CHRONIC IDIOPATHIC URTICARIA Eveline Y. Wu, MD Assistant Professor of Pediatrics University of North Carolina at Chapel Hill N.C. Children’s Hospital Sarbjit Saini, MD, FAAAAI Associate Professor of Medicine Johns Hopkins University School of Medicine Johns Hopkins Asthma & Allergy Center

History of Present Illness 42-year-old female is referred for further evaluation and management of refractory chronic urticaria Spontaneous onset 6 months ago Describes erythematous, irregular-shaped, and raised swellings of her skin Lesions occur almost daily, but are transient Lesions are pruritic and often disrupt her sleep Lesions do not leave residual bruising or pigmentation No symptoms suggestive of angioedema Other than mild fatigue, no other symptoms suggestive of systemic illness

History of Present Illness No identifiable triggers for her episodes of hives Tried many combinations of loratadine, cetirizine, and fexofenadine, even up to 4 times licensed doses, with inadequate control Also tried montelukast briefly, but developed tremors Treated several times with bursts of oral prednisone with marked relief, but hives rebounded each time after completion of therapy

Medical History Past medical history: No other chronic medical conditions Medications: Fexofenadine 360 mg every morning Cetirizine 20 mg every evening Hydroxyzine 50 mg every 6 hours as needed for breakthrough Allergies: No known allergies Social/environmental history: Lives with her husband and 2 children There is also 1 dog and 1 cat in the home Family history: Mother with hypothyroidism

Examination and Testing Several urticarial lesions involving forearms and trunk Otherwise unremarkable Ancillary studies: Recently had normal CBC/D, blood chemistries, iron profile, and thyroid studies performed by primary care provider for evaluation of fatigue http://www.atlasdermatologico.com.br

Question 1 Of the following, the MOST helpful laboratory finding to confirm the diagnosis is: A) Blood or skin prick tests for environmental allergy B) Blood or skin prick tests for food allergy C) Antinuclear antibody D) Autologous serum skin test E) None of the above ANSWER on Next Slide

Question 1 Of the following, the MOST helpful laboratory finding to confirm the diagnosis is: A) Blood or skin prick tests for environmental allergy B) Blood or skin prick tests for food allergy C) Antinuclear antibody D) Autologous serum skin test E) None of the above CORRECT ANSWER

Chronic Urticaria Defined as urticaria that is intermittently or continuously present for at least 6 weeks Estimated incidence of 1.4% per year Estimated prevalence of 0.5% to 5% Approximately 40% of patients with chronic urticaria have angioedema that may occur simultaneously or separately Most patients have no identifiable trigger and are thus classified as having chronic idiopathic urticaria (CIU) Also referred to as chronic spontaneous urticaria (CSU) Bernstein JA, et al. J Allergy Clin Immunol 2014. Kaplan AP. Ann Allergy Asthma Immunol 2014. Kaplan AP. J Allergy Clin Immunol 2004.

CIU: Laboratory Evaluation Extensive routine testing for exogenous and rare causes of CIU is not warranted Skin or in vitro testing for IgE to inhalants or foods in CIU is also not recommended Limited laboratory testing based on history and physical examination may be appropriate and may include CBC with differential, sedimentation rate and/or C-reactive protein, liver enzymes, and thyroid-stimulating hormone Bernstein JA, et al. J Allergy Clin Immunol 2014.

In patients with CIU, extensive laboratory testing is not cost-effective, is often low yield, and rarely results in changes in management or improved outcomes Bernstein JA, et al. J Allergy Clin Immunol 2014. Tarbox JA, et al. Ann Allergy Asthma Immunol 2011. http://www.choosingwisely.org.

CIU: Management Mainstay of initial treatment is monotherapy with nonsedating, second generation H1 antihistamines Avoidance of potential exacerbating factors, including nonsteroidal anti-inflammatory drugs, heat, tight clothing, among others Approximately 55% of patients with CIU are inadequately responsive or completely refractory to H1 antihistamines Bernstein JA, et al. J Allergy Clin Immunol 2014. Kaplan AP. Ann Allergy Asthma Immunol 2014.

Bernstein JA, et al. J Allergy Clin Immunol 2014.

