Background

Omalizumab is being reviewed for the treatment of chronic idiopathic urticaria (CIU) in patients 12 years of age and older who remain symptomatic despite H₁ antihistamine treatment.² The recommended dose is 150 mg or 300 mg administered once every four weeks by subcutaneous injection. Prescribers are advised to periodically reassess the need for continued therapy.²

The price of omalizumab is $612 per 150 mg single-use vial,³ which corresponds to an annual cost of $7,956 (150 mg dose) and $15,912 (300 mg dose). The manufacturer is seeking reimbursement in line with the Health Canada indication and added the following criteria: disease duration greater than or equal to six months, moderate to severe CIU (Urticaria Activity Score over seven days [UAS7] ≥ 16 or Dermatology Life Quality Index ≥ 10), and CIU patients who remain symptomatic (presence of hives or associated itching) despite H₁ antihistamine treatment. Further, the manufacturer noted that response to treatment should be assessed 12 weeks following omalizumab initiation. For patients initiated on 150 mg every four weeks and who do not adequately respond by week 12, consideration should be given to increase the dose to 300 mg every four weeks. Response to treatment should be reassessed 12 weeks thereafter.

Omalizumab 150 mg was previously reviewed by the Canadian Expert Drug Advisory Committee (CEDAC, now the Canadian Drug Expert Committee [CDEC]) for the treatment of moderate to severe persistent asthma in adults and adolescents whose symptoms are inadequately controlled with inhaled corticosteroids and received a “do not list” recommendation.⁴

A cost-utility analysis was submitted comparing omalizumab plus standard of care (SOC) to SOC alone, over a 20-year time horizon and under the perspective of a publicly funded health care system, in adults and adolescents 12 years of age and older with moderate to severe CIU who remain symptomatic despite standard of care treatment. Three base-case scenarios were presented:

• Scenario 1 compared omalizumab 300 mg as a third- or fourth-line drug added on to SOC (defined as up to four times the standard H₁ antihistamine dose combined with H₂ antagonists, leukotriene receptor antagonists [LTRAs], or both) with SOC alone. Efficacy and safety data were sourced from the GLACIAL⁵ trial.
• Scenario 2 compared omalizumab 150 mg as a second-line drug added on to SOC (defined as standard H₁ antihistamine dose) with SOC alone. Efficacy and safety data were sourced from ASTERIA I⁶ and ASTERIA II.⁷
• Scenario 3 compared omalizumab 300 mg as a second-line drug added on to SOC (defined as standard H₁ antihistamine dose) with SOC alone. Efficacy and safety data were sourced from ASTERIA I⁶ and ASTERIA II.⁷

The economic submission was based on a Markov model with five key health states based on UAS7. Patients began in either the moderate or severe urticaria health states and moved through the model every four weeks for 24 weeks. Patients who responded to treatment at 24 weeks (UAS7 ≤ 6) were eligible for re-treatment upon relapse (UAS7 ≥ 16). Progression through the model was also driven by whether patients experienced a spontaneous remission of symptoms or dropped out. Utilities were obtained from pooled data from GLACIAL, ASTERIA I, and ASTERIA II.

Summary of Identified Limitations and Key Results

The CADTH Common Drug Review (CDR) identified several limitations with the submitted model, the most important ones being the uncertain long-term clinical efficacy of omalizumab upon relapse, the lack of consideration of a treatment waning effect, and uncertainty with the natural remission rate. There is no evidence to suggest that the efficacy of omalizumab over repeated treatments is maintained. Further, CIU is a naturally remitting disease, and some sources reported natural remission rates of more than 80% within 10 years.⁸ CDR was able to undertake reanalyses varying the following parameters: reducing the time horizon to 10 years (to account for potential treatment waning and the fact that a majority of patients might have complete resolution of symptoms by 10 years); assuming initial response probabilities upon relapse (instead of assuming response would be similar to that of initial treatment); applying higher spontaneous remission rates; assuming re-treatment of mild patients who relapsed after the first course of treatment; equating the costs associated with LTRAs to $0; and altering the proportion of males to females to determine all-cause mortality rates. When omalizumab is used as a third- or fourth-line drug (Scenario 1), a combined reanalysis of these limitations resulted in an incremental cost-utility ratio (ICUR) for omalizumab 300 mg plus SOC versus SOC alone of $120,009 per quality-adjusted life-year (QALY). Further, upon stratifying by severity of CIU (severe or moderate), the ICUR ranged from $88,480 per QALY when 100% of patients initiated treatment in the severe health state (UAS7 28 to 42) to $419,033 per QALY when 100% of patients initiated treatment in the moderate health state (UAS7 16 to 27). If omalizumab is used as a second-line drug (as an add-on to H₁ antihistamines), the ICUR was $137,192 per QALY. Upon stratifying by severity, the ICUR was $79,192 per QALY for the severe health state; for the moderate health state, omalizumab 300 mg plus SOC was dominated by SOC (less effective, more costly).

Conclusions

There is significant clinical uncertainty with omalizumab efficacy upon re-treatment. CDR reanalyses showed that at a dose of 300 mg by subcutaneous injection every four weeks, when omalizumab is used as either a second-line drug or a third- or fourth-line drug added on to SOC in patients refractory to H₁ antihistamines, the ICURs for omalizumab plus SOC compared with SOC alone were above $120,000 per QALY. A price reduction of 50% to 60% would be needed for the ICUR of omalizumab 300 mg plus SOC to be reduced to commonly accepted thresholds. Further, results of the stratified analysis suggest that the ICURs are substantially higher in moderate versus severe patients.