urticaria-and-angioedema Accessed 26 July 2012.
(14) Grattan CE, Humphreys F and British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. British Journal of Dermatologist 2007;157(6):1116-23.
(15) ClinicalTrials.gov. A study of xolair (omalizumab) in patients with chronic idiopathic urticaria (CIU) who remain symptomatic with antihistamine treatment (H1). http://clinicaltrials.gov/ct2/show/study/NCT00866788 Accessed 27 July 2012.
(16) Maurer M, Altrichter S, Bieber T et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. Journal of Allergy and Clinical Immunology 2011;128:202–209.e5.
(17) ClinicalTrials.gov. Efficacy and safety of omalizumab in adults (18-70 years) with moderate to severe chronic urticaria. http://clinicaltrials.gov/ct2/show/study/NCT00481676 Accessed 7 September 2012.
(18) ClinicalTrials.gov. A study of the efficacy and safety of xolair (omalizumab) in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) who remain symptomatic despite antihistamine treatment (H1). http://clinicaltrials.gov/ct2/show/NCT01287117 Accessed 27 July 2012.
(19) ClinicalTrials.gov. A study to evaluate the efficacy, response duration and safety of xolair (omalizumab) in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) who remain symptomatic despite antihistamine treatment (H1). http://clinicaltrials.gov/ct2/show/NCT01292473 Accessed 27 July 2012.
(20) ClinicalTrials.gov. A safety study of xolair (omalizumab) in patients with chronic idiopathic urticaria (CIU) who remain symptomatic despite treatment with H1 antihistamines, H2 blockers, and/or leukotriene receptor antagonists. http://clinicaltrials.gov/ct2/show/study/NCT01264939 Accessed 27 July 2012.
Notes: