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24th May 2023
The rate of exacerbations in COPD patients with type 2 inflammation is lowered by treatment with dupilumab, according to the findings of a recent randomised, placebo trial.
Patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation experience a lower annualised rate of moderate to severe disease exacerbations when dupilumab is added to standard triple therapy, the BOREAS clinical trial group found.
Published in the New England Journal of Medicine, the study looked at COPD patients with type 2 inflammation, based on an elevated eosinophil count (≥300 cells/µL), who were in receipt of standard triple therapy. They were randomised them to either dupilumab 300 mg or placebo, given subcutaneously once every two weeks.
The primary endpoint was the annualised rate of moderate or severe exacerbations of COPD. Secondary outcomes included the change in the prebronchodilator FEV1 and the St. George’s Respiratory Questionnaire (SGRQ) for which lower scores indicated a better quality of life. In addition, the Evaluating Respiratory Symptoms in COPD (E-RS–COPD) scale was used, with, again, lower scores indicative of less severe symptoms.
A total of 939 patients were included and randomised to either dupilumab (468) or placebo. The mean baseline absolute blood eosinophil count was 401.
The annualised rate of moderate or severe exacerbations was 0.78 (95% CI 0.64 – 0.93) for those given dupilumab and 1.10 (95% CI 0.93 to 1.30) with placebo (rate ratio, RR = 0.70, 95% CI 0.58 to 0.86, p < 0.001).
For the secondary outcomes, the prebronchodilator FEV1 increased from baseline to week 12 by a mean of 160 ml with dupilumab and 77 ml with placebo (p < 0.001) and this difference was sustained through to week 52. Similarly, both the SGRQ and E-RS–COPD scores were significantly lower in those receiving dupilumab at week 52.
The authors concluded that the use of dupilumab in COPD patients with a type 2 inflammation phenotype, experience a lower annualised rate of moderate to severe exacerbations, improved quality of life and better lung function.
COPD exacerbations are linked to an accelerated decline in lung function, especially in patients with eosinophil counts greater than 350 cells/µL and not using inhaled corticosteroids.
Type 2 inflammation is present in a sub-set of COPD patients, with one study finding a prevalence of 37%, and such individuals show a better response to systemic corticosteroids such as prednisolone. Type 2 inflammation is characterised by increased eosinophil counts together with elevated levels of various interleukins including interleukin-5, interleukin-4 and interleukin-13.
Monoclonal antibody treatment targeting interleukin-5 with a view to reducing disease exacerbations has, to date, produced mixed results. For instance, use of benralizumab was not associated with a lower annualised rate of COPD exacerbations. In contrast, treatment with mepolizumab, did lower the annual rate of moderate or severe exacerbations. An alternative, yet untested therapeutic approach, is the use of dupilumab, which blocks two other interleukins elevated in those with the type 2 inflammation phenotype, namely, interleukin-4 and 13.
13th April 2023
Dupilumab treatment for 12 months leads to the lowest number of exacerbations and better improvements in FEV1 compared to two commonly used monoclonal antibodies (mAbs), omalizumab or mepolizumab, in adults with moderate to severe asthma, according to comparative analysis by US researchers.
The prevalence of severe asthma varies between 3.6 and 6.1% of all patients with the disease. Individuals with moderate to severe asthma have the opportunity of being treated with several monoclonal antibodies, which target key inflammatory cytokines involved in disease pathogenesis. All of these currently approved biologic therapies have been shown to improve asthma-related outcomes in individuals with asthma uncontrolled with conventional therapy. However, for patients with more than one phenotype such as allergic and eosinophilic asthma, trying to identify the most suitable agent is less clear. In the absence of direct head-to-head comparative trials, researchers can often utilise observational data to emulate a hypothetical pragmatic randomised trial, which is referred to as the target trial.
In the current analysis, the research team emulated a hypothetical randomised trial, making use electronic health records from a large US-based academic health care system. They included adult participants with baseline IgE levels between 30 and 700 IU/mL and peripheral eosinophil counts of at least 150 cells/μL with the objective of comparing the effectiveness of dupilumab treatment with omalizumab or mepolizumab in patients with moderate to severe asthma. The main outcomes of interest were the incidence of asthma-related exacerbations and the change in baseline FEV1 value over 12 months of follow-up.
Dupilumab treatment and asthma outcomes over 12 months
In all, 68 individuals received dupilumab treatment 68 received omalizumab and 65 received mepolizumab.
Over the 12 month period of follow-up, asthma-related exacerbations occurred in 25.0% of those receiving dupilumab treatment compared to 43.1% for mepolizumab (adjusted hazard ratio, aHR = 0.35, 95% CI 0.18 – 0.71). Compared to omalizumab group, asthma exacerbations occurred in 39.7% of patients, giving a corresponding adjusted hazard ratio of 0.42 (95% CI 0.20 – 0.87).
The change in FEV1 for the different agents were 0.11 L (95% CI -0.003 to 0.222 L) for dupilumab versus mepolizumab and 0.082 L (95% CI -0.040 to 0.204 L) for dupilumab versus omalizumab.
In patients with eosinophil counts of at least 300 cells/μL, the HR for dupilumab compared to mepolizumab was 0.26 (95% CI 0.10 – 0.67) and 0.24 (95% CI 0.09 – 0.63) for dupilumab vs omalizumab.
Based on these findings, the authors concluded that among patients with asthma and eosinophil counts of at least 150 cells/μL and IgE levels of 30 to 700 kU/L, dupilumab was associated with greater improvements in exacerbation and FEV1 value than either omalizumab or mepolizumab.
Citation
Akenroye AT et al. Comparative effectiveness of omalizumab, mepolizumab, and dupilumab in asthma: A target trial emulation. J Allergy Clin Immunol 2023
26th September 2022
Although dupilumab is licensed for moderate to severe atopic eczema from 6 years of age, the drug also appears to be effective in children under 6 years of age according to the findings of a randomised, double-blind, placebo-controlled trial by US researchers.
Atopic eczema is a common childhood condition with a global real-world prevalence study in the paediatric population finding that the 12-month prevalence ranged from 2.7% to 20.1% across countries but that severe disease was generally less than 