Agents for Refractory Chronic Urticaria Colchicine (D) Cyclosporine (B) Dapsone (D) Doxepin (D) Hydroxychloroquine (D) Methotrexate (D) Omalizumab (A) Sulfasalazine (D) Bernstein JA, et al. J Allergy Clin Immunol 2014.

Question 2 Which one of the following agents has regulatory approval for the treatment of CIU refractory to H1 antihistamines? A) Cyclosporine B) Hydroxychloroquine C) Omalizumab D) A and C E) None of the above ANSWER on Next Slide

Question 2 Which one of the following agents has regulatory approval for the treatment of CIU refractory to H1 antihistamines? A) Cyclosporine B) Hydroxychloroquine C) Omalizumab D) A and C E) None of the above CORRECT ANSWER

Omalizumab for Refractory CIU Omalizumab is a recombinant humanized monoclonal antibody directed against immunoglobulin E (IgE) Approved in 2014 for adolescents and adults (≥ 12 years of age) with CIU who remain symptomatic despite H1 antihistamine treatment Two approved doses: 150 mg or 300 mg SC every 4 weeks Efficacy and safety of omalizumab in refractory CIU rigorously investigated in three phase III clinical trials Saini SS, et al. J Invest Dermatol 2015. Kaplan A, et al. J Allergy Clin Immunol 2013. Maurer M, et al. N Engl J Med 2013.

Omalizumab for CIU: Study Designs Casale TB, et al. J Allergy Clin Immunol Pract 2015.

ASTERIA I 40-week, randomized, double-blind, placebo-controlled study Objective was to evaluate safety and efficacy of omalizumab over longer duration and as add-on therapy in patients with CIU refractory to approved doses of H1 antihistamines Participants randomized to placebo or omalizumab 75 mg, 150 mg, or 300 mg doses subcutaneously every 4 weeks for 24 weeks (6 doses total) 319 patients were randomized, and 262 (82.1%) completed the study Use of additional H1 antihistamine allowed after week 12 Follow-up period of 16 weeks with no omalizumab given Saini SS, et al. J Invest Dermatol 2015.

ASTERIA I Patient-reported outcomes recorded in a diary Itch severity, number of hives, and size of largest hive (all scored 0-3) recorded every morning and evening Sleep interference (range 0-3), activity interference (range 0-3), rescue medication (range 0-9), angioedema (yes or no), angioedema treatment, and healthcare contacts recorded once daily Diary compliance was high (>90%) and was similar among all groups The daily Urticaria Activity Score (UAS) is an average of the morning and evening scores for number of hives and itch severity (range 0-6) UAS7 is the sum of the daily UAS over 7 days (range 0-42) Weekly Itch Severity Score (ISS) is the sum of the daily ISS over 7 days (range 0-21) Saini SS, et al. J Invest Dermatol 2015.

ASTERIA I – Outcomes Primary end point was change from baseline in weekly ISS at week 12 Secondary end points Change from baseline in UAS7 at week 12 Change from baseline in weekly hive number score at week 12 Time to minimally important difference (MID) response (≥5 point decrease) in weekly ISS Proportion of patients with UAS7≤6 at week 12 Proportion of weekly ISS MID responders at week 12 Change from baseline in weekly size of largest hive score at week 12 Change in Dermatology Life Quality Index (DLQI) score at week 12 Proportion of angioedema-free days during weeks 4 to 12 Proportion of patients with complete response (UAS7=0) at week 12 Saini SS, et al. J Invest Dermatol 2015.

ASTERIA I – Change in Weekly ISS At week 12, mean weekly ISS was significantly decreased from baseline for each omalizumab group as compared to placebo Reductions in weekly ISS observed as early as week 1 in all groups Saini SS, et al. J Invest Dermatol 2015.

ASTERIA I – Responder Analysis Proportion of patients achieving well-controlled disease (UAS7≤6) at week 12 was significantly greater in each omalizumab group as compared to placebo Proportion of patients achieving complete response (UAS7=0) at week 12 was significantly greater in omalizumab 300 mg group as compared to placebo Saini SS, et al. J Invest Dermatol 2015.

