Dual biological treatments in immune-mediated disorders: a single center experience

Abstract

Background

Physicians may encounter situations where they need to co-administer omalizumab with non–IgE-targeting monoclonal antibodies. In this study, we share our experience with these dual biologic treatments.

Objective

To evaluate the efficacy and safety of dual biological therapy using omalizumab and non-IgE-targeting monoclonal antibodies at a single center.

Methods

We retrospectively reviewed the medical records of adults treated with a dual biological therapy regimen consisting of omalizumab and another biologic between 2020 and 2022.

Results

Our review identified nine patients (age range: 51–75 years, 7 women and 2 men) who were treated with omalizumab for high Th2 disorders, including chronic spontaneous urticaria (n = 7) and asthma (n = 2). Seven patients received a second biologic for co-existing non-Th2 disorders, while two received an additional biologic to better control their Th2-mediated disorders. The patients were treated with the following biologics: anti-IL-5 agents (mepolizumab [n = 1] and benralizumab [n = 1]), the IL-4/13 inhibitor dupilumab (n = 1), the anti-IL-17 biologic secukinumab (n = 1), the IL-1 inhibitor anakinra (n = 1), the anti-calcitonin gene–related peptide agent fremanezumab (n = 1), and anti-TNF-α agents (etanercept [n = 1], golimumab [n = 1], and adalimumab [n = 1]). Dual biotherapy was administered for 3–34 months with observed clinical improvement. No adverse events or infections were reported.

Conclusions

Dual biological treatment with omalizumab and another biologic appears to be safe, with no need to discontinue non–IgE-targeting agents during omalizumab therapy.

Introduction

The introduction of omalizumab, a humanized anti-immunoglobulin (Ig)E monoclonal IgG1 antibody, has revolutionized the treatment of patients with allergic and immune-mediated disorders [1]. The list of related treatment indications continues to expand and currently includes conditions such as chronic spontaneous urticaria (CSU) [2] and asthma [3], and the incidence of diagnosed patients with asthma and CSU receiving omalizumab has increased [2, 3]. Off-label use of omalizumab, such as for bullous pemphigoid, also is expanding [4]. As a result, a subgroup of the omalizumab-treated population may require dual therapy with another biologic. The two agents may target a similar immune pathway as do dupilumab and omalizumab, which both manipulate the T helper (Th)2-mediated response [5]. However, patients also are receiving dual biologics that target different and unrelated immune pathways, such as interleukin (IL)−17 [6], tumor necrosis factor (TNF)α [7], and IL-23 [8].

Treating physicians therefore may face the option to co-administer omalizumab and non–IgE-targeting agents with or without a shared immune mechanism, leading to questions about the safety and efficacy of omalizumab in these cases. In addition, combining biologics may raise concerns about immune suppression or increased susceptibility to infection, among other considerations, that can lead to discontinuation of one of the treatments.

Here, we present our experience with the combination of omalizumab and non–IgE-targeting monoclonal antibodies. For decision-making, we suggest a mechanism-based approach that enables a broad view of the immune system and treatment modalities.

Methods

Study design and patients

This is a retrospective review of computerized medical charts of adult patients (> 18 years) treated with omalizumab and another biological therapy from January 2020 to December 2022. Data regarding treatment indications, disease presentation, course, and outcome were retrieved from medical records. Patients for whom documented details were lacking were excluded from the study.

Review of the literature

A computerized search of English-language literature was conducted using the PubMed database. Key words included “omalizumab” and [“combined” or “dual” or “biologics” or “monoclonal antibodies”]. The search was constrained to find studies published during the period of 2002–2022. Studies with missing details or with unavailable full-length manuscripts were excluded from the search.

Ethical review of the study

All methods were performed in accordance with relevant guidelines and regulations. This study was approved by the Institutional Review Board of Hadassah Medical Center (IRB number: HMO-0729-22). The study exclusively consisted of retrospective medical chart analysis. Hence, the IRB allowed for a waiver of signed, informed consent from patients.

Results

Patient characteristics

Clinical characteristics of the patient cohort are detailed in Table 1. Our search identified nine patients (seven women and two men) receiving dual treatment with omalizumab and another biologic. Eight patients were Jewish, and one was Arab. Their mean age was 60.55 (range 51–75) years. Indications for initiation of treatment with omalizumab were CSU (n = 7) and asthma (n = 2). For eight patients, the omalizumab dose was 300 mg every 4 weeks, and for one patient with asthma, the dose was 300 mg every 2 weeks. Patients were treated with omalizumab alone for a mean of 18.2 (range 1–34) months. Immunosuppressive and immunomodulatory drugs were administered to eight patients prior to the addition of a second monoclonal antibody (corticosteroids, n = 7; methotrexate, n = 1; colchicine, n = 1; salazopyrin, n = 1; and hydroxychloroquine, n = 1).

