Management of Chronic Idiopathic Urticaria

Transcription

1 9/3/216 Management of Chronic Idiopathic Urticaria Brian Berman, M.D., Ph.D. Professor Emeritus of Dermatology and Dermatologic Surgery, University of Miami Co-Director Center for Clinical and Cosmetic Research Aventura FL Relevant Financial Disclosures Management of Chronic Idiopathic Urticaria Brian Berman, M.D, Ph.D. Consultant/Speakers Bureau: Genentech Off FDA labeled usages are discussed EAACI/GA 2 LEN/EDF/WAO Guideline for the definition, classification, diagnosis and management of Urticaria: YES YES 1-antihistamines for chronic spontaneous urticaria: An abridged Cochrane Systematic Review Systematic search of major databases for randomized controlled 1-A trials on CSU Yielded 73 studies with 9,759 participants; 3 studies: outcome data, 23: comparisons In the short-term (<2wks) and intermediate-term (>2wks<3months) Cetirizine 1 mg daily led to greater complete suppression of urticaria than placebo) (RR 2.72) Levocetirizine 2 mg daily was effective for short-term use (RR 2.87) as was 5 mg for intermediate-term use (RR 52.88) Desloratadine 2 mg was effective for short-term (RR 15.97) as was 5 mg in the intermediate-term (RR 37.) No evidence to suggest difference in adverse event rates between treatments Little evidence of benefit at higher doses Zuberbier et al. Allergy 69 (21) Sharma et al. J Am Acad Dermatol 215;73;71-16 Cetirizine: 2 Enantiomers Dextrocetirizine 1

2 9/3/216 Levocetirizine Prescribing Low Receptor Occupancy with a Low Affinity Antihistamine A A A A A A A A A igh Receptor Occupancy with a igh Affinity Antihistamine A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A Correlation of Skin Concentration, RO, and Wheal-and-Flare Inhibition Unbound skin concentration, RO and wheal-and-flare inhibition at 2 hours Omalizumab for Chronic Idiopathic Urticaria (CIU) Unbound Skin Concentration (ng/g) 1 Receptor Occupancy (%) 2 Wheal Inhibition Over (%) 2 Flare Inhibition Over (%) 2 Levocetirizine 5 mg Frossard N, et al. Brit J Clin Pharamcol. In press. Maurer et al. NEJM Feb. 2, 213,

3 9/3/216 Omalizumab is a recombinant humanized (95%) monoclonal anti-ige antibody Omalizumab effective in the treatment of allergic asthma 1,2, rhinitis 3 5 and Chronic Idiopathic Urticaria (CIU) 6 1. Solér M, et al. Eur Respir J 21; 18: Busse W, et al. J Allergy Clin Immunol 21; 18: Adelroth E, et al. J Allergy Clin Immunol 2; 16: Casale TB, et al. JAMA 21; 286: Chervinsky P, et al. Ann Allergy Asthma Immunol 23; 91: Maurer et al. N Engl J Med. 213;368:92 Omalizumab Prevents IgE Binding the FceRI Receptor by Complexing with IgE IgE Fc RI receptor Effector cell Omalizumab Prevents IgE Binding the FceRI Receptor by Complexing with IgE IgE Omalizumab CIU Assessment Measures: Weekly Itch Severity, ive Count and UAS7 Scores 1,2 Fc RI receptor Omalizumab Effector cell Daily scores: patient-reported daily average (AM and PM) severity of itch symptoms and number of hives (range -3) Itch (Pruritus) Intensity ive Count Score None Mild 1 Moderate 2 Severe 3 No hives 1-6 hives hives 2 >12 hives 3 Weekly scores: are the sum of the average daily scores over 7 consecutive days (range -21 for itch severity, and hive count scores) UAS7 is the sum of weekly itch and hive count scores (range -2) 1. Saini et al. J Invest Derm. Advance online publication, 21 August 21; 2. Maurer et al. N Engl J Med. 213;368:92. Omalizumab CIU Studies 1 and 2: Efficacy End Points 1,2 Primary Efficacy End Point (at Week 12) Change from baseline in weekly Itch Severity Score Key Secondary Efficacy End Points (at Week 12) Change from baseline in weekly ive Count Score Proportion of patients with a Complete Response (UAS7=) Omalizumab CIU Studies: Key Inclusion/Exclusion Criteria 1,2 Inclusion Criteria Exclusion Criteria Patients years of age CIU history of 6 months UAS7 of 16 on a -2 scale Weekly Itch Severity Score 8 on a -21 scale Symptomatic despite 1 antihistamine treatment at approved doses Clearly defined underlying etiology for chronic urticaria Daily (or every other day) doses for 5 consecutive days of systemic glucocorticoids, hydroxychloroquine, methotrexate, an immunosuppressant, cyclophosphamide, or IVIG within the previous 3 days for any indication Use of any 2 antihistamine or LTRA within 7 days preceding the screening visit Use of 1 antihistamines at greater-than-licensed doses within 3 days preceding the screening visit istory of malignancy Weight <2 kg Known hypersensitivity to or treatment with omalizumab within the previous year Pregnancy CIU = chronic idiopathic urticaria. 1. Saini et al. J Invest Derm. Advance online publication, 21 August 21; 2. Maurer et al. N Engl J Med. 213;368:92. UAS7 = 7-day urticaria activity score; IVIG = intravenous immunoglobulin ; LTRA = leukotriene receptor antagonist. 1. Saini et al. J Invest Derm. Advance online publication, 21 August 21; 2. Maurer et al. N Engl J Med. 213;368:92. 3

