Karin Rosén

Oma liz u mab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria

BACKGROUND Many patients with chronic idiopathic urticaria (also called chronic spontaneous urticaria) do not have a response to therapy with H-antihistamines, even at high doses. In phase 2 trials, omalizumab, an anti-IgE monoclonal antibody [corrected] that targets IgE and affects mast-cell and basophil function, has shown efficacy in such patients. METHODS In this phase 3, multicenter, randomized, double-blind study, we evaluated the efficacy and safety of omalizumab in patients with moderate-to-severe chronic idiopathic urticaria who remained symptomatic despite H-antihistamine therapy (licensed doses). We randomly assigned 323 patients to receive three subcutaneous injections, spaced 4 weeks apart, of omalizumab at doses of 75 mg, 150 mg, or 300 mg or placebo, followed by a 16-week observation period. The primary efficacy outcome was the change from baseline in a weekly itch-severity score (ranging from 0 to 21, with higher scores indicating more severe itching). RESULTS The baseline weekly itch-severity score was approximately 14 in all four study groups. At week 12, the mean (±SD) change from baseline in the weekly itch-severity score was -5.1±5.6 in the placebo group, -5.9±6.5 in the 75-mg group (P=0.46), -8.1±6.4 in the 150-mg group (P=0.001), and -9.8±6.0 in the 300-mg group (P<0.001). Most prespecified secondary outcomes at week 12 showed similar dose-dependent effects. The frequency of adverse events was similar across groups. The frequency of serious adverse events was low, although the rate was higher in the 300-mg group (6%) than in the placebo group (3%) or in either the 75-mg or 150-mg group (1% for each). CONCLUSIONS Omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H-antihistamines. (Funded by Genentech and Novartis Pharma; ClinicalTrials.gov number, NCT01292473.).

Exploring the Effects of Omalizumab in Allergic Asthma

RATIONALE For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects. OBJECTIVES To assess the potential of fractional exhaled nitric oxide (FE(NO)), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab. METHODS The EXTRA omalizumab study enrolled patients (aged 12-75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to FE(NO), blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint). MEASUREMENTS AND MAIN RESULTS A total of 850 patients were enrolled. Data were available from 394 (46.4%), 797 (93.8%), and 534 (62.8%) patients for FE(NO), blood eosinophils, and serum periostin, respectively. After 48 weeks of omalizumab, reductions in protocol-defined exacerbations were greater in high versus low subgroups for all three biomarkers: FE(NO), 53% (95% confidence interval [CI], 37-70; P = 0.001) versus 16% (95% CI, -32 to 46; P = 0.45); eosinophils, 32% (95% CI, 11-48; P = 0.005) versus 9% (95% CI, -24 to 34; P = 0.54); and periostin, 30% (95% CI, -2 to 51; P = 0.07) versus 3% (95% CI, -43 to 32; P = 0.94). CONCLUSIONS The difference in exacerbation frequency between omalizumab and placebo was greatest in the three high-biomarker subgroups, probably associated with the greater risk for exacerbations in high subgroups. Additional studies are required to explore the value of these biomarkers in clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT00314574).

Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy

BACKGROUND Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1-antihistamines along with 1 or more add-on therapies. OBJECTIVES We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H₁-antihistamines at up to 4 times the approved dose plus H₂-antihistamines, leukotriene receptor antagonists, or both. METHODS In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. RESULTS The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was -8.6 (95% CI, -9.3 to -7.8) in the omalizumab group compared with -4.0 (95% CI, -5.3 to -2.7) in the placebo group (P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. CONCLUSION Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H₁-antihistamines (up to 4 times the approved dose) plus H₂-antihistamines, leukotriene receptor antagonists, or both.

Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICS) and long-acting β(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING 193 investigational sites in the United States and 4 sites in Canada. PATIENTS 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE Genentech and Novartis Pharmaceuticals.

A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine–refractory chronic idiopathic urticaria

BACKGROUND Proof-of-concept studies with omalizumab in patients with chronic idiopathic urticaria (CIU) have shown significant decreases in mean urticaria activity scores (UASs). OBJECTIVE We sought to evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite concomitant H(1)-antihistamine therapy. METHODS This phase II, prospective, double-blind, placebo-controlled, dose-ranging study investigated omalizumab in patients aged 12 to 75 years in the United States and 18 to 75 years in Germany with a UAS over 7 days (UAS7) of 12 or greater despite antihistamine therapy. Patients were randomized 1:1:1:1 to receive a single subcutaneous dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H(1)-antihistamine. The primary efficacy outcome was change from baseline to week 4 in UAS7. Patients were followed for an additional 12 weeks to monitor safety. RESULTS Ninety patients from the United States or Germany were enrolled. Both the 300-mg omalizumab group (-19.9 vs -6.9, P < .001) and the 600-mg omalizumab group (-14.6 vs -6.9, P = .047) showed greater improvement versus the placebo group in UAS7. No meaningful difference was observed for the 75-mg omalizumab group. Similar results were seen for key secondary end points of weekly hive and itch scores. Onset of effect occurred after 1 to 2 weeks. Omalizumab was well tolerated, and the incidence of adverse events was similar across treatment groups. CONCLUSION This study demonstrated that a fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H(1)-antihistamines.