Table 1 Clinical characteristics of patients receiving dual biological treatment with omalizumab

Indications for adding a second biologic to omalizumab

Details regarding the indications for adding a second biologic in the nine patients are provided in Table 1. Patients with CSU treated with omalizumab monotherapy experienced a significant clinical response, achieving complete or near-complete remission in most cases. In seven patients, a second biologic was introduced to manage non-Th2-mediated disorders. Among these, five patients with omalizumab-treated CSU required an additional biologic due to coexisting non-Th2 autoimmune conditions. Specifically, P1 and P7 required treatment for ankylosing spondylitis (AS), P4 for inflammatory pericarditis, P5 for rheumatoid arthritis (RA), and P7 for psoriatic arthritis (PA).

In addition, two patients receiving omalizumab were administered a second biologic for non-Th2, non-immune-mediated conditions. P4 was treated for chronic obstructive pulmonary disease (COPD), while P6 was treated for chronic migraines.

Two patients, P2 and P3, required an additional biologic to achieve better control of Th2-mediated disorders due to an insufficient response to omalizumab alone. In P2, who had both CSU and nasal polyposis (NP), omalizumab monotherapy failed to control NP-related symptoms, while dupilumab monotherapy did not resolve CSU. Only combined therapy with omalizumab and dupilumab successfully managed both conditions. P3 was treated with omalizumab for several years, resulting in improvements in allergic rhinitis and asthma exacerbations. However, the forced expiratory volume in one second (FEV1) continued to decline, and the patient experienced persistent dyspnea. Due to asthma with eosinophilia, treatment was switched to benralizumab, resulting in significant improvement in lung function (from 35% to nearly 70%), alleviation of chronic dyspnea, and reduced use of chronic steroids. Nevertheless, following the discontinuation of omalizumab, the patient experienced recurrent exacerbations upon allergen exposure, accompanied by worsening allergic rhinitis and asthma attacks. Consequently, omalizumab was reintroduced. The combined treatment with omalizumab and benralizumab successfully reduced exacerbations, maintained improved lung function, and sustained reduction in steroid use.

Biological agents co-administered with omalizumab

Monoclonal antibodies targeting the Th2-mediated response were the IL-5 axis inhibitors mepolizumab and benralizumab (n = 1, each) and the IL-4/13 receptor α subunit inhibitor dupilumab (n = 1). Biologics targeting non–Th2-pathways were the IL-1 inhibitor anakinra (n = 1), the IL-17 A inhibitor secukinumab (n = 1), the TNF-α inhibitors etanercept (n = 1), golimumab (n = 1), and adalimumab (n = 1), and the calcitonin gene-related peptide (CGRP) inhibitor fremanezumab (n = 1). The mean duration of dual biologics therapy was 15 (range 1–34) months. Regarding immunosuppressive treatment (Table 1), the baseline prednisone dose before the addition of the second biologic was 20 mg/day in four patients and 40 mg/day in three patients. Reduction of immunosuppression and discontinuation of oral corticosteroids were achieved in all patients during dual biologic treatment. Overall mean follow-up from the initial visit at the clinic was 52.67 (range 4–141) months.

Safety of the dual biological treatment

No adverse events (AEs) were observed in any of the patients while being treated with omalizumab alone. After the addition of a second biologic, there were no reports of biologics-related infections, AEs, severe adverse events (SAEs), or suspected unexpected serious adverse reactions (SUSARs). No mortality was observed in the patient cohort during treatment with omalizumab alone or with the dual biologic therapy. One patient (P4) discontinued omalizumab after initiating mepolizumab for COPD, following concerns from the treating pulmonologist about potential immune suppression, despite the absence of supporting clinical symptoms and objective test results. None of the other eight patients discontinued either biologic treatment.

Discussion

In this study, we summarize our experience with dual biologics therapy consisting of omalizumab and non-IgE-targeting monoclonal antibodies. Biologics targeting IL-5, IL-4/13, TNFα, CGRP, IL-1, and IL-17 were safely co-administered with omalizumab. None of the patients had immune-mediated reactions or recurrent infections, and all experienced clinical improvement under the dual treatment.

Our report emphasizes the need for a mechanism-based approach when treating patients with complex immune-mediated disorders. A review of the literature identified 50 patients from 16 previously published reports, who were treated with dual biologic therapy with omalizumab and another monoclonal antibody (Table 2). Most patients were adults, and the female: male ratio was 29:21. Indications for omalizumab in these studies included bullous pemphigoid (n = 18), asthma (n = 15), CSU (n = 9), allergic bronchopulmonary aspergillosis (n = 4), and chronic rhinosinusitis with NP (n = 1). Among monoclonal agents co-administered with omalizumab, treatments targeting the IL-5 pathway were the most common (mepolizumab, n = 19; benralizumab, n = 5). Other biologics co-administered with omalizumab consisted of treatments targeting CD20 (rituximab, n = 17), IL-4/13α (dupilumab, n = 7), TNFα (etanercept, n = 1; adalimumab, n = 1), IL-17 (secukinumab, n = 1) and IL-23 (guselkumab, n = 1). Dual biologics were given for 1–41 months and enabled tapering of corticosteroids in eight studies. None of the patients who received dual biologics experienced adverse events, including recurrent infections or immune-mediated reactions.