4 D D D D D D D D D D D 9/3/216 Study 1 Primary Efficacy Results: Omalizumab Reduced Mean Weekly Itch Severity Score Mean Weekly Itch Severity Score Week Primary end point Treatment period 6.66 ( 7.7%) a 9. ( 66.6%) a Primary efficacy Treatment analysis completed 15 mg (n=8) Difference in LS mean vs placebo = 2.95 (P=.12 [95% CI:.72, 1.18]) 3 mg (n=81) Difference in LS mean vs placebo = 5.8 (P<.1 [95% CI: 7.9,.1]) Follow-up period Following discontinuation of active treatment, weekly itch severity scores increased to levels similar to placebo + 1 (n=8) Doses qwk Study 2 Primary Efficacy Results: Omalizumab Reduced Mean Weekly Itch Severity Score Mean Weekly Itch Severity Score Week Treatment period Primary end point Primary efficacy analysis Treatment completed 15 mg (n=82) Difference in LS mean vs placebo = 3. (P=.11 [95% CI:.85, 1.2]) 8.1 ( 56.%) a 9.77 ( 7.6%) a Follow-up period Following discontinuation of active treatment, weekly itch severity scores increased to levels similar to placebo 3 mg Difference in LS mean vs placebo =.81 (P<.1 [95% CI: 6.9, 3.13]) + 1 Doses qwk All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. a During study 1 and study 2, the itch severity score was measured twice a day (AM and PM) on a scale of (none) to 3 (severe). The daily itch severity score is the average of the morning and evening scores, and the weekly itch severity score is the sum of the daily itch severity score over 7 days (range, -21). qwk = every weeks. Saini et al. J Invest Derm. Advance online publication, 21 August 21. All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. a During study 1 and study 2, the itch severity score was measured twice a day (AM and PM) on a scale of (none) to 3 (severe). The daily itch severity score is the average of the morning and evening scores, and the weekly itch severity score is the sum of the daily itch severity score over 7 days (range, -21). qwk = every weeks. Maurer et al. N Engl J Med. 213;368:92. Omalizumab Reduced Weekly ive Count Score Omalizumab 3 mg (n=81) Baseline score: 17.1 Mean change in weekly hive count score (points) ( 67.%) P<.1 vs placebo Omalizumab 15 mg (n=8) ( 5.2%) P=.17 vs placebo (n=8) ( 25.%) Study 2 Secondary Efficacy Results: Omalizumab Reduced Weekly ive Count Score Omalizumab 3 mg Baseline score: 15.8 Mean change in weekly hive count score (points) ( 73.8%) P<.1 vs placebo Omalizumab 15 mg (n=82) ( 57.3%) P<.1 vs placebo ( 31.3%) LS mean difference vs placebo (95% CI): 6.93 ( 9.1 to.76) 3. ( 5.57 to 1.32) LS mean difference vs placebo (95% CI): 7.1 ( 9.3 to.9).5 ( 6.7 to 2.) All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. During study 1 and 2, the hive count score was measured twice a day (am and pm) on a scale of (no hives) to 3 (more than 12 hives). The daily hive count score is the average of the morning and evening scores, and the weekly hive count score is the sum of the daily hive count score over 7 days (range, -21). All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. During study 1 and 2, the hive count score was measured twice a day (am and pm) on a scale of (no hives) to 3 (more than 12 hives). The daily hive count score is the average of the morning and evening scores, and the weekly hive count score is the sum of the daily hive count score over 7 days (range, -21). 1. Maurer et al. N Engl J Med. 213;368:92. UAS7= UAS7= UAS7= (no itch and no hives) at week 12 UAS7= (no itch and no hives) at week % Omalizumab 3 mg (n=81) Baseline UAS7 score: 31.3 % of patients 15% Omalizumab 15 mg (n=8) 3.3 9% (n=8) 31.1 % of patients % Omalizumab 3 mg Baseline UAS7 score: % Omalizumab 15 mg (n=82) 31. 5% 31. All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. Saini et al. J Invest Dermatol. 215;135: All patients received their dose of the study drug in addition to stable doses of their pre-randomization 1 antihistamine. 1. Maurer et al. N Engl J Med. 213;368:92.

