Monoclonal antibody (mAbs) treatments have important therapeutic applications in different diseases. Currently, a number of biological drugs are available that have proven to be quite effective and efficient in reducing exacerbations1 and improving quality of life2 in adults and children with moderate to severe asthma (SA).3–5 In this sense, severe uncontrolled asthma (SUA) is as an important challenge not only for health professionals but also for patients who suffer from it.6

Different mAbs have emerged to treat different types of SUA. Specifically, there are four biologic mAbs approved for clinical use. These are Omalizumab for allergic asthmatic patients (anti-IgE)7–9 and three others targeting eosinophilic inflammation (mepolizumab,10,11 reslizumab, and benralizumab,12–14,3,15 all which show very positive results.

Among these, Omalizumab was the first mAb approved by the Food and Drug Administration (FDA) in 2003,16 and by the European Medicines Agency (EMA) in 2005.17 In the last five years three new mAbs have emerged for use in eosinophilic SUA. Much of the literature cites both the benefits and drawbacks of using these drugs in SUA. However, given the complexity of asthma and its management, the presence of SUA, and specifically, to what extent these mAbs are or are not prescribed and why is not fully understood.

Different health professionals have been involved in controlling the disease depending on where the patients seek help, i.e. general practitioners or specialists. However, in some cases there is not always an accurate diagnosis of asthma, thus leading to the inadequate management of SA.18 Due to this, the mAbs prescription that comes from the different health consultations is not well characterised. That is, in the field of pulmonology, due to the complex and very heterogeneous inflammatory nature of respiratory processes, the use of these treatments has been delayed despite a high prevalence of SUA cases in this specialty. Furthermore, given that sex has been reported to play a key role in asthma,19 assessing how these mAbs treatment patterns may differ between males and females is of particular interest.

Given the gap in knowledge regarding the mAbs prescription in Spain, in this study we aimed to characterise the management pattern of mAbs in a large sample of patients with SUA treated by Spanish pulmonologists. Complementary to this, we also assessed the prevalence of mAbs prescriptions by sex and specialty.

The current study belongs to a broader project where the objective is to describe a global map of mAbs prescription for SUA in Spain, as well as the characteristics of such prescriptions.20 In the present study, we evaluate the mAbs prescriptions’ patterns, by sex, by hospital complexity level, by geographical area, type of mAb, as well as treatment interruptions, switches and restarts.

A total of 91 centres were initially included. One of them was discarded because there was missing information regarding the objective of the study. The classification of the 90 final participant centres by the capacity of the hospital was: level 1 n=20 (22.2%), level 2 n=30 (33.4%), level 3 n=19 (21.1%) and level 4 n=21 (23.3%). 100% of pulmonology specialists prescribed mAb for SUA.

Prevalence of mAb treatments by sex

Global current mean prevalence (95% confidence interval [CI]) of cases treated with mAbs was 10.4% (8.8–12.1%). There was a significant difference in the prevalence of current mAb treatment by sex (p<0.001) (Fig. 1a) with females showing a higher prevalence: 13.3% (11.1–15.5%) in females and 7.4% (6.3–8.6%) in males. The distribution by sex of the total number of patients treated with mAbs since their use was established in each centre and it showed the same trend (p<0.001): median (Q1, Q3) in females 23 (12, 37.8); and in males 11 (6.2, 18.8) (Fig. 1b).

Fig. 1.

Prevalence and number of patients with mAb prescription by sex. (a) Prevalence of patients with mAb prescription by sex. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients with mAb prescription by sex. Numerical data indicate mean (standard deviation).

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Prevalence of mAb treatments by hospital complexity level

By hospital complexity level, the prevalence was 8.8% (6.9–10.6%) in level 1, 11.7% (7.1–16.3%) in level 2, 11.7% (9.6–13.8%) in level 3 and 9.4% (8.3–10.5%) in level 4; no statistically significant differences were observed (p=0.597) (Fig. 2).

Fig. 2.

Prevalence and number of patients treated with mAb by hospital level. (a) Prevalence of patients treated with mAb by hospital level. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients treated with mAb by hospital level. Numerical data indicate mean (standard deviation).