Table 2 Literature review of patients receiving treatment combining omalizumab and other biological agents

In our cohort, excluding P2 and P3, the addition of a second biologic in the remaining seven patients was indicated for a distinct, non-Th2-mediated disorder unrelated to omalizumab treatment. For instance, in P1, omalizumab was prescribed for CSU, and secukinumab was later added to manage co-existing ankylosing spondylitis. Our report highlights the feasibility of dual biologic therapy. The cost-benefit ratio of each treatment—omalizumab and non-omalizumab biologics—should be evaluated separately, considering the specific indication and potential adverse effects of each drug. In P2 and P3, dual therapy was found to be superior to omalizumab monotherapy. In P2, who had both CSU and NP, only dual treatment with omalizumab and dupilumab was successful in managing both conditions. Notably, P3 exhibited characteristics of both allergic and eosinophilic asthma. Treatment with a combination of omalizumab and benralizumab proved more effective than monotherapy with either agent, leading to improved lung function, fewer asthma exacerbations, and reduced chronic steroid use. The addition of a monoclonal antibody that inhibits the Th2-mediated response upstream can enhance the inhibitory effect of omalizumab. A good example is dupilumab, which inhibits the activity of IL-4, thus decreasing class switch of B cells into IgE-secreting plasma cells, reducing IgE plasma levels and contributing to the anti-IgE activity of omalizumab [21].

In addition, the known redundancy of the immune system supports the notion that dual biologics therapy would offer benefits. For example, in clinical trials of asthma patients, the humanized selective anti-IL-13 IgG4 monoclonal antibody tralokinumab failed to reduce corticosteroid dependency or increase asthma-related quality of life [22]. Another unsuccessful trial involved pascolizumab, a selective IL-4 inhibitor [23]. Dupilumab blocks the α subunit of the common receptor for IL-4 and IL-13, however, and thus offers a dual cytokine blocking effect. It has a well-documented efficacy in decreasing asthma exacerbations, improving lung function, and allowing for better disease control in corticosteroid-dependent patients [24].

The rationale for dual biologics therapy is further supported by the recent introduction of bispecific monoclonal antibodies. Treatment targeting both TNF-α and CXCL10 was used in experimental arthritis in vivo murine models and proved to be more effective than a selective anti-TNFα agent alone [25]. A superior effect of bispecific over-selective biologics treatment was also seen with an agent targeting IL-1β and IL-17 A [26]. Increased rates of infection were not noted in these models [25, 26].

Nevertheless, caution is needed when combining biological agents that are both inhibitors of Th2 inflammation. The addition of dupilumab to omalizumab treatment could increase the risk of parasitic infections, especially in high-prevalence countries. For example, dupilumab has been postulated to induce demodicosis in adolescent patients [27].

In one of our patients (P4), concerns arose that the dual treatment would increase infection risk, so that after mepolizumab treatment, omalizumab was discontinued. This decision was not, however, supported by the results of our retrospective patient data analysis and literature review. In fact, suppression of Th2-mediated immunity by targeting IL-5, IL-4, IL-13, or IgE could increase interferon-γ production by Th1 cells, thus reducing the risk of viral infection. With dupilumab treatment, repolarization towards Th1 was seen in patients expressing dominant-negative variants of signal transducer and activator of transcription-3(STAT3) that lead to enhanced Th2 inflammation [28]. Moreover, IL-5–modulating agents and omalizumab were the most reported dual biologics in our review of previously published studies, and none of the patients were reported to have had infections (Table 2) [9,10,11,12,13,14,15,16].

Our findings also highlight the feasibility of combining omalizumab with anti-TNFα, anti-IL-1, anti-CGRP, or anti-IL-17 monoclonal antibodies. Dual treatment with omalizumab and anti-TNFα or anti-IL-17 biologics has been described previously (Table 2) [6, 7, 18], but our report is, to the best of our knowledge, the first description of omalizumab co-administered with anti-CGRP and anti-IL-1 agents with no adverse events. Dual treatment with biologics targeting these molecules appears to be safe.

Our study has several limitations, including a small sample size and a retrospective design. Additionally, long-term follow-up data are lacking. We also did not employ a biomarker-based approach to guide the selection of the most appropriate biologic for each patient at the optimal time. Such decisions should be informed by a comprehensive understanding of the immune pathways involved in each disorder and tailored to individual patient profiles. Therefore, biologic therapies should be used in accordance with current clinical guidelines for each condition. Further prospective studies evaluating serum biomarkers in these patients are needed to optimize treatment strategies. Nevertheless, our findings aim to reassure physicians when considering dual biologic therapy involving omalizumab and another biologic for patients with complex clinical presentations. As demonstrated in our results, this approach can benefit more patients and appears safe, without increasing the risk of infections or other severe adverse events.

Conclusions

Dual biologic therapy with omalizumab and non–IgE-targeting monoclonal antibodies appears feasible. Immediate discontinuation of non–IgE-targeting agents in patients receiving omalizumab may be unnecessary, and a mechanism-based approach is recommended. Further large-cohort, prospective studies with serum biomarker monitoring are needed to evaluate the long-term effects of dual biologic therapy.