Safety of combining biologics in severe asthma: Asthma‐related and unrelated combinations

Abstract

Monotherapies with antibodies approved for severe asthma treatment were reported to be safe, with side effects close to placebo1. However, the safety of concomitant treatments with several biologics in asthma is poorly understood. Two scenarios for treatment with two or more biologics in asthma exist. Firstly, patients may receive an additional biologic approved for severe asthma, either to treat insufficiently controlled typical co-morbidities, or as an add-on treatment for insufficiently controlled asthma. Secondly, patients may receive another biologic not approved for asthma for the treatment of an unrelated disease. Concomitant treatment with 2 immunomodulating antibodies is approved in oncologic diseases such as melanoma 2 or mesothelioma 3; however, possible autoimmune toxicities remain a concern. In rheumatoid arthritis or inflammatory bowel diseases, concomitant treatment with two or more biologics is currently avoided, because of concerns related to serious infections 4, 5. In contrast, the safety of concomitant treatments with two or more biologics in asthma is unclear. There was no safety signal (but also no additive efficacy) in a trial investigating concomitant treatment with the anti-interleukin 4 receptor antibody dupilumab and the anti-interleukin 33 antibody itepekimab 6. However, despite several single case reports 7-10, there are no larger case series investigating this issue. Therefore, seven German academic severe asthma centres (Rostock, Hannover, Mainz/Heidelberg, Berlin, Magdeburg, Kiel, Munich) were asked to report all severe asthma cases documented in their databases with a concomitant treatment (for at least 3 months) with two or more biologics. In order to minimise biases, there were no other specific inclusion or exclusion criteria (for instance, clinical efficacy of dual therapy was not a criterion, to exclude a healthy survivor effect). Patients with a smoking history of more than 10 pack years were also included, because these patients can have typical type 2 marker profiles and are often candidates for a treatment with biologics in real life 11. A total of 25 patients (15 women, 10 men; median age: 54 years) were identified (Tables 1 and 2). Fifteen patients concomitantly received 2 biologics approved for asthma: 8 were treated for co-morbidities such as CRSwNP, atopic dermatitis, urticaria or EGPA, while 7 received treatment for a combined action on asthma control (Group A, Table 1). In all 15 cases, a switch to another biologic (as a monotherapy) was evaluated or done before starting the dual therapy. The other 10 patients received one biologic for asthma treatment and another (not approved for asthma treatment) for an unrelated disease (Group B, Table 2). The median duration of dual treatment (time point: February 2022) was 9 months (3–38 months) in group A and 24 months (6–49 months) in group B. In Group A, the dual treatment was stopped in 4 patients: in all cases, this was done because of clinical ineffectiveness, not because of adverse effects (Table 1, Non-Responders). All other patients continue to receive two or three biologics concomitantly, with currently no reported adverse effects during this treatment (time point: February 2022). SA CRS SA EGPA CRS NERD SA NERD SA NERD SA AD SA EGPA SA FA Taken together, our case series confirms evidence from several single case reports 7-10 and a recent clinical trial 6 that a dual therapy with biologics involving at least one biologic approved for asthma treatment appears to be safe in patients with severe asthma. The safety of the anti-TSLP antibody tezepelumab (which reduces all type 2 biomarkers by blocking TSLP, a target upstream of the inflammatory cascade) may serve as an additional clue for the safety of treatments with several antibodies targeting downstream mediators in severe asthma 12. These findings are in contrast to dual immunomodulatory treatments in cancer 2, 3, rheumatoid arthritis and inflammatory bowel diseases 4, 5, where the initiation of a second (approved) biologic was associated with an increased risk for autoimmune toxicities or serious infections. Despite the small number, our data provide preliminary reassurance for clinicians treating patients with severe asthma, that, as far as safety and biologics approved for asthma treatment are concerned, a treatment with an additional biologic can be considered safe in specific, well-documented cases. However, patients need to be informed that safety data are still very limited and that prospective, larger and longer data collections are needed to come to a more robust recommendation. None. Open Access funding enabled and organized by Projekt DEAL. ML reports lecturing and/or consulting fees and/or research grants from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, TEVA. HS reports lecturing and consulting fees and/or research grants from AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi Genzyme. SK reports lecturing and consulting fees and/or research grants from AstraZeneca, Chiesi, GlaxoSmithKline, MedImmune, Novartis, Roche, and Sanofi Genzyme. KCB reports lecturing and consulting fees and/or research grants from ALK, Allergopharma, Almirall, AstraZeneca, Bencard, Chiesi, GSK, HAL, Lofarma, Mundipharma, Novartis, Sanofi. JS reports lecturing and consulting fees and/or research grants from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi, MSD. TB reports lecturing and/or consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Roche, Boehringer Ingelheim. KFR reports lecturing and consulting fees and/or research grants from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, DevPro, Gilead, GSK, Novartis, Orion, Sanofi/Regeneron. RB reports lecturing and consulting fees and/or research grants from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Sanofi, Roche and Teva. JCV reports lecturing and/or consulting fees from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, Genzyme, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Regeneron, Revotar, Sanofi-Aventis, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila. KM reports lecturing and/or consulting fees from AstraZeneca, GlaxoSmithKline, Janssen, Novartis, Sanofi. Informed consent for anonymous publication of the data was obtained from the participants.

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