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Prevalence of mAb treatments by geographical area

By geographical area, the prevalence was 13.3% (13.3–13.3%) in the Canary Islands, 5.8% (4.4–7.3%) in the central area, 8.9% (7.0–10.8%) in the eastern area, 9.1% (7.6–10.6%) in the northern area, and 15.9% (10.1–21.7%) in the southern area; statistically significant differences were observed (p=0.01) (Fig. 3).

Fig. 3.

(a) Prevalence and number of patients treated with mAb by geographical area. Numerical data indicate the mean (95% confidence interval [CI]). (b) Number of patients treated with mAb by geographical area. Numerical data indicate mean (standard deviation).

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Table 1 shows the descriptive results of the population treated by sex, hospital complexity level, and geographic area.

Table 1.

Population treated by sex, hospital level and geographical area.

	Population treated with mAb in pulmonology, median (P25, P75)	p value
Sex
Men	11.0 (6.25,18.8)	<0.001
Women	23.0 (12.0,37.8)
Hospital level
Level 1	12.0 (7.50,23.2)	<0.001
Level 2	29.5 (15.5,37.0)
Level 3	50.0 (34.5,80.5)
Level 4	57.0 (42.0,78.0)
Geographical area
Canary Islands	52.0 (51.0,63.0)	0.391
Central area	30.5 (21.8,45.5)
East area	31.0 (21.5,47.5)
North area	29.5 (13.2,48.0)
South area	37.0 (19.2,93.5)

mAb: monoclonal antibodies; P25, P75, percentile 25 and 75.

Prescription of mAb

For each of the four mAbs, the prevalence of treatment by pulmonology services was: omalizumab, 6.2% (4.8–7.5%); mepolizumab, 2.9% (2.6–3.2%); reslizumab, 0.4% (0.2–0.5%); and benralizumab, 1.0% (0.8–1.2%) (Fig. 4). eTable1 shows the results of the prevalence of treatment by sex, hospital complexity level, and geographic area. The descriptive results of the population treated with each of the mAbs by sex, hospital complexity level and geographic area shown in eTable 2 of eSupplement Material.

Fig. 4.

Prevalence of treatment. Numerical data indicate the mean (95% confidence interval [CI]). Patients’ distribution attending different mAb prescriptions (a) since mAb prescription was established in each centre and (b) patients who discontinued the mAb treatment and do not continue with other mAb. Numerical data indicate mean (standard deviation).

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mAb prescribed: treatment interruption, switches and restarts

eTable3 shows the total number of treatment interruptions of mAbs, along with the reasons for all centres. Discontinuations were higher for omalizumab, followed by mepolizumab. The main reason for discontinuation was a lack of effectivity (Fig. 5a).

Fig. 5.

(a) Number of treatment interruptions of mAbs treatments. (b) Number of patients where the first prescribed mAb was restarted after a switch from ≥2mAbs.

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Table 2 shows the distribution of the total number of patients who have had their prescribed mAbs switched, with omalizumab showing the highest number of switches, especially to mepolizumab. Again, the main reason for switching was a lack of effectiveness of treatment. The second mAb showing more switches was mepolizumab to benralizumab (Fig. 6).

Table 2.

mAbs switches and reasons.

Switch	Total	Adverse effects	Lack of effectivity	Other reasons	Unknown
Omalizumab to mepolizumab	424	32	368	13	11
Omalizumab to reslizumab	45	5	37	1	2
Omalizumab to benralizumab	82	3	71	6	2
Mepolizumab to benralizumab	102	14	82	1	5
Mepolizumab to omalizumab	7	0	6	1	0
Mepolizumab to reslizumab	28	2	25	0	1
Reslizumab to benralizumab	3	1	2	0	0
Reslizumab to mepolizumab	3	1	1	1	0
Reslizumab to omalizumab	0	0	0	0	0
Benralizumab to mepolizumab	5	3	2	0	0
Benralizumab to omalizumab	1	0	1	0	0
Benralizumab to reslizumab	2	0	2	0	0

mAb: monoclonal antibodies.

Fig. 6.

Number of patients who have had their prescribed mAbs switched.

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eTable4 shows the distribution of the total number of patients where the first prescribed mAb was restarted after a switch from ≥2mAbs. There were a few restarts to the first treatment that, in most cases, was omalizumab, followed by benralizumab and mepolizumab. The lack of effectiveness appeared as the main reason for restarting the first mAb treatment (Fig. 5b).

