Severe asthma in the US population and eligibility for mAb therapy

To the Editor:

Asthma is a disease with high morbidity. In the United States, about 26 million individuals have asthma, accounting for 1.7 million emergency department visits and 440,000 hospitalizations annually.¹ Most patients with severe asthma respond to inhaled corticosteroid (ICS) therapy combined with short-acting beta-agonists or long-acting beta-agonists (LABAs); however, about 3.6% to 10% of subjects with asthma have severe disease refractory to maintenance therapy with ICS, and account for a disproportionate percentage of asthma-related costs.^2,3 The development of mAbs for the treatment of asthma has revolutionized the care of these patients with severe asthma.

At the time of this writing, the Food and Drug Administration has approved 5 biologics for the treatment of severe asthma. These are omalizumab, an anti-IgE antibody for allergic asthma; 3 anti–IL-5 or receptor antagonists (anti–IL-5; mepolizumab, reslizumab, and benralizumab) for severe eosinophilic asthma; and dupilumab, an IL-4 receptor alpha antagonist approved for the treatment of moderate to severe eosinophilic asthma or corticosteroid-dependent asthma.⁴ Our goal was to evaluate the percentage of patients with asthma in the United States who met criteria for eligibility for any of these mAbs and to assess the degree of overlap of participants eligible for these biologics.

We identified participants with severe asthma from the 2005–2012 National Health and Nutrition Examination Survey (NHANES) to generate a nationally representative sample. Participants with severe asthma were 6 years or older with current asthma; on ICS combined with LABA or an anticholinergic for at least a year, or on oral corticosteroids for at least 3 months at the time of interview; and had 1 or more exacerbation in the previous year requiring an emergency room or urgent care center visit. We determined whether subjects were eligible for a biologic on the basis of Food and Drug Administration–approved indications. For omalizumab, this included age, weight, IgE, and perennial sensitivity. Because only NHANES 2005–2006 had IgE and perennial sensitivity data available, we imputed these for the period 2007 to 2012. For the anti–IL-5s and dupilumab, eligibility included age and eosinophil count. For dupilumab, eligibility also included patients on oral steroid for at least 90 days at the time of the interview. We conducted sensitivity analyses to evaluate the impact of varying duration of ICS/LABA use and oral corticosteroid use on proportion of patients classified as having severe asthma. Full details of methods can be found in this article’s Methods section in the Online Repository at www.jacionline.org.

There were 3039 survey participants with current asthma. There was a female preponderance (63% [60–66]). Almost a quarter (22% [19–27]) had an emergency room or urgent care visit for asthma in the previous year. Ninety-nine (3.1% [2.3–4.2]) participants met criteria for severe asthma (see Table E1 and Fig E1 in this article’s Online Repository at www.jacionline.org). This proportion was robust to various definitions of severity based on duration of ICS/LABA or oral corticosteroid use (see Fig E2 in this article’s Online Repository at www.jacionline.org). Seventy-six percent of participants younger than 18 years had eosinophil counts of greater than 150 cells/mm³, and 40% of these participants had eosinophil counts of greater than or equal to 400 cells/mm³, compared with 67% and 25%, respectively, of those 18 years or older (Table I). Table E2 in this article’s Online Repository at www.jacionline.org presents results of imputation of IgE and perennial sensitivity.

Table I.

Proportion of participants with asthma and severe asthma eligible for mAb therapy

mAb eligibility		Weighted % (95% CI)*
	Overall	≤18 y	>18 y
Eligible for at least 1 biologic
All asthma (n = 3039)	2.8 (1.9–3.7)	2.6 (1.4–3.9)	2.8 (1.8–3.8)
Severe asthma (n = 104)	84.7 (73.0–96.4)	89.7 (74.1–97.9)	83.9 (70.4–97.4)
Eligible for all the 5 biologics
All asthma	0.2 (0.0–0.5)	0	0.2 (0.0–0.6)
Severe asthma	6.4 (3.1–15.9)	0	7.4 (3.5–18.3)
Anti-IL-5 therapy
Mepolizumab
All asthma	2.2 (1.5–3.1)	2.5 (1.5–3.1)	2.1 (1.5–3.1)
Severe asthma	72.1 (59.6–81.8)	88.5 (62.9–97.2)	66.9 (53.3–78.2)
Benralizumab
All asthma	1.3 (0.8–2.1)	1.9 (1.0–3.5)	1.1 (0.6–1.9)
Severe asthma	40.2 (26.7–55.4)	62.8 (42.8–82.6)	32.3 (18.7–49.7)
Reslizumab
All asthma	0.5 (0.3–1.0)	0	0.7 (0.4–1.4)
Severe asthma	14.8 (7.1–28.4)	0	19.5 (9.4–36.0)
Anti-IL-4/13 receptor alpha
Dupilumab
All asthma	2.4 (1.7–3.3)	1.9 (1.0–3.5)	2.5 (1.8–3.5)
Severe asthma	73.4 (63.4–81.4)	67.8 (46.2–83.7)	75.1 (64.0–83.7)
Anti-IgE†
Omalizumab
All asthma	1.4 (0.6–2.1)	1.3 (0.2–2.4)	1.4 (0.5–2.2)
Severe asthma	41.4 (22.8–60.1)	42.5 (10.1–75.0)	41.3 (19.5–63.2)
Original data
All asthma	1.6 (0.7–3.8)	QNS	QNS
Severe asthma	58.5 (30.7–81.8)	QNS	QNS

QNS, Insufficient sample.