ASTERIA II 28-week, randomized, double-blind, placebo-controlled study Objective was to evaluate safety and efficacy of omalizumab as add-on therapy in patients with CIU refractory to approved doses of H1 antihistamines Participants randomized to placebo or omalizumab 75 mg, 150 mg, or 300 mg doses subcutaneously every 4 weeks for 12 weeks only (3 doses total) 323 patients were randomized, and 290 (89.8%) completed the study Follow-up period of 16 weeks with no omalizumab given Patients continued prerandomization H1 antihistamine doses during treatment, and use of additional H1 antihistamine was allowed only during 16-week follow-up period Maurer M, et al. N Engl J Med 2013.

ASTERIA II – Outcomes Patient-reported outcomes recorded in a diary Itch severity, number of hives, and size of largest hive (all scored 0-3) recorded every morning and evening Sleep interference (range 0-3), activity interference (range 0-3), rescue medication (range 0-9), angioedema (yes or no), angioedema treatment, and healthcare contacts recorded once daily Diary compliance was high (>85%) and was similar among all groups Primary end point was change from baseline in weekly ISS at week 12 Secondary end points were the same to those analyzed in ASTERIA I trial Maurer M, et al. N Engl J Med 2013.

ASTERIA II – Change in Weekly ISS At week 12, mean weekly ISS was significantly decreased from baseline for omalizumab 300 mg and 150 mg groups, but not omalizumab 75 mg group, as compared to placebo Maurer M, et al. N Engl J Med 2013.

ASTERIA II – Change in Hive Number At week 12, mean weekly hive number score was significantly decreased from baseline for omalizumab 300 mg and 150 mg groups as compared to placebo Maurer M, et al. N Engl J Med 2013.

GLACIAL 40-week, randomized, double-blind, placebo-controlled study Objective was to evaluate safety and efficacy of omalizumab in patients already receiving standard-of-care treatments used in clinical practice for refractory CIU Included patients with CIU who remained symptomatic despite treatment with up to 4 times approved doses of H1 antihistamines plus an H2 antihistamine, a leukotriene receptor antagonist (LTRA), or both Participants randomized in a 1:3 ratio to receive placebo or omalizumab 300 mg subcutaneously every 4 weeks for 24 weeks (6 doses total) 335 patients were randomized, and 290 (86.3%) completed the study During treatment, patients continued prerandomization doses of H1 antihistamines, H2 antihistamine, and LTRA Follow-up period of 16 weeks with no omalizumab given Kaplan A, et al. J Allergy Clin Immunol 2013.

GLACIAL – Outcomes Patient-reported outcomes recorded in a diary Itch severity, number of hives, and size of largest hive (all scored 0-3) recorded every morning and evening Sleep interference (range 0-3), activity interference (range 0-3), rescue medication (range 0-9), angioedema (yes or no), angioedema treatment, and healthcare contacts recorded once daily Diary compliance was high (>97%) and was similar among all groups Primary end point was safety of omalizumab 300 mg compared to placebo, assessed by incidence and severity of adverse events (AEs) and serious AEs and change in vital signs and pre-specified clinical laboratory evaluations Primary efficacy end point was change from baseline in weekly ISS at week 12 Secondary efficacy end points were the same to those analyzed in ASTERIA I and II trials Kaplan A, et al. J Allergy Clin Immunol 2013.

GLACIAL – Change in Weekly ISS At week 12, mean weekly ISS was significantly decreased from baseline for omalizumab 300 mg group as compared to placebo Kaplan A, et al. J Allergy Clin Immunol 2013.

GLACIAL – Responder Analysis (A) Proportion of patients achieving well-controlled disease (UAS7≤6) at week 12 was significantly greater in omalizumab 300 mg group as compared to placebo (B) Proportion of patients achieving complete response (UAS7=0) at week 12 was significantly greater in omalizumab 300 mg group as compared to placebo Kaplan A, et al. J Allergy Clin Immunol 2013.

GLACIAL – Omalizumab Safety During 40-week study period, incidence and severity of AEs and serious AEs were similar between omalizumab and placebo groups No serious AEs were suspected to be caused by study drug No clinically meaningful trends in laboratory parameters or vital signs associated with omalizumab therapy Kaplan A, et al. J Allergy Clin Immunol 2013.