When this study was first constructed and designed, it was the first study to describe the pattern and type of mAb prescription in SUA. It was implemented in a large sample of public health centres with a pulmonology service, taking into account sex, hospital complexity level and geographical area. In January 2022, an international registry that describes real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma was published.25 In our study, notably, a sex difference was found, with females showing a higher prevalence of mAbs being prescribed. As in the international registry,25 Omalizumab was the most prescribed mAb, as it has been available for a longer period of time, followed by mepolizumab. However Omalizumab also showed the highest levels of treatment discontinuation. The main switches were from omalizumab to mepolizumab, and from mepolizumab to benralizumab. These results are similar to those published in the international registry.25 There were few restarts to the first treatment (after a change of ≥2mAbs) which in most cases was omalizumab. Lack of effectivity was the main reason for treatment discontinuation and switches.

Patients with SUA are eligible for mAb treatments, depending on different clinical and medical criteria. However, there is a lack of characterisation of mAb prescription mapping, especially in some European countries. Routine options for treating asthma remain limited and there are very few studies on the proportion of patients eligible for mAb. We found that 10.4% of patients with SUA were treated with mAbs. In a population with SA from a Canadian allergist's practice, between 41% and 78% of patients (depending on the mAb) were eligible for at least one mAb.26 Our data are fall below these eligibility percentages. A study conducted in Spain on a sample of 303 patients with SA (67% women) shows that mAb are not usually prescribed during the severe exacerbation phases, but only during the stable phase in 39% of cases.27

Consistent with previous studies,27,28 mAb treatments were prescribed significantly more in females. Sex plays an important role in asthma, from males having the highest prevalence in childhood to females in adulthood.19 A new hypothesis related to SA pathophysiology phenotypes involves asthma with non-eosinophilic inflammation, obesity and occurrence only in females.29 In this regard, future studies on mAb prescription should take into account the type of SA. Therefore, there is a need to better characterise and phenotype patients with SA before requesting mAb treatment, also taking into account the phases (stable or exacerbations) in which patients seek healthcare help.30 Studies on the impact of sex on treatment effectiveness are unclear, with some studies indicating that sex does not predict response to mAbs.31,32

Omalizumab was the most prescribed mAb, followed by mepolizumab. Omalizumab was the first mAb approved for allergic SA.33 There is variability in the published data on the percentage of patients with allergic and eosinophilic asthma. Allergic asthma is demonstrable in a variable proportion of patients (11–60% of cases) while the eosinophilic phenotype accounts for about 25–58% of the cases,34,35 the idiosyncrasies of patients in the centres evaluated may contribute to these results.

Interestingly, since patients with SA may present with an overlap of eosinophilic and allergic phenotypes, both omalizumab and mepolizumab, primarily, are commonly discussed as the best treatment for these cases.36 In this regard, both mAbs have shown similar efficacy in patients with SUA.37 Previous literature shows that the high heterogeneity of cases and the different selection criteria for the use of the two mAbs probably do not allow for a specific and concrete criterion for using one or the other mAb, also taking into account that they have similar efficacy patterns.37

The prevalence of treatment discontinuation was also more reported for these two mAbs. Omalizumab withdrawal rates have been shown to vary considerably depending on the type of study, ranging from 2% to 19% in double-blind and open-label studies.38

In SUA cases, switching between mAbs can occur.39 Most switches were observed from omalizumab (about 78%, 551 out of 702) to mepolizumab (60%), and from mepolizumab to benralizumab (14%). There is a clear effect of sample size treated with omalizumab that makes treatment discontinuation more evident for this mAb. This could be because it was the monoclonal available for most of the study period. It could also be possible that more failures could have been seen with other mAbs if the study had lasted longer. In addition, despite omalizumab being considered the gold standard treatment in severe allergic asthma, it is possible that incorrect asthma phenotype selection has occurred, leading to a negative clinical outcome.40 Some studies suggest that switching from omalizumab to mepolizumab in patients with uncontrolled severe allergic and eosinophilic asthma may lead to clinically significant improvements in asthma control.40,41 The literature is not sufficiently clear on which mAb (mepolizumab or benralizumab) is the best for treating eosinophil SA. On one hand, studies highlight similar efficacy42; however on the other hand, some studies attribute unique characteristics to benralizumab in inhibiting the mechanism of eosinophil depletion and maturation in the bone marrow, thus inducing cell-mediated, antibody-dependent cytotoxicity in both circulating and tissue-resident eosinophils43–45 that have not been attributed to other mAbs (i.e. mepolizumab). Benralizumab is therefore postulated as an alternative to other agents targeting the IL-5 pathway in the treatment of eosinophilic asthma.44