^*NHANES sample weights based on the complex sampling survey design were used in constructing estimates.

^†Original data are from the period 2005–2006. IgE and sensitivity to perennial allergens for the period 2007–2012 imputed. Only 8 participants were eligible for omalizumab from 2005 to 2006, and only 20 had “severe” asthma.

Of those with asthma, 2.4% were dupilumab-eligible, 2.2% mepolizumab-eligible, 1.6% omalizumab-eligible, 1.3% benralizumab-eligible, and 0.5% reslizumab-eligible. Among those with severe asthma, 73% were dupilumab-eligible, 72% mepolizumab-eligible, 41% omalizumab-eligible, 40% benralizumab-eligible, and 15% reslizumab-eligible (Table I). About 2.8% of participants with asthma and 85% of those with severe asthma were eligible for at least 1 biologic. Every participant eligible for anti–IL-5 was also eligible for dupilumab except for participants aged 6 to 11 years who were eligible for mepolizumab (7% of mepolizumab-eligible participants) but not for dupilumab. Ninety-one percent, 55%, and 22% of dupilumab-eligible participants were eligible for mepolizumab, benralizumab, and reslizumab, respectively. More than 70% of omalizumab-eligible participants were dupilumab- or mepolizumab-eligible. Conversely, about 40% of participants eligible for dupilumab- or anti–IL-5 were eligible for omalizumab (Fig 1, A and B). Overall, on the basis of these eligibility criteria, 702,000 (95% CI, 468,000–962,000) people in the United States would be eligible for at least 1 biologic as a treatment for asthma.

FIG 1.

For the heat map, the value in the cell reflects what percentage of participants eligible for the biologic in the row (A-E) were eligible for the biologics in the column. For instance, 73% of participants eligible for omalizumab were eligible for mepolizumab but only 44% of those eligible for mepolizumab were eligible for omalizumab.

In a nationally representative sample of the US population, we found that more than 80% of participants with severe asthma and 2.8% of participants with asthma may be eligible for 1 of the currently available biologics. To our knowledge, this is the first study to date providing an estimate of Americans eligible for asthma biologics. These levels of eligibility are similar to the levels in a study of 69 patients with uncontrolled asthma, in which 43.5% were eligible for omalizumab, but higher than levels in a retrospective study of mepolizumab eligibility among patients referred to a tertiary center for severe asthma, which found that 49% were eligible for mepolizumab.^5,6 These results are also consistent with previous studies on asthma phenotypes including a study using NHANES to generate clusters of asthma phenotype,⁷ which showed that 78% of children and 69% of adults had eosinophilic asthma. This distribution of eosinophilic asthma is likely related to the percentage of participants we have found as eligible to 1 of these biologics given that 4 of the 5 currently available biologics are indicated for eosinophilic asthma.

The proportion of omalizumab-eligible participants eligible for mepolizumab in this study is slightly higher than previously reported. The Identification and Description of sEvere Asthma patients in a cross-sectionaL study, IDEAL,⁸ an observational study of patients with severe asthma, showed that 53% of omalizumab-eligible patients from Australia and North America were eligible for anti–IL-5. Another study showed that 47% of omalizumab-eligible patients were eligible for anti–IL-5.⁵ However, our results of the proportion of patients eligible for anti–IL-5 or mepolizumab who were eligible for omalizumab are similar to the 37% and 36% reported by IDEAL⁸ and Lee et al,⁵ respectively. Switches between these biologics are possible due to the overlap although the proportion of eligible participants dropped significantly as eligibility criteria became stricter based on age and eosinophil count. This was most notable for reslizumab, approved for those 18 years or older and with eosinophil counts of greater than 400 cells/mm³ (see Table E3 in this article’s Online Repository at www.jacionline.org). Only a quarter of adults with severe asthma in this study had eosinophil count of greater than or equal to 400 cells/mm³ and just 2 of 10 mepolizumab-eligible participants were reslizumab-eligible. This is similar to the 18% of mepolizumab-eligible patients eligible for reslizumab in IDEAL.⁸

Because the study design was cross-sectional, we are unable to make inferences about how disease severity or treatment changed over time. We could have also misclassified participants’ disease severity. Our estimates of omalizumab eligibility are imprecise because of the small number of subjects with IgE data. Questionnaire data are self-reported, and the definition of asthma severity may be influenced by health care utilization patterns and medication adherence. However, these are real-life challenges that clinicians face when defining asthma severity in practice. Also, we have not addressed comparative effectiveness or costs of these biologics and this will be important for future research. Regardless of eligibility, providers may need to incorporate other factors such as insurance, costs, and route of administration into their decision to prescribe these biologics. For instance, dupilumab and mepolizumab are approved for home administration, whereas reslizumab is given intravenously. Furthermore, annual costs of these biologics, the wholesale acquisition costs, range from $27,950 for reslizumab to $48,472 for the first year on benralizumab.⁹ Despite these limitations, however, this study provides important insights into available treatments options for patients with severe asthma for clinicians in real-world settings.

In summary, using a nationally representative sample, we were able to show that 80% of participants with severe asthma, and about 700,000 Americans, would meet criteria for 1 of the currently available biologics. These results could help inform therapeutic choices for providers caring for patients with asthma who may be considering initiating therapy with a biologic agent or switching to an alternative agent.