Selecting among biologic agents in persistently uncontrolled asthma

일부 환자들은 고용량 흡입 글루코코르티코이드와 1개 이상의 nonglucocorticoid controller 약물에도 불구하고 천식이 지속적으로 조절되지 않습니다. 이 환자들 중 일부에게 나이, 혈청 IgE 수치, eosinophilic phenotype에 따라 anti-immunoglobulin E (anti-IgE) therapy, anti-interleukin-5 (anti-IL-5), anti-IL-4 therapy를 시행할 수 있습니다. Anti-IgE agent인 omalizumab은 6세 이상 & moderate-to-severe persistent allergic asthma & IgE level of 30 ~ 700 IU/mL & perennial allergen에 대한 allergen skin 또는 specific IgE tests 양성 & inhaled glucocorticoid treatment에 불완전한 증상 호전을 보이는 환자에서 사용하도록 FDA에 승인되었습니다. Interleukin (IL)-5는 eosinophil hematopoiesis의 potent mediator이고 기도에서 eosinophilic inflammation에 기여하는 pro-eosinophilic cytokine입니다. Mepolizumab과 reslizumab은 anti-IL-5 monoclonal antibodies이고 benralizumab은 anti-IL-5 receptor alpha antibody입니다. Mepolizumab은 blood eosinophil counts > 150/microL인 severe asthma 환자에서 exacerbations을 줄입니다. Mepolizumab은 12세 이상이고 eosinophilic phenotype이 있는 severe asthma의 add-on, maintenance treatment를 위해서 FDA와 NICE에 승인되었습니다. FDA는 특정 threshold를 정하지 않은 반면 NICE는 absolute blood eosinophil ≥300/microL를 권고합니다. 임상 시험 데이터에 따르면 이 약제의 효능에는 absolute blood eosinophil count ≥ 150/microL을 필요로 합니다. Reslizumab은 18세 이상이고 eosinophilic phenotype이 있는 severe asthma의 add-on, maintenance therapy를 위해 FDA에 승인되었습니다. Benralizumab은 12세 이상 & eosinophilic phenotype & severe asthma 환자의 add-on therapy로서 FDA에 승인된 IL-5 receptor alpha에 대한 cytotoxic monoclonal antibody입니다.

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Our approach to selection of biologic agents for add-on therapy for severe asthma in adolescents and adults*

Agent and target	US FDA-approved age	Patient selection	Route	Dose	Dosing interval	Adverse effects
For patients with elevated IgE and sensitivity to perennial allergens¶
Omalizumab (anti-IgE)	≥6 years	IgE 30 to 700 int. units/mL in United States; 30 to 1500 int. units/mL in Europe	SC	Based on weight and IgE Doses ≥225 mg need to be divided over >1 injection site Maximal dose: 375 mg every 2 weeks in United States; 600 mg every 2 weeks in Europe	2 to 4 weeks depending on IgE level and body weight	Local injection site reaction (severe 12%), usually within 1 hour Thromboembolic disease ≤3% Anaphylaxis, immediate or delayed <1% Antibody development (<1%)
For patients with eosinophilic phenotype¶
Mepolizumab (anti-IL-5)	≥6 years	Peripheral blood eosinophils ≥150/microL	SC	100 mgΔ	4 weeks	Headache (19%) Local injection site reaction (8 to 15%) Anaphylaxis: immediate or delayed <1% Human anti-human neutralizing antibody (<1%) Herpes zoster (<1%): Administration of zoster vaccine is suggested prior to initiation
Benralizumab (anti-IL-5 receptor alpha)	≥12 years	Peripheral blood eosinophils ≥300/microL	SC	30 mg	4 weeks for first 3 doses, then 8 weeks	Human anti-human antibody development (13%; neutralizing 12%) Headache 8% Fever 3% Hypersensitivity (anaphylaxis, angioedema, urticaria; 3%): typically within hours of injection but can be delayed (3%)
Dupilumab (anti-IL-4 receptor subunit alpha)§	≥12 years	Peripheral blood eosinophils ≥150/microL	SC◊	First week, 2 doses of 200 mg (total 440 mg), then 200 mg every 2 weeks	2 weeks	Human anti-human antibody development in patients receiving the 300 mg dose every 2 weeks for 52 weeks (6%; 2% neutralizing antibodies) and in patients taking 200 mg dose every 2 weeks for 52 weeks (9%; 4% neutralizing antibodies) Transient eosinophilia (4%); over 3000 cells/mL (1.2%) Anaphylaxis and other hypersensitivity reactions (<1%) Injection site reactions, conjunctivitis, keratitis, oral and other herpes simplex viral infections
				First week, 2 doses of 300 mg (total 600 mg), then 300 mg every 2 weeks§	2 weeks
Reslizumab (anti-IL-5)	≥18 years	Peripheral blood eosinophils ≥400/microL	IV	3 mg/kg	4 weeks	Human anti-human antibody development (5%) Anaphylaxis 0.3% during infusion or within 30 minutes after infusion; may occur as early as second dose or can be delayed Transient increase in creatine phosphokinase (20%)

These agents are for use in patients with uncontrolled asthma despite regular use of a combination of medium-to-high dose inhaled glucocorticoid and long-acting beta-2 agonists and FEV1 <80% predicted. Refer to UpToDate topic on management of severe asthma for additional details regarding choice of therapy and administration.

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IgE: total serum immunoglobulin E; IL-5: interleukin-5; SC: subcutaneous injection; IV: intravenous infusion; FEV1: forced expiratory volume in one second.

* Helminth infection should be excluded or treated prior to initiation of therapy. These agents should be administered in a setting prepared to handle anaphylaxis. Patients should be observed for 2 hours after each of the first 3 injections and for 30 minutes after each subsequent injection. It is advised that patients receiving omalizumab should carry an epinephrine autoinjector for at least 24 hours after each injection due to late occurrences of anaphylaxis.

¶ For patients who meet criteria for both omalizumab and anti-eosinophil medications, selection of a biologic agent may be based on factors such as clinician experience with the agent, assessment of relative contributions of IgE-mediated allergic asthma and eosinophil mediated asthma, frequency of dosing, and availability.

Δ For children age 6 to 11 years, the dose of mepolizumab is 40 mg, subcutaneously, every 4 weeks.

◊ Dupilumab can be administered at home after appropriate training.

§ The higher dose of dupilumab is advised for patients with oral glucocorticoid-dependent asthma or comorbid moderate-to-severe atopic dermatitis.

 

REF. UpToDate 2020.05.24