5 9/3/216 Omalizumab Warnings and Precautions - Anaphylaxis Anaphylaxis has been reported to occur after administration of omalizumab in premarketing clinical trials (.1%) for a different indication and in postmarketing spontaneous reports (at least.2%; 57,3 patients) Observe patients closely for an appropriate period of time after administration of omalizumab, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing spontaneous reports Anaphylaxis occurred with the first dose of omalizumab in 2 patients and with the fourth dose in 1 patient; the time to onset of anaphylaxis was 9 minutes after administration in 2 patients and 2 hours after administration in 1 patient Omalizumab Warnings and Precautions - Malignancy Malignant neoplasms were observed in 2 of,127 (.5%) Omalizumab-treated patients compared with 5 of 2,236 (.2%) control patients in clinical studies of adults and adolescents ( 12 years of age) for a different indication and other allergic disorders, not for chronic idiopathic urticaria The observed malignancies in Omalizumab-treated patients were a variety of 1 types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once, and five other types occurring once each A subsequent 5-year observational study of 5,7 Omalizumab-treated and 2,829 non-omalizumab-treated patients for a different indication found that the incidence rates of primary malignancies (per 1 patient years) were similar in both groups (12.3 vs 13., respectively) Study limitations which include the observational study design, the bias introduced by allowing enrollment of patients previously exposed to Omalizumab (88%), enrollment of patients (56%) while a history of cancer or a premalignant condition were study exclusion criteria, and the high study discontinuation rate (%) preclude definitively ruling out a malignancy risk with Omalizumab Omalizumab Warnings and Precautions - Cardiovascular and Cerebrovascular Events A 5-year observational study was conducted in 5,7 Omalizumab-treated and 2,829 non-omalizumab-treated patients for a different indication, not for chronic idiopathic urticaria, to evaluate the long term safety of Omalizumab, including the risk of malignancy A higher incidence rate (per 1, patient-years) of overall cardiovascular and cerebrovascular serious adverse events (SAEs) was observed in Omalizumabtreated patients (13.) compared to non-omalizumab-treated patients (8.1) Increases in rates were observed for transient ischemic attack (.7 vs.1), myocardial infarction (2.1 vs.8), pulmonary hypertension (.5 vs ), pulmonary embolism/venous thrombosis (3.2 vs 1.5), and unstable angina (2.2 vs 1.), while the rates observed for ischemic stroke and cardiovascular death were similar The results suggest a potential increased risk of serious cardiovascular and cerebrovascular events in patients treated with Omalizumab, however the observational study design, and other study factors limit the ability to quantify the magnitude of the risk Omalizumab Warnings and Precautions - Cardiovascular and Cerebrovascular Events A pooled analysis of 25 randomized double-blind, placebo-controlled clinical trials of 8 to 52 weeks in duration was conducted to further evaluate the imbalance in cardiovascular and cerebrovascular SAEs noted in the observational cohort study described on the previous slide. A total of 3,32 Omalizumab-treated patients and 2,895 placebo-treated patients were included in the pooled analysis. The patients had a mean age of 38 years, and a mean followup duration of 6.8 months. No notable imbalances were observed in the rates of cardiovascular and cerebrovascular SAEs listed on the previous slide. owever, the results of the pooled analysis were based on a low number of events, slightly younger patients, and shorter duration of follow-up than the observational cohort study; therefore, the results are insufficient to confirm or reject the findings noted in the observational cohort study. Omalizumab in patients with severe and refractory solar urticaria: A phase II multicentric study 1 patients with severe & refractory solar urticaria were phototested for MUD and 3-mg omalizumab injected SC qwks intervals x 3 total Proportion of patients achieving significant increase in efficacy end points at weeks 12 and 2 MUD DLQI \ 6 VAS5 UAS7 = Wk 12 Wk 2 Wk 12 Wk 2 Wk 12 Wk 2 Wk 12 Wk 2 2% % % 11% % % 3% 11% DLQI, Dermatology Life Quality Index; MUD, minimal urticarial dose; UAS7, urticarial activity score over 7 d; VAS5, 5% improvement from baseline in solar urticaria severity as measured on a visual analog scale No adverse events Thank you! Aubin et al. J Am Acad Dermatol 216;7;57-5 5