Other Key Study Results In ASTERIA I and GLACIAL, omalizumab 300 mg group met all 9 secondary efficacy end points In ASTERIA II, omalizumab 300 mg and 150 mg groups met all secondary efficacy end points Exception is angioedema-free days in weeks 4 through 12 for omalizumab 150 mg group During 16-week follow-up period, mean weekly ISS did increase in each omalizumab group to values similar to those in placebo group, but did not return to baseline Duration of suppression in weekly ISS after week 12 was greater in patients receiving higher omalizumab doses Saini SS, et al. J Invest Dermatol 2015. Kaplan A, et al. J Allergy Clin Immunol 2013. Maurer M, et al. N Engl J Med 2013.

Omalizumab for Refractory CIU Omalizumab is safe and effective in reducing symptoms of refractory CIU regardless of background therapy In a post hoc analysis, efficacy and safety data from the three phase III clinical trials were pooled and analyzed Regardless of background therapy for CIU, similar treatment effect sizes were observed in reduction in mean weekly ISS and other multiple efficacy end points Regardless of background therapy for CIU, similar adverse events were observed and omalizumab was well tolerated Safety profile was similar to that of omalizumab in allergic asthma without any new safety concerns identified Casale TB, et al. J Allergy Clin Immunol Pract 2015.

No increased incidence rate of primary malignancy FDA approved label changes in 2014 for omalizumab after review of 5-year safety study in patients receiving omalizumab for moderate to severe asthma Possible increased risk of cerebrovascular and cardiovascular serious adverse events with omalizumab Transient ischemic attacks, myocardial infarction, unstable angina, pulmonary embolism/venous thrombosis, pulmonary hypertension Signal not corroborated by a pooled analysis of 25 randomized double-blind clinical trials comparing omalizumab to placebo Information added to the Adverse Reactions section No increased incidence rate of primary malignancy 12.3/1,000 patient years in omalizumab-treated versus 13.0/1,000 patient years in non-omalizumab treated patients Information added to the Warnings and Precautions section http://www.fda.gov/Drugs/DrugSafety

Question 3 After discussion with you and reading further about omalizumab, your patient agrees to proceed with omalizumab therapy. Which of the following assessments prior to starting treatment would be most appropriate? A) Pulmonary function tests B) Blood or skin prick tests for environmental allergy C) Total IgE level D) A and C E) None of the above CORRECT ANSWER: E ANSWER on Next Slide

Question 3 After discussion with you and reading further about omalizumab, your patient agrees to proceed with omalizumab therapy. Which of the following assessments prior to starting treatment would be most appropriate? A) Pulmonary function tests B) Blood or skin prick tests for environmental allergy C) Total IgE level D) A and C E) None of the above CORRECT ANSWER: E CORRECT ANSWER

Omalizumab for CIU – Key Points Approved for chronic idiopathic urticaria in adolescents and adults (≥ 12 years of age) who remain symptomatic despite H1 antihistamine treatment 2 approved doses: 150 mg or 300 mg SC every 4 weeks Dosing and treatment response are not dependent on serum IgE level, atopic history, or body weight No testing required prior to initiation of omalizumab treatment In CIU, omalizumab has a quick onset with dose-response observed in efficacy and time to improvement

Omalizumab for CIU – Key Points Administered in doctor’s office with monitoring according to recommended guidelines due to risk for anaphylaxis All patients should be prescribed epinephrine autoinjector All patients need observation for 2 hours for the first 3 doses Potential increased risk for cerebrovascular and cardiovascular events No increased incidence rate for primary malignancy All patients need observation for 2 hours after administration for the first 3 doses, just like as for asthma indication

Omalizumab for CIU – Key Points Therapy duration in CIU has not been evaluated, though it has been used safely for 12 and 24 weeks in clinical trials Periodically reassess the need for continued therapy Rebound in urticaria is common after discontinuation of omalizumab, suggesting it does not substantially modify the underlying disease process Duration of suppression of urticaria is longer with higher omalizumab doses Mechanism of action of omalizumab in refractory CIU is not yet fully understood