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Investigational agents for asthma

Investigational agents for asthma
Literature review current through: Jan 2024.
This topic last updated: Jun 13, 2023.

INTRODUCTION — The standard treatment of patients with asthma is based upon trigger avoidance, bronchodilation, and anti-inflammatory therapy. Beta agonists, inhaled and systemic glucocorticoids, leukotriene modifiers, omalizumab, anti-interleukin (IL)-5 agents, anti-IL-4 receptor alpha subunit antibody, anti-thymic stromal lymphopoietin, and, to a lesser extent, methylxanthines and muscarinic antagonists (anticholinergic agents) all have a role in the conventional treatment of asthma. However, some patients do not achieve adequate control of their asthma with conventional therapy or experience adverse effects with conventional agents. Ongoing research is attempting to identify more effective and less toxic agents to control asthma.

Investigational approaches to asthma management, both promising and unsuccessful, will be reviewed here. Standard treatment regimens for asthma and complementary, alternative, and integrative approaches are discussed separately. (See "An overview of asthma management" and "Complementary, alternative, and integrative therapies for asthma" and "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma' and "Anti-IgE therapy".)

BIOLOGIC AGENTS — Several biologic agents targeting steps in the cascade of cytokines implicated in asthma inflammation have been developed in hopes of ameliorating the inflammation that underlies chronic asthma. A novel glucocorticoid receptor agonist approaches immunomodulation in a different way, by activating the glucocorticoid receptor, but possibly without the usual adverse effects of traditional glucocorticoids. (See "Pathogenesis of asthma", section on 'Airway inflammation'.)

Anti-IgE agents — Immunoglobulin E (IgE) plays a central role in the mechanism of immediate bronchoconstriction and the influx of inflammatory cells in allergic asthma. Ligelizumab (QGE031) is an investigational monoclonal anti-IgE antibody that binds IgE with higher affinity than omalizumab; both omalizumab and ligelizumab are discussed separately. (See "Anti-IgE therapy", section on 'Higher-affinity anti-IgE'.)

Anti-IL-2R antibody — Activation of type 2 helper T lymphocyte (Th2) cells by allergen leads to production of interleukin (IL)-2 and its receptor IL-2R. Binding of IL-2 to Th2 cells expressing IL-2R leads to proliferation of that clone of specifically sensitized Th2 cells. The humanized monoclonal antibody to the CD25 subunit of IL-2R, daclizumab, inhibits various T cell functions, including T cell proliferation and cytokine production. In a randomized trial, 115 patients with moderate to severe asthma were assigned (3:1) to intravenous daclizumab or placebo every two weeks for 12 weeks [1]. Daclizumab treatment was associated with small improvements in pulmonary function and asthma control. Daclizumab is no longer commercially available. Nonetheless, the potential risks of suppression of the IL-2 pathway may limit the utility of this type of immunosuppression in asthma.

Anti-IL-13 antibodies — IL-13 promotes IgE production by B cells, generation of eosinophil chemoattractants, and contractility of airway smooth muscle cells, among other effects, and is therefore of interest as a potential target for asthma therapy. Clinical studies, however, have not documented a benefit to the anti-IL-13 monoclonal antibodies, lebrikizumab and tralokinumab; however, lebrikizumab is used for treatment of atopic dermatitis [2-6]. (See "Pathogenesis of asthma", section on 'Th2 lymphocytes'.)

The humanized IgG4 monoclonal anti-IL-13 antibody lebrikizumab has been examined in several randomized trials:

Lebrikizumab was compared with placebo in 219 subjects with asthma that was inadequately controlled at baseline by medium-to-high dose of inhaled glucocorticoids [3]. At 12 weeks, subjects who received lebrikizumab had a significant increase in FEV1 (mean 5.5 percent); however, the improvement in FEV1 was no longer significant at 24 weeks. A subgroup analysis found that subjects with high initial peripheral blood periostin levels (an indirect measure of baseline IL-13 activity) had a greater response to lebrikizumab than the low-periostin group. No differences in asthma exacerbations, symptom scores, or beta agonist rescue use were noted over the 24 weeks of the trial.

In a separate study, 212 patients with asthma who were not taking inhaled glucocorticoids were randomly assigned to receive lebrikizumab 125 mg, 250 mg, 500 mg, or placebo subcutaneously at monthly intervals for 12 months [4]. No significant improvement was noted in FEV1 at 12 weeks between dose groups or placebo, even after analysis of a subgroup with high periostin levels. In addition, albuterol usage and ACQ scores were not different between lebrikizumab and placebo. While lebrikizumab protected against treatment failure compared with placebo, the effect was not greater than that expected with inhaled glucocorticoid therapy.

In parallel, randomized trials with a total of 2148 adults with uncontrolled asthma, lebrikizumab (37.5 mg or 125 mg) or placebo was administered subcutaneously every 4 weeks for 52 weeks with predetermined stratification by periostin and peripheral blood eosinophil levels [5]. The trials demonstrated inconsistent results in terms of a clinically meaningful reduction in exacerbations. Six serious adverse events were reported: one case of aplastic anemia and five cases of increased peripheral blood eosinophil counts.

Tralokinumab, another human IgG4 monoclonal antibody to IL-13, demonstrated inconsistent effects in reducing exacerbations in parallel randomized trials of 2063 patients with severe, uncontrolled asthma: one trial found a borderline benefit in participants with a high fraction of exhaled nitric oxide (FENO), while the other study did not support this finding [6]. In a separate trial of 79 participants with suboptimally-controlled moderate-to-severe asthma, tralokinumab did not reduce eosinophil counts, but did reduce FENO and IgE concentrations, suggesting that IL-13 is not essential for eosinophilic airway inflammation [7]. In a previous, dose-ranging trial with 194 adults with moderate-to-severe uncontrolled asthma, the change from baseline in mean ACQ score was not different between the groups and the improvement in FEV1 in the tralokinumab group compared with placebo did not reach statistical significance [8].

Anti-IL-23 antibody — IL-23 appears to contribute to airway inflammation through elaboration of cytokines from Th2 lymphocytes and proliferation of Th17 lymphocytes. Risankizumab, an anti–interleukin-23p19 monoclonal antibody, is used in the treatment of psoriasis (see "Pathophysiology of plaque psoriasis", section on 'Interleukin-23'). However, risankizumab was not beneficial in a randomized trial in 212 patients with severe asthma in which the time to the first asthma worsening was shorter and the annualized rate of asthma worsening was higher with risankizumab than placebo [9]. This observation indicates that IL-23 has a limited role in augmenting type 2 inflammation and is not critical for the development of Th17 cells [10].

Anti-IL-33 and anti-IL-33/ST2 monoclonal antibodies — IL-33 is released by several cell types, including airway epithelial and endothelial cells and mast cells, in response to cell stress or damage (eg, from exposure to viruses, tobacco smoke, air pollution, allergens) and is categorized as an "alarmin" [11]. IL-33 activates a number of effector cells, such as eosinophils, mast cells, basophils, innate lymphoid type 2 cells (ILC2s), and Th2 lymphocytes, thus involving both the innate and adaptive immune systems. Strategies targeting IL-33, such as itepekimab, an anti-IL-33 antibody, and astegolimab, an IL-33/ST2 receptor antibody, may be beneficial in patients with a component of non-type 2 asthma that does not respond to agents focused on type 2 cytokines.

Itepekimab – Itepekimab was evaluated in a phase 2 trial comparing four subcutaneous regimens, itepekimab (300 mg), itepekimab plus the IL-4 receptor antibody dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks in 296 patients with moderate-to-severe asthma [12]. All patients received a LABA and inhaled glucocorticoids for the first 4 weeks of the trial, after which the LABA was stopped. Inhaled glucocorticoids were tapered over 2 to 3 weeks starting at week 6 and stopped. Events indicating a loss of asthma control (ie, a reduction in the morning peak expiratory flow of at least 30 percent from baseline on two consecutive days; at least six additional puffs of short-acting beta agonists in a 24-hour period on two consecutive days; an asthma exacerbation leading to systemic glucocorticoid treatment; an increase by a factor of at least four in the most recent dose of inhaled glucocorticoids; or an asthma-related hospitalization or emergency department visit) occurred in 22 percent in the itepekimab group, 27 percent of the combination group, and 19 percent in the dupilumab group, compared with 41 percent in the placebo group. Monotherapy with either itepekimab or dupilumab increased the prebronchodilator FEV1 compared with placebo, but combination therapy did not. Quality of life measures improved in all the active treatment groups. More study is needed to clarify why combination therapy was not superior to the individual agents in this study.

Astegolimab – Astegolimab is a monoclonal IgG2 antibody that interrupts signaling between IL-33, a member of the IL-1 class of cytokines implicated in asthma, and its receptor ST2 [13]. ST2 is expressed on a spectrum of cell types (eg, innate lymphoid cells, T lymphocytes, eosinophils, mast cells, dendritic cells, macrophages, and endothelial cells), encompassing both type 2 and nontype 2 inflammatory pathways.

A phase 2b multicenter randomized trial (ZENYATTA) assigned 502 adults with poorly controlled severe asthma to one of three doses of astegolimab (70 mg, 210 mg, or 490 mg) or placebo administered subcutaneously every four weeks [13]. Over 52 weeks of treatment, the reductions in the annualized asthma exacerbation rates with astegolimab, relative to placebo, were 43 percent (P = 0.005), 22 percent (P = 0.18), and 37 percent (P = 0.01) in the 490 mg, 210 mg, and 70 mg groups, respectively. Results in patients with <300 eosinophils/microL were similar to the overall group, while results in patients with ≥300 eosinophils/microL were not different from placebo. Blood eosinophils were reduced in all astegolimab groups, but FENO levels were not different after receiving astegolimab or placebo. All doses of astegolimab were safe and well tolerated, with similar AE rates in treatment and placebo arms. The benefit in patients with low blood eosinophils supports the hypothesis that IL-33 participates in asthma pathogenesis independent of Th2 pathways.

TOLL-LIKE RECEPTOR 9 AGONIST — Toll-like receptor 9 (TLR9), a component of the innate immune system primarily located in B cells and plasmacytic dendritic cells, recognizes cytosine guanine dinucleotide (CpG) motifs in microbial DNA and shifts T lymphocyte responses from Th2-dominant to Th1-dominant. (See "Toll-like receptors: Roles in disease and therapy".)

AZD1419 is an investigational oligonucleotide containing immunostimulatory CpG motifs that activates TLR9; it is administered by inhalation [14]. In a randomized trial, 81 participants with moderate to severe asthma, who were using an inhaled glucocorticoid and long-acting beta agonist (LABA) as their only maintenance treatment, were assigned to take AZD1419 or placebo weekly for 13 doses with staged withdrawal of LABA and inhaled glucocorticoids [15]. Time to loss of asthma control was not different between AZD1419 and placebo. Cytokine studies (eg, CXCL10) validated sufficient dosing of study drug to achieve an innate type 1 response. Another study using a TLR9 agonist (CYT003) in persistent allergic asthma by subcutaneous injection was terminated due to lack of efficacy compared to placebo [16]. No further follow-up was obtained.

It appears that a TLR9 agonist will not be helpful in asthma unless a specific subset of asthmatic patients is found that responds to this type of agent.

PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS — Prostaglandins are one of the major groups of metabolites (along with thromboxanes and leukotrienes) derived from arachidonic acid (figure 1). Prostaglandin D2 (PGD2) is the predominant prostaglandin produced by mast cells and is also produced by Th2 lymphocytes and dendritic cells. It has bronchoconstrictive and chemokinetic effects that may contribute to asthma pathogenesis, such as being a potent eosinophil chemoattractant. PGD2 acts on the PGD2 receptor 2 (DP2 receptor) on mast cells, eosinophils, and basophils. The DP2 receptor mediates migration of Th2 lymphocytes, delays Th2 cell apoptosis and stimulation of Th2 cells to produce interleukin-4 (IL-4), IL-5, and IL-13 among other effects.(See "Pathogenesis of asthma", section on 'Early and late phase reactions'.)

Studies of oral PGD2 antagonists have suggested potential improvement as add-on therapy for asthma, as demonstrated below:

Fevipiprant – In two phase III trials, each with approximately 900 patients, add-on therapy with the DP2 receptor antagonist fevipiprant (150 mg or 450 mg) failed to demonstrate a reduction in annualized asthma exacerbation rate versus placebo [17]. However, pooled analysis of the studies showed a 22 percent reduction in the exacerbation rate with the 450 mg fevipiprant dose and a nonsignificant 10 percent reduction with the lower dose. Small improvements in lung function and patient-reported asthma control were not statistically significant with either dose. Serious adverse events and rates of discontinuation were similar between the groups.

GB001 – In a trial of patients with mild asthma tapered off controller medications, GB001, an oral antagonist of the DP2 receptor, reduced asthma symptoms, rescue inhaler use, and time to worsening compared with placebo [18]. A subsequent trial of 480 patients evaluated GB001 (20 mg, 40 mg, or 60 mg daily) compared with placebo as add-on therapy for patients with eosinophilic asthma (blood eosinophil count >250/microL) and either frequent exacerbations or poor asthma control [19]. Although fewer patients using GB001 experienced asthma worsening (odds ratio [OR] approximately 0.66), this difference was not statistically significant for any dose. The highest dose of GB001 in the trial led to pruritus and reversible elevations in liver enzymes that resulted in higher rates of discontinuation; the medication was otherwise well-tolerated.

The suggestion of clinical effect in the above trials of oral therapies may lead to further investigation of these drugs or other agents in their class.

NOVEL GLUCOCORTICOID RECEPTOR AGONIST — The novel glucocorticoid receptor agonist AZD5423 is a nonsteroidal compound that binds to the glucocorticoid receptor in a different manner from traditional glucocorticoids. It appears to suppress production of proinflammatory proteins (like traditional glucocorticoids), but with reduced adverse effects in animal models. An inhaled dry powder formulation of AZD5423 was assessed in a trial that randomly assigned 20 subjects with mild allergic asthma to pretreatment with AZD5423 (75 or 300 mcg daily), budesonide (200 mcg twice daily), or placebo for seven days followed by allergen-bronchoprovocation [20]. AZD5423 attenuated the fall in FEV1 during the late phase asthmatic response compared with budesonide or placebo, but did not affect the early decrease in FEV1. AZD5423 also decreased allergen-induced sputum eosinophilia and allergen-induced airway hyperresponsiveness at 24 hours, compared with placebo. AZD5423 inhalation was well-tolerated. However, due to the brief duration of the study, potential adverse effects associated with glucocorticoids were not fully evaluated. Additional studies are needed to determine the safety and efficacy of AZD5423 compared with inhaled glucocorticoids.

AGENTS DIRECTED AT MAST CELLS

Tyrosine kinase inhibitors — The tyrosine kinase of the KIT proto-oncogene receptor mediates the activity of stem cell factor, the major survival and growth factor for mast cells. Mast cells are typically increased in numbers in the airways of people with asthma and are associated with increased bronchial hyperresponsiveness.

The tyrosine kinase inhibitor imatinib reduces the number of bone marrow mast cells and serum tryptase levels, which reflect the number and activation of systemic mast cells. This effect raises the possibility that imatinib may ameliorate severe asthma. In a randomized trial of 62 adults with severe asthma, the effect of imatinib (200 mg/day orally for first two weeks, then 400 mg/day) on airway hyperresponsiveness, as measured by the dose of methacholine required to decrease the forced expiratory volume in one second by 20 percent (PC20), was compared with placebo [21]. After six months, the PC20 in the imatinib group increased by 1.73±0.60 doubling doses (decreased airway hyperresponsiveness), compared with 1.07±0.60 doubling doses in the placebo group (p = 0.048). Serum tryptase levels decreased with imatinib more than with placebo (decrease of 2.02±2.32 versus 0.56±1.39 ng/mL, p = 0.02). These results support a role for mast cells in the pathogenesis of severe asthma, as has been expected. Whether tyrosine kinase inhibition will prove to be a safe and effective treatment for severe asthma awaits further study.

GATA3-SPECIFIC DNAZYME — GATA3 is a transcription factor that is essential for Th2 lymphocyte differentiation and activation (see "The adaptive cellular immune response: T cells and cytokines", section on 'Th2'). SB010 is a synthetic DNA molecule (DNAzyme) that binds uniquely to GATA3 messenger RNA and cleaves it. The effect of SB010 was assessed in 43 patients with mild allergic asthma who were randomly assigned to inhalation of SB010 10 mg or placebo once daily for 28 days [22]. The late asthmatic response to allergen bronchoprovocation was significantly attenuated by SB010 (34 percent decrease in area under the curve [AUC] for FEV1), while the AUC associated with placebo increased by 1 percent. The early asthmatic response was also attenuated. While the degree of suppression of the late response was similar to that of inhaled glucocorticoids, this study supports a potential role for disruption of GATA3 (and thus Th2 cells and possibly other cells that contain GATA3) in asthma.

IMMUNOMODULATORY AGENTS WITH SIGNIFICANT LIMITATIONS — A number of other agents with anti-inflammatory properties have been tried in patients with asthma but have not been demonstrated to have a clear benefit. These agents include macrolide antibiotics, anti-tumor necrosis factor (TNF)-alpha agents, methotrexate, gold, cyclosporine, colchicine, hydroxychloroquine, parenteral immunoglobulin, and dapsone.

Macrolide antibiotics — Macrolide antibiotics have both antimicrobial and anti-inflammatory actions, but guidelines suggest not using macrolides for severe asthma unless indicated for treatment of specific infections, due to the potential for development of macrolide-resistant organisms [23,24].

Some patients with severe asthma have persistent infection with Chlamydia pneumoniae or Mycoplasma pneumoniae that may contribute to neutrophilic inflammation in the airways and poor asthma control [25,26]. One possible role for macrolide antibiotic therapy is to eradicate these infections. Another hypothesis is that macrolides may be useful as glucocorticoid-sparing agents due to their anti-inflammatory effects.

A systematic review and meta-analysis of 25 trials found that macrolides administered for at least four weeks reduced exacerbations compared with placebo (odds ratio 0.47; 95% CI 0.20-1.12; 529 participants), including exacerbations requiring hospitalization or treatment with oral glucocorticoids (rate ratio 0.65; 95% CI 0.53-0.80) [27]. Forced expiratory volume in one second (FEV1) was minimally improved; quality of life and symptom scores were not substantially improved (based on low-certainty evidence). Further research is needed to clarify the effects of macrolide therapy on quality of life and determine whether the benefits pertain to patients from all severe asthma phenotypes and persist after treatment cessation.

Troleandomycin is a macrolide antibiotic that was used in the past as a glucocorticoid-sparing agent in chronic, severe asthma. Its mechanism of action is primarily related to reduced hepatic glucocorticoid metabolism rather than specific anti-inflammatory or antibacterial properties. A meta-analysis of 112 patients in three studies failed to show a significant reduction in the required dose of oral glucocorticoids in patients treated with troleandomycin [28]. There was no improvement in lung function when pooled data from two of these studies were analyzed.

As Next Generation Sequencing, a genetic means for increased sensitivity of detecting microbes in low concentrations in the airways, becomes more feasible to use on a clinical basis, better identification and direction of treatment for asthmatic patients who have these subacute infections will likely evolve.

Anti-TNF-alpha agents — The expression of TNF-alpha is increased in severe asthmatic airways in association with airway neutrophilia [24,29]. Among the anti-TNF-alpha agents, infliximab and golimumab are monoclonal antibodies that bind and neutralize TNF-alpha, whereas etanercept is a soluble TNF-alpha receptor fusion protein that binds TNF-alpha and has a longer half-life than the native soluble receptor. (See "Overview of biologic agents in the rheumatic diseases", section on 'TNF inhibition'.)

Trials of anti-TNF-alpha agents in patients with severe asthma do NOT support a beneficial effect [29-31]. As examples:

A large trial randomly assigned 309 patients with severe asthma to treatment with the fully humanized monoclonal antibody to TNF-alpha, golimumab, or placebo for one year [30]. The trial did not achieve the primary endpoints of reduction in exacerbations and improvement in FEV1; substantial side effects were noted.

In a randomized, open-label study, etanercept was administered for 12 weeks to 10 patients with refractory asthma, 10 patients with mild-to-moderate asthma, and 10 patients without asthma [29]. None of the subjects could reduce or discontinue other therapies, although most patients experienced statistically significant improvements in symptom scores and quality of life [31].

Further studies are unlikely due to the limited benefit and serious adverse effects associated with TNF-alpha blockade [24]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Methotrexate — The exact mechanism by which low dose methotrexate (MTX; 5 to 50 mg per week) exerts its anti-inflammatory effect is uncertain, but may be related to increasing cellular levels of adenosine or inhibition of replication (eg, of activated T lymphocytes). It has been proposed that MTX may increase the sensitivity of lymphocytes to the inhibitory effects of glucocorticoid and reduce serum immunoglobulins in asthma [32,33]. However, MTX is associated with frequent and serious adverse effects in up to one-third of patients. Based on the minimal evidence for benefit, known adverse effects, and requirements for monitoring, guidelines suggest that methotrexate not be used in severe asthma [24,34,35]. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Mechanism of action' and "Major side effects of low-dose methotrexate" and "Methotrexate-induced lung injury".)

The use of MTX in severe asthma has been examined in two systematic reviews:

One review examined 12 randomized trials in which low-dose MTX was given to glucocorticoid-dependent asthmatics [35]. MTX was associated with a 6 percent improvement in FEV1 and a 3.3 mg/day reduction in oral glucocorticoid use.

A separate review that included 10 trials and 185 patients with severe asthma noted a 3 to 4 mg reduction in daily glucocorticoid dose, but no significant improvement in spirometry [34].

Gastrointestinal complaints and transient elevations in liver enzymes were more common in patients randomized to MTX, and three patients with MTX developed potentially life-threatening complications, including pneumonitis in two patients, and severe liver dysfunction in one patient. MTX has also been reported to result in an increased risk of Pneumocystis pneumonia, which can cause death [36-38].

Gold — The precise mechanism of action by which gold exerts an anti-inflammatory effect is unknown, but it has been reported to inhibit neutrophil and lymphocyte activity, antibody secretion, and IgE-induced release of histamine. A systematic review evaluated three trials that included 311 patients with glucocorticoid-dependent asthma [39]. A small decrease in the required oral glucocorticoid dose was noted, but there were insufficient data to study effects on lung function or other clinical outcomes. Given the known adverse effects of gold compounds, their use in asthma is not recommended.

Cyclosporine — Cyclosporine may have a glucocorticoid-sparing effect in some patients with severe asthma, but these modest benefits are outweighed by the significant adverse effects associated with oral cyclosporine [40]. Cyclosporine probably works by altering lymphokine (interleukin [IL]-2, IL-4, IL-5) production by T-lymphocytes, and IL-1 production by monocytes and macrophages. Cyclosporine may also induce apoptosis of CD4+ T-lymphocytes, which are crucial to the late asthmatic response [41].

Three placebo controlled trials, using parallel or crossover design, have been systematically reviewed [40]. Overall, cyclosporine treatment resulted in a 0.5 to 1 mg reduction in the required daily glucocorticoid dose, with a modest improvement in spirometry noted in one study [42].

For this indication, typical doses of cyclosporine range from 3 to 5 mg/kg per day, with serum concentrations between 120 and 150 mcg/mL. These doses and levels are lower than those normally seen among patients taking cyclosporine following organ transplantation.

The adverse effects of cyclosporine include hypertension, renal and liver impairment, hypertrichosis, paresthesias, tremor, and headache. Aerosolized cyclosporine, designed to limit systemic absorption and adverse effects, is under active investigation [43]. (See "Pharmacology of cyclosporine and tacrolimus".)

Colchicine — Colchicine is an anti-inflammatory agent primarily used for the control of gouty arthritis and familial Mediterranean fever. Although low dose oral colchicine (0.6 mg twice daily) has few significant side effects, studies examining the effectiveness of colchicine in asthmatics have also revealed mixed results [44,45].

A prospective multicenter study evaluated the ability of colchicine to be substituted for inhaled glucocorticoids in moderate asthma [45]. Patients were stabilized on triamcinolone acetonide (400 mcg twice daily) and then enrolled in a two-week run-in period, during which all 71 patients took both colchicine (0.6 mg twice daily) and triamcinolone. The patients were then randomized to colchicine or placebo with discontinuation of the inhaled glucocorticoid. After glucocorticoid withdrawal, 60 percent of colchicine-treated and 56 percent of placebo-treated subjects were considered treatment failures. There were no significant differences between the placebo and colchicine groups with regard to "survival" curves, FEV1, peak flow, symptoms, rescue albuterol use, or quality of life scores.

A systematic review found no clinical trials that assessed the effect of colchicine in severe, oral glucocorticoid dependent asthma [46].

Hydroxychloroquine — The antimalarial agent hydroxychloroquine is effective in a number of connective tissue diseases, including rheumatoid arthritis and lupus erythematosus, although the exact mechanism of its anti-inflammatory effect is unknown. Observational data are conflicting concerning the efficacy of this agent among patients with asthma [47-49]. The only serious adverse effect is dose-dependent retinopathy, which can culminate in blindness.

Neither hydroxychloroquine nor the closely related chloroquine is recommended for use in asthma.

Immunoglobulin — Intravenous or subcutaneous immunoglobulin (IG, also known as IVIG when given intravenously) is used as replacement therapy in certain immune deficiency disorders and as an immunomodulator in various immune-mediated disorders. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Due to its general anti-inflammatory actions, IG has been investigated as a possible therapeutic agent in patients with severe asthma. The limited number of studies using high-dose (eg, 1 to 2 g/kg per month) IVIG for asthma have yielded conflicting results; however, the largest trials did not support a beneficial effect, as illustrated by the following examples [50-56]:

In a multicenter trial, patients with severe asthma were randomly assigned to one of three groups, 2 g IVIG/kg per month (16 patients); 1 g IVIG/kg per month (9 patients); or 2 g IV albumin solution (placebo)/kg per month (15 patients) for seven months [56]. The primary outcome was mean daily prednisone-equivalent dose requirements and there was no significant difference in this parameter among the groups. In addition, no differences were noted in the number of emergency department visits, hospitalizations, or missed days of work or school. Three patients in the high dose IVIG group developed symptoms consistent with aseptic meningitis.

A prospective, double-blind, placebo controlled trial was performed in children with severe bronchial asthma, and incorporated a two month stabilization period, three month treatment period of IVIG (1 g/kg) or placebo, and one additional month of follow-up [53]. The IVIG or placebo was given as two initial doses one day apart then two additional doses at four-week intervals. There were no statistical differences between groups in symptom scores, bronchial hyperreactivity, or peak flow variability. Although the incidence of upper respiratory tract infections was also similar between groups, the IVIG group appeared to have less protracted infections.

Another double-blind, placebo controlled trial of IVIG (loading dose 2 g/kg, then 400 mg/kg every three weeks) in 28 patients showed mixed results [54]. Significant reduction in oral glucocorticoid (GC) dose was observed with both IVIG and placebo, which reinforces the necessity of placebo controlled studies. Only patients requiring >2000 mg of oral GC in the year prior to the study had a significant reduction of oral GC dose with IVIG therapy.

One open label, uncontrolled study of high dose IVIG over six months investigated potential mechanisms of action [55]. IVIG acted synergistically with dexamethasone in suppressing lymphocyte activation and significantly improved GC binding affinity, although no difference in efficacy was observed among GC sensitive and GC insensitive asthmatics. (See "Mechanisms and clinical implications of glucocorticoid resistance in asthma".)

Dapsone — Dapsone has both well-known antimicrobial activity (eg, in leprosy) and anti-inflammatory effects, and it has therefore been evaluated as a possible therapeutic agent for chronic asthma. An observational study of 10 patients with asthma, for example, found that twice a day treatment with 100 mg of dapsone had significant GC-sparing effects, such that the average cumulative monthly prednisone dose decreased from 428 to 82 mg [57]. Despite this decrease in GC use, pulmonary function and asthmatic symptoms remained unchanged. Nine of the ten patients, however, developed significant anemia, with an average fall in hemoglobin of 3.6 g/dL. A subsequent systematic review concluded that, given the absence of a randomized trial, there was no reliable evidence to support the use of dapsone in the management of chronic severe asthma [58].

NEBULIZED AGENTS — Lidocaine and heparin are thought to have anti-inflammatory effects in addition to their respective anesthetic and anticoagulant effects. It was hoped that administering these agents by nebulization would deliver the anti-inflammatory effects to the airways without the adverse effects of systemic therapy. However, neither has sufficient benefit by inhalation to pursue further.

Nebulized lidocaine — Lidocaine inhibits exercise-induced bronchospasm [59], and anti-inflammatory effects have been postulated [60]. However, the drug is associated with seizures and fatalities in overdose and is not currently being developed commercially for use in asthma.

A randomized trial evaluated the efficacy of nebulized lidocaine (4 percent solution, 100 mg four times daily) compared to placebo in 50 patients with mild-to-moderate asthma [61]. All subjects were receiving inhaled glucocorticoid therapy at baseline, and additionally received nebulized lidocaine or placebo. Treatment took place over two months, during which subjects were instructed to reduce their inhaled glucocorticoid medication by one-half at weekly intervals, and discontinue it at week four. Patients receiving lidocaine showed improvements in symptom scores, nighttime awakenings, bronchodilator use, forced expiratory volume in one second (FEV1), and eosinophil counts. Patients inhaling placebo showed decrements in these measurements of asthma severity.

An earlier uncontrolled study suggested benefit in a small number of patients with severe, glucocorticoid-dependent asthma [62].

Nebulized heparin — Heparin decreases inflammation, smooth muscle proliferation, eosinophil recruitment, and fibrosis in vitro, raising the possibility that it could reduce airway inflammation and remodeling in asthma [63-65]. Nebulized heparin reduces airway inflammation and hyperresponsiveness in patients with asthma and allergic rhinitis, but evidence of clinical benefit is lacking [66-68]. One placebo controlled study in patients with atopic asthma examined the effect upon the late asthmatic response (LAR) and the baseline FEV1 of multiple doses of nebulized heparin (1000 units/kg per dose) given at 90 and 30 minutes pre-allergen and at 2, 4, and 6 hours post-allergen [66]. In this study, nebulized heparin was found to significantly reduce the LAR (p = 0.005). In addition, although no statistically significant difference was found between the acute effects of heparin and placebo upon baseline FEV1, a beneficial trend with heparin was observed (p = 0.08). Whether heparin or its derivatives are beneficial in the management of chronic asthma is the subject of ongoing investigation.

ANTIFUNGAL AGENTS — Many patients with asthma are sensitized to fungi such as Alternaria, Aspergillus, Cladosporium, Penicillium, Candida, and Trichophyton [69,70]. It is hypothesized that inhalational exposure to these airborne fungi may lead to low level airway colonization, sufficient to cause an ongoing allergic reaction. However, clinical trials have not found sustained improvement in asthma control with antifungal therapy.

A randomized trial in 58 participants with severe asthma and allergic fungal sensitization, but not allergic bronchopulmonary aspergillosis, examined whether treatment with itraconazole for 32 weeks would lead to improved asthma control [69]. The Asthma Quality of Life Questionnaire (AQLQ) score, morning peak flow, and total serum IgE were all statistically improved in the itraconazole group, although these improvements were not sustained after discontinuation of itraconazole. (See "Treatment of allergic bronchopulmonary aspergillosis", section on 'Antifungal therapy'.)

In a randomized trial of 65 patients with moderate-to-severe asthma and IgE sensitization to Aspergillus fumigatus, voriconazole 200 mg twice daily did not reduce exacerbation rates during the three months of treatment or the subsequent nine months, when compared with placebo [71].

SUMMARY AND RECOMMENDATIONS

Biologic agents – Several biologic agents targeting steps in the cascade of cytokines implicated in asthma inflammation have been developed in hopes of ameliorating the inflammation that underlies chronic asthma. (See 'Biologic agents' above and "Pathogenesis of asthma", section on 'Airway inflammation'.)

The main cytokines that are believed to regulate asthmatic airway inflammation are interleukins (IL)-2, 4, 5, and 13. Agents such as monoclonal antibodies (eg, to IL-5, 13, thymic stromal lymphopoietin) and antibodies to receptors (eg, IL-2, IL-5, IL-4, IL-33/ST2) that interfere with these cytokines or deplete cells expressing these receptors continue to be assessed for use in patients with severe asthma. (See 'Biologic agents' above.)

IL-13 promotes IgE production by B cells, generation of eosinophil chemoattractants, and contractility of airway smooth muscle cells, among other effects. However, the anti-IL-13 monoclonal antibodies (ie, lebrikizumab and tralokinumab) have not demonstrated significant clinical benefit in severe asthma. These monoclonal antibodies may need to be directed to certain phenotypes of asthmatic individuals and not the population as a whole. (See 'Anti-IL-13 antibodies' above.)

Other novel therapies – GATA3-specific DNAzyme and a novel glucocorticoid receptor agonist are promising agents based on early clinical trials. (See 'GATA3-specific DNAzyme' above and 'Novel glucocorticoid receptor agonist' above and "Treatment of severe asthma in adolescents and adults", section on 'Anti-thymic stromal lymphopoietin (tezepelumab)'.)

Agents not thought to be helpful

Macrolides – While macrolide antibiotics have anti-inflammatory effects in addition to their antibacterial effects, guidelines suggest not using macrolides for severe asthma unless indicated for treatment of specific infections. This suggestion is based on concerns that widespread use of macrolides would promote development of macrolide-resistant bacteria. (See 'Macrolide antibiotics' above.)

Disease-modifying antirheumatic drugs – Several agents that have anti-inflammatory effects in rheumatic diseases do not appear to be of benefit in asthma, or their adverse effects outweigh the modest benefits. These agents include methotrexate, gold, cyclosporine, hydroxychloroquine, immunoglobulin, and dapsone. (See 'Immunomodulatory agents with significant limitations' above.)

Nebulized lidocaine and heparinLidocaine and heparin are thought to have anti-inflammatory effects in addition to their respective anesthetic and anticoagulant effects. Attempts to administer these agents by nebulization, and thus achieve anti-inflammatory effects in the airways without the adverse effects of systemic therapy, have not been of sufficient benefit to pursue further. (See 'Nebulized agents' above.)

Antifungal therapy (in the absence of allergic bronchopulmonary aspergillosis) – While patients with asthma are often sensitized to fungi (eg, Alternaria, Aspergillus, Cladosporium, Penicillium, Candida, and Trichophyton), antifungal therapy does not lead to sustained improvement in asthma control. (See 'Antifungal agents' above.)

  1. Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008; 178:1002.
  2. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med 2011; 183:1007.
  3. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088.
  4. Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132:567.
  5. Hanania NA, Korenblat P, Chapman KR, et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med 2016; 4:781.
  6. Panettieri RA Jr, Sjöbring U, Péterffy A, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir Med 2018; 6:511.
  7. Russell RJ, Chachi L, FitzGerald JM, et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir Med 2018; 6:499.
  8. Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J 2013; 41:330.
  9. Brightling CE, Nair P, Cousins DJ, et al. Risankizumab in Severe Asthma - A Phase 2a, Placebo-Controlled Trial. N Engl J Med 2021; 385:1669.
  10. Bardin PG, Foster PS. Clinical Translation of Basic Science in Asthma. N Engl J Med 2021; 385:1714.
  11. Kosloski MP, Kalliolias GD, Xu CR, et al. Pharmacokinetics and pharmacodynamics of itepekimab in healthy adults and patients with asthma: Phase I first-in-human and first-in-patient trials. Clin Transl Sci 2022; 15:384.
  12. Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma. N Engl J Med 2021; 385:1656.
  13. Kelsen SG, Agache IO, Soong W, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial. J Allergy Clin Immunol 2021; 148:790.
  14. Jackson S, Candia AF, Delaney S, et al. First-in-Human Study With the Inhaled TLR9 Oligonucleotide Agonist AZD1419 Results in Interferon Responses in the Lung, and Is Safe and Well-Tolerated. Clin Pharmacol Ther 2018; 104:335.
  15. Psallidas I, Backer V, Kuna P, et al. A Phase 2a, Double-Blind, Placebo-controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma. Am J Respir Crit Care Med 2021; 203:296.
  16. Casale TB, Cole J, Beck E, et al. CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study. Allergy 2015; 70:1160.
  17. Brightling CE, Gaga M, Inoue H, et al. Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials. Lancet Respir Med 2021; 9:43.
  18. Asano K, Sagara H, Ichinose M, et al. A Phase 2a Study of DP2 Antagonist GB001 for Asthma. J Allergy Clin Immunol Pract 2020; 8:1275.
  19. Moss MH, Lugogo NL, Castro M, et al. Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma. Chest 2022; 162:297.
  20. Gauvreau GM, Boulet LP, Leigh R, et al. A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses. Am J Respir Crit Care Med 2015; 191:161.
  21. Cahill KN, Katz HR, Cui J, et al. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med 2017; 376:1911.
  22. Krug N, Hohlfeld JM, Kirsten AM, et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N Engl J Med 2015; 372:1987.
  23. Reiter J, Demirel N, Mendy A, et al. Macrolides for the long-term management of asthma--a meta-analysis of randomized clinical trials. Allergy 2013; 68:1040.
  24. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343.
  25. Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest 2007; 132:1962.
  26. Martin RJ, Kraft M, Chu HW, et al. A link between chronic asthma and chronic infection. J Allergy Clin Immunol 2001; 107:595.
  27. Undela K, Goldsmith L, Kew KM, Ferrara G. Macrolides versus placebo for chronic asthma. Cochrane Database Syst Rev 2021; 11:CD002997.
  28. Evans DJ, Cullinan P, Geddes DM. Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002987.
  29. Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697.
  30. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179:549.
  31. Morjaria JB, Chauhan AJ, Babu KS, et al. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008; 63:584.
  32. Vrugt B, Wilson S, Bron A, et al. Low-dose methotrexate treatment in severe glucocorticoid-dependent asthma: effect on mucosal inflammation and in vitro sensitivity to glucocorticoids of mitogen-induced T-cell proliferation. Eur Respir J 2000; 15:478.
  33. Corrigan CJ, Shiner RJ, Shakur BH, Ind PW. Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy. Clin Exp Allergy 2005; 35:579.
  34. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000; :CD000391.
  35. Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials. Respir Med 1998; 92:1059.
  36. Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study. Ann Intern Med 1991; 114:353.
  37. Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma. Thorax 1991; 46:936.
  38. Vallerand H, Cossart C, Milosevic D, et al. Fatal pneumocystis pneumonia in asthmatic patient treated with methotrexate. Lancet 1992; 339:1551.
  39. Evans DJ, Cullinan P, Geddes DM. Gold as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002985.
  40. Evans DJ, Cullinan P, Geddes DM. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; :CD002993.
  41. Ying S, Khan LN, Meng Q, et al. Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 in asthmatics. Eur Respir J 2003; 22:207.
  42. Coren ME, Rosenthal M, Bush A. The use of cyclosporin in corticosteroid dependent asthma. Arch Dis Child 1997; 77:522.
  43. Sato H, Ogawa K, Kojo Y, et al. Development of cyclosporine A-loaded dry-emulsion formulation using highly purified glycerol monooleate for safe inhalation therapy. Int J Pharm 2013; 448:282.
  44. Schwarz YA, Kivity S, Ilfeld DN, et al. A clinical and immunologic study of colchicine in asthma. J Allergy Clin Immunol 1990; 85:578.
  45. Fish JE, Peters SP, Chambers CV, et al. An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Am J Respir Crit Care Med 1997; 156:1165.
  46. Dewey A, Dean T, Bara A, et al. Colchicine as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2003; :CD003273.
  47. Roberts JA, Gunneberg A, Elliott JA, Thomson NC. Hydroxychloroquine in steroid dependent asthma. Pulm Pharmacol 1988; 1:59.
  48. Charous BL. Open study of hydroxychloroquine in the treatment of severe symptomatic or corticosteroid-dependent asthma. Ann Allergy 1990; 65:53.
  49. Charous BL. Effectiveness of long-term treatment of severe asthma with hydroxychloroquine (HCQ). Ann N Y Acad Sci 1991; 629:432.
  50. Mazer BD, Gelfand EW. An open-label study of high-dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991; 87:976.
  51. Landwehr LP, Jeppson JD, Katlan MG, et al. Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma. Chest 1998; 114:1349.
  52. Vrugt B, Wilson S, van Velzen E, et al. Effects of high dose intravenous immunoglobulin in two severe corticosteroid insensitive asthmatic patients. Thorax 1997; 52:662.
  53. Niggemann B, Leupold W, Schuster A, et al. Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma. Clin Exp Allergy 1998; 28:205.
  54. Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999; 103:810.
  55. Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin. J Allergy Clin Immunol 1999; 103:421.
  56. Ballow M. Is steroid-dependent asthma a disease treatable with intravenous immunoglobulin? Clin Immunol 1999; 91:123.
  57. Berlow BA, Liebhaber MI, Dyer Z, Spiegel TM. The effect of dapsone in steroid-dependent asthma. J Allergy Clin Immunol 1991; 87:710.
  58. Dewey A, Bara A, Dean T, Walters H. Dapsone as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2002; :CD003268.
  59. Enright PL, McNally JF, Souhrada JF. Effect of lidocaine on the ventilatory and airway responses to exercise in asthmatics. Am Rev Respir Dis 1980; 122:823.
  60. She ZW, Liming JD, Fagan JB, et al. Inhibition of hypochlorous acid by lidocaine and native components of alveolar epithelial lining fluid. Am Rev Respir Dis 1991; 144:227.
  61. Hunt LW, Frigas E, Butterfield JH, et al. Treatment of asthma with nebulized lidocaine: a randomized, placebo-controlled study. J Allergy Clin Immunol 2004; 113:853.
  62. Hunt LW, Swedlund HA, Gleich GJ. Effect of nebulized lidocaine on severe glucocorticoid-dependent asthma. Mayo Clin Proc 1996; 71:361.
  63. Koyama N, Kinsella MG, Wight TN, et al. Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells. Circ Res 1998; 83:305.
  64. Li CM, Newman D, Khosla J, Sannes PL. Heparin inhibits DNA synthesis and gene expression in alveolar type II cells. Am J Respir Cell Mol Biol 2002; 27:345.
  65. Lever R, Page C. Glycosaminoglycans, airways inflammation and bronchial hyperresponsiveness. Pulm Pharmacol Ther 2001; 14:249.
  66. Diamant Z, Timmers MC, van der Veen H, et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med 1996; 153:1790.
  67. Vancheri C, Mastruzzo C, Armato F, et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 2001; 108:703.
  68. Ceyhan B, Celikel T. Effect of inhaled heparin on methacholine-induced bronchial hyperreactivity. Chest 1995; 107:1009.
  69. Denning DW, O'Driscoll BR, Powell G, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med 2009; 179:11.
  70. Matsuoka H, Niimi A, Matsumoto H, et al. Specific IgE response to trichophyton and asthma severity. Chest 2009; 135:898.
  71. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol 2014; 134:33.
Topic 526 Version 71.0

References

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