There were few restarts of the first treatment after a switch from ≥2mAbs, and, in the few cases, it was to omalizumab. We found that the rates of withdrawal or switches from omalizumab, as well as the other mAbs, have been associated with a lack of efficacy, in agreement with previous studies.46,47 The question here is: where do these severe cases that do not respond to even two treatment switches stand? It seems difficult to find an alternative in severe cases that maximises disease control.

This study is not without limitations. The nature of the survey method has several inherent advantages, but also weaknesses. For example, there were centres that were difficult to access, as we could not survey the initially calculated sample size. The reliability of the survey also depends on different factors, such as errors in the data due to non-response, or differences in the number of respondents (in this case, centres) who chose to participate from those who chose not to, which creates bias.

In conclusion, we found differences in overall mAb prescribing according to sex, specialty and hospital complexity level. Omalizumab appeared as the most prescribed mAb, but also with higher rates of treatment discontinuation, mainly due to lack of effectiveness. Proper knowledge and management of the disease as well as its associated comorbidities are essential for the successful management of the disease in the future, as there are still high drop-out rates.

Funding obtained from the Asthma Area of the Spanish Society of Pneumology and Thoracic Surgery.

All the authors of this document made substantial contributions to conception and design. FC contributed to draft it and all authors revised it critically for important intellectual content; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

Francisco Casas-Maldonado declares that he has received fees in the last three years for acting as a speaker from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, CSL Behring, GlaxoSmithKline, Grifols, Laboratorios Esteve, Laboratorios Ferrer, Menarini, Novartis, Rovi, TEVA, VERTEX, and Zambon; he has also received grants for conference attendance from Boehringer Ingelheim, Grifols, Menarini, and Novartis; finally, he has received consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, CSL Behring, and Grifols. Marina Blanco Aparicio declares that in the last three years she has received fees for participating as a speaker at meetings sponsored by Astrazeneca, Novartis, TEVA, and GSK and as a consultant for AstraZeneca, GSK, Chiesi, Novartis, and Bial. She also received financial aid to attend congresses. Francisco-Javier González-Barcala declares that in the last three years he has received grants for attending congresses, lectures or research grants from ALK, Astra-Zeneca, Bial, Boehringer Ingelheim, Chiesi, Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Menarini, Mundipharma, Novartis, Rovi, Roxall, Stallergenes-Greer, and Teva. Christian Domingo Ribas declares having received in the last three years collaborations for travel and participation in congresses, conferences or scientific meetings from Novartis, Sanofi, GSK, TEVA, Boehringer-Ingelheim, Esteve, Almirall, Astra-Zeneca, Chiesi, Menarini, Takeda, Pfizer, Ferrer, Stallergenes, ALK-Abelló, Allergy therapeutics, Hall Allergy, Inmunotek, and Roxall. Carolina Cisneros Serrano declares having received fees in the last three years for acting as a speaker from Astrazeneca, GSK, TEVA, Menarini, Mundipharma, and Novartis; she received grants for attending congresses from Chiesi, TEVA, Menarini, and Mundipharma; and she has also received fees for acting as a consultant from ALK, Astrazeneca, MundiPharma, TEVA, GSK, and Novartis. Gregorio Soto Campos reported having received fees in the last three years for acting as a speaker for Astrazeneca, Boehringer and Novartis and as a consultant for AstraZeneca, GSK, Chiesi, Novartis, and Bial. He also received financial aid for attending congresses from Boehringer, Menarini, and Novartis and received grants for research projects from Novartis, GSK and Boehringer. Berta Román Bernal in the last three years reports having received honoraria for participating as a speaker from Astrazeneca, Teva, Novartis, and GSK. She has also received grants for attending congresses and courses from Astrazeneca, Teva, Novartis, Menarini, and GSK. Francisco-Javier González-Barcala declares that in the last three years he has received grants for attending congresses, lectures or research grants from ALK, Astra-Zeneca, Bial, Boehringer Ingelheim, Chiesi, Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Menarini, Mundipharma, Novartis, Rovi, Roxall, Stallergenes-Greer, and Teva.