Efficacy and Safety of Omalizumab in Patients with Chronic Idiopathic/Spontaneous Urticaria Who Remain Symptomatic on H1 Antihistamines: A Randomized, Placebo-Controlled Study

ASTERIA I was a 40-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous omalizumab as add-on therapy for 24 weeks in patients with chronic idiopathic urticaria/spontaneous urticaria (CIU/CSU) who remained symptomatic despite H1 antihistamine treatment at licensed doses. Patients aged 12–75 years with CIU/CSU who remained symptomatic despite treatment with approved doses of H1 antihistamines were randomized (1:1:1:1) in a double-blind manner to subcutaneous omalizumab 75 mg, 150 mg, or 300 mg or placebo every 4 weeks for 24 weeks followed by 16 weeks of follow-up. The primary end point was change from baseline in weekly itch severity score (ISS) at week 12. Among randomized patients (N=319: placebo n=80, omalizumab 75 mg n=78, 150 mg n=80, 300 mg n=81), 262 (82.1%) completed the study. Compared with placebo (n=80), mean weekly ISS was reduced from baseline to week 12 by an additional 2.96 points (95% confidence interval (CI): −4.71 to −1.21; P=0.0010), 2.95 points (95% CI: −4.72 to −1.18; P=0.0012), and 5.80 points (95% CI: −7.49 to −4.10; P<0.0001) in the omalizumab 75-mg (n=77), 150-mg (n=80), and 300-mg groups (n=81), respectively. The omalizumab 300-mg group met all nine secondary end points, including a significant decrease in the duration of time to reach minimally important difference response (⩾5-point decrease) in weekly ISS (P<0.0001) and higher percentages of patients with well-controlled symptoms (urticaria activity score over 7 days (UAS7) ⩽6: 51.9% vs. 11.3% P<0.0001) and complete response (UAS7=0: 35.8% vs. 8.8% P<0.0001) versus placebo. During the 24-week treatment period, 2 (2.9%), 3 (3.4%), 0, and 4 (5.0%) patients in the omalizumab 75-mg, 150-mg, 300-mg, and placebo groups, respectively, experienced a serious adverse event. Omalizumab 300 mg administered subcutaneously every 4 weeks reduced weekly ISS and other symptom scores versus placebo in CIU/CSU patients who remained symptomatic despite treatment with approved doses of H1 antihistamines.

High eosinophil count: A potential biomarker for assessing successful omalizumab treatment effects

High No. of protocol-defined asthma exacerbations, n (%) 0 41 (80.4) 25 (62.5) 1 9 (17.6) 9 (22.5) >_2 1 (2.0) 6 (15.0) Unadjusted exacerbation rate* 0.25 0.59 Poisson regression§ Ratio of exacerbation rates (95% CI) 0.41 (0.20-0.82) P value .0125 Low (n 5 56) (n 5 70) No. of protocol-defined asthma exacerbations, n (%) 0 48 (85.7) 60 (85.7) 1 7 (12.5) 9 (12.9) >_2 1 (1.8) 1 (1.4) Unadjusted exacerbation rate* 0.17 0.16 Poisson regression Ratio of exacerbation rates§ (95% CI) 1.07 (0.45-2.53) P value .8807

Development of a daily diary for patients with chronic idiopathic urticaria

BACKGROUND Chronic idiopathic urticaria (CIU) is a disease characterized by itching and skin hives or wheals of unknown cause that vary in size and last for at least 6 weeks. The criterion standard for measuring disease activity is the urticaria activity score (UAS). However, content validity of the UAS has not been previously reported. OBJECTIVES To identify outcomes important to patients with CIU, create an urticaria patient daily diary based on the UAS and input from patients, and assess its content validity. METHODS A qualitative research study was conducted in 2 stages using one-on-one telephone interviews of patients with CIU. In stage 1, patients were asked to discuss the impact of CIU on aspects of their life and to evaluate the content of the UAS. On the basis of this information, a patient daily diary, including UAS items, was developed. In stage 2, patients were interviewed to determine whether the urticaria patient daily diary was comprehensive and easily understood. RESULTS Stage 1 interviews showed that CIU has an extensive impact on patients, from the primary symptoms of itching, hives, and angioedema to the broader aspects of sleep and health-related quality of life. Stage 2 interviews demonstrated the content validity of the urticaria patient daily diary and resulted in minor modifications to the diary. When the urticaria patient daily diary was administered in conjunction with the Dermatology Life Quality Index and Medical Outcomes Study Sleep Scale, patients considered the assessment to be comprehensive, although some recommendations were made to include more items on emotional issues and other aspects of angioedema. CONCLUSIONS The final urticaria patient daily diary is an easy-to-administer, comprehensive assessment of symptoms for CIU patients. Future research is needed to establish its additional psychometric properties.

Erratum: Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: A randomized, placebo-controlled study (Journal of Investigative Dermatology (2015) 135 (67-75)) DOI: 10.1038/jid.2014.306)

Citation for pulished version (APA): Saini, S. S., Bindslev-Jensen, C., Maurer, M., Grob, J-J., Bülbül Baskan, E., Bradley, M. S., ... Rosén, K. (2015). Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized, placebo-controlled study. Journal of Investigative Dermatology, 135(1), 67-75. https://doi.org/10.1038/jid.2014.306

A randomized multicenter study evaluating Xolair persistence of response after long-term therapy

Background Few data are available to assist clinicians with decisions regarding long‐term use of asthma therapies, including omalizumab. Objective We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long‐term omalizumab treatment. Methods Evaluating the Xolair Persistency Of Response After Long‐Term Therapy (XPORT) was a randomized, double‐blind, placebo‐controlled withdrawal study that included subjects with moderate‐to‐severe persistent asthma receiving long‐term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol‐defined severe asthma exacerbation. The secondary outcome was time to first protocol‐defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores. Results Significantly more subjects in the omalizumab group (67%) had no protocol‐defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol‐defined exacerbation analysis revealed a significantly different between‐group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, −1.16 [4.14] vs placebo, −2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high‐affinity IgE receptor. No safety concerns were noted. Conclusion Continuation of omalizumab after long‐term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk.