Rapidly-expanding suite of biologics to reduce asthma exacerbationsJune 11, 2019
Monoclonal antibodies (mAbs) are antibodies produced artificially through genetic engineering and related techniques.
mAbs target various proteins that influence cell activity, such as receptors or other proteins present on the surface of normal and cancer cells. These biologic therapeutics are currently used extensively to treat cancer, cardiovascular diseases, inflammatory conditions etc.
Several mAbs have been developed to target asthma phenotypes.
Omalizumab is directed against immunoglobulin E (IgE). It binds circulating IgE, causing decreased IgE levels, inhibition of IgE binding with its receptors, and downregulation of IgE receptors on mast cells, basophils and dendritic cells. This results in decreased release of inflammatory mediators related to the allergic response.
Omalizumab is the only biologic therapy approved for paediatric use in children 6 years and older.
A recent Cochrane review of omalizumab use in adults and children with asthma found that omalizumab use compared with placebo reduced asthma exacerbations.
In the adolescent/adult studies, high levels of type 2 inflammatory markers such as fractional exhaled nitric oxide (FeNO) levels, eosinophilia, periostin levels, and IgE levels23 have predicted improved response to omalizumab.
A 2003 analysis of pooled clinical trial data reported a malignancy risk of 0.5% in omalizumab-treated patients.
Currently in development, ligelizumab is a humanized anti-IgE monoclonal antibody that binds circulating IgE. In a phase 1 study, ligelizumab has been shown to be more potent at suppressing free IgE and IgE bound to mast cells and basophils than omalizumab.
In a phase 2 double-blind parallel-group trial in 37 adults with mild allergic asthma, ligelizumab elicited a 3-fold greater provocative concentration of allergen, causing a 15% decrease in FEV1 compared with omalizumab and 16-fold greater than placebo at 12 weeks. Ligelizumab was administered subcutaneously every 2 weeks. So far, no studies have been done in children or adolescents, and there is no data on phenotypic response.
Mepolizumab targets IL5, a cytokine that promotes both the activation and longevity of eosinophils. The Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA) study randomised 576 adolescents and adults with severe eosinophilic asthma found that asthma exacerbations requiring oral corticosteroids (OCS) were reduced 47% and 53% with IV and SC mepolizumab compared with placebo, respectively. Asthma exacerbations requiring an ED visit were reduced 32% and 61% with intravenous (IV) and subcutaneous (SC) mepolizumab.
The 3 randomized controlled trials included only patients with eosinophilic asthma on the basis that an antibody that reduces eosinophil levels would be most effective in eosinophilic asthma.
Mepolizumab has been shown to decrease eosinophil counts in both serum and sputum.
There are no studies on children above 12 years old, as of now, although many studies included adolescents.
Mepolizumab is approved by USFDA as add-on maintenance therapy in patients who are 12 years and older with eosinophilic asthma.
Two randomised, double-blind, placebo-controlled trials (RDBPCT) have been conducted on reslizumab in adolescents and adults with eosinophilic asthma. A phase 3 trial of 374 adolescents and adults aged 12–75 years with inadequately controlled eosinophilic asthma. This study noted improved asthma control compared with placebo. However, the quality of life measure trended to improve in the 0.3mg/kg dose of reslizumab but was only significant for the higher dose.
Two duplicate RDBPCTs (phase 3) in adolescents and adults with uncontrolled eosinophilic asthma with serum eosinophils =400 cells/µL on medium-to-high dose ICS therapy noted a significant reduction in asthma exacerbation frequency as well as improvements in time to exacerbation, asthma control, and quality of life
As with mepolizumab, the presence of eosinophilia as a biomarker for reslizumab efficacy was demonstrated in an RDBPCT of reslizumab in adult asthmatics, which demonstrated no clinically significant effect on either lung function or symptom control in patients unselected for baseline eosinophil levels.
Reslizumab has been shown to decrease blood eosinophil counts, but studies are not available to show differentiation between responders and nonresponders in the magnitude of reduction in blood eosinophils.
Reslizumab is USFDA approved for add-on therapy in adults aged 18 and older with eosinophilic asthma.
An RDBPCT of 369 adults with severe asthma requiring oral steroid therapy use noted that benralizumab use of 30 mg SC either every 4 weeks or every 8 weeks reduced median final oral glucocorticoid dose from baseline by 75%, compared with a 25% reduction in the placebo group. Benralizumab use reduced the annual exacerbation rate by 55% versus placebo when administered every 4 weeks and by 70% when administered every 8 weeks. No significant effect on forced respiratory volume 1 (FEV1) was noted.
Increased blood eosinophil levels of more than 300 cells/µL have been identified in some studies as a biomarker of benralizumab efficacy. However, a pooled analysis of SIROCCO and CALIMA study data supported the use of benralizumab in patients with blood eosinophil counts =150 cells/µL73 and a newly released subsequent pooled analyses extended the efficacy irrespective of eosinophil count, although noting that the higher the eosinophil count the greater the benefit.
Benralizumab is FDA approved for patients with severe asthma aged 12 years and above, who have an eosinophilic phenotype.
Dupilumab is a human monoclonal antibody to the alpha subunit of the IL4 receptor, thereby blocking the activity of IL4 and IL13. Dupilumab is the only drug approved for self-administration.
The IL4 cytokine is an essential cytokine to T helper 2 (Th2) cell polarization, whereas the IL13 cytokine is associated with periostin production in the bronchial epithelial cells, ultimately resulting in smooth muscle contraction, mucous production, airway remodeling and hyper-responsiveness. IL13 also works with IL4 to result in IgE production.
An RDBPCT of dupilumab use in 104 adults aged between 18 and 65 years with moderate-to-severe asthma and high blood or sputum eosinophil counts above 300 cells/µL and 3% respectively on medium-to-high dose ICS plus LABAs resulted in an 87% reduction in asthma exacerbations and increased time to asthma exacerbation despite stopping LABA and ICS therapy while on dupilumab compared with placebo. There was noted improvement in FEV1 as early as the second week of treatment, which was maintained for the 12 weeks of the study. An RDBPCT of dupilumab using 300mg SC every 2 weeks for 24 weeks in 210 adults with OCS-dependent asthma noted a 59% decrease in severe exacerbations in the dupilumab group despite a -70.1% reduction in OCS. An RDBPCT of 1902 adolescents and adults with uncontrolled asthma noted that dupilumab reduced severe exacerbations by 47.7% compared with placebo while increasing FEV1.
Dupilumab has been shown to reduce FeNO levels and other levels of Th2 inflammation including TARC, eotaxin-3, and IgE.
Dupilumab has been approved by US FDA for adolescents and adults aged 12 years and older with moderate-to-severe asthma as add-on maintenance therapy.
Lebrikizumab is a humanized monoclonal antibody against IL13. IL13 also works with IL4 to result in IgE production. The IL4 receptor (alpha subunit) is critical for both IL4 and IL13 signal transduction.
A phase 2 RDBPCT of lebrikizumab using 250 mg dosage strength SC once a month in 219 adults with asthma uncontrolled on medium-to-high dose ICS therapy noted a significant improvement in FEV1 after 12 weeks of lebrikizumab (5.5% points higher than placebo) although no significant change was noted in several other secondary efficacy outcomes including asthma control.
Another phase 2 RDBPCT of 212 adults aged 18–65 years not receiving ICS therapy noted no significant improvement in FEV1 with multiple different doses of lebrikizumab compared with placebo even with stratification based on periostin levels, although there was a reduced risk of treatment failure in all lebrikizumab dose groups.
Periostin levels have emerged from the mentioned studies as a biomarker strongly correlated with lebrikizumab efficacy. Lebrikizumab has been associated with a decrease in FeNO, with greater reductions in FeNO in the high periostin groups.
There are a small number of studies thus far that are limited to the adult population
Tralokinumab targets IL13. A phase 2 RDBPCT of multiple doses of tralokinumab in 194 adults aged 18–65 years with moderate-to-severe asthma noted no significant improvement in control with tralokinumab although there was a significant decrease in beta-agonist use.
A phase 2 RDBPCT of tralokinumab in 452 adults with severe uncontrolled asthma noted that tralokinumab use of 300 mg SC every 2 or 4 weeks did not result in significant percentage change in annual asthma exacerbation rates. Prebronchodilator FEV1 was significantly increased in the tralokinumab every 2 weeks group compared with placebo but not in the tralokinumab every 4 weeks group. Subgroup analysis identified adults with a high baseline serum dipeptidyl peptidase-4, or high serum periostin levels had improved FEV1, asthma control and exacerbation rates.
Tezepelumab is a human anti-TSLP monoclonal immunoglobulin that prevents binding of TSLP with its receptor, preventing TSLP-initiated inflammatory responses through the activation of dendritic cells and mast cells. There has only been one proof-of-concept RDBPCT of tezepelumab in 31 adults with allergic asthma that noted attenuation of both the early and late asthmatic responses, with a 45.9% smaller decrease in FEV1 during the late phase response after 12 weeks of treatment.
A phase 2 RDBPCT of tezepelumab in adults with uncontrolled asthma despite medium-to-high ICS and LABA therapy noted significant reductions in exacerbation rates with tezepelumab, independent of baseline serum eosinophil levels, as well as an improvement in FEV1. No studies have been done in the paediatric population, the biomarker profile of those most likely to respond remains unknown.
Many small molecule drugs are also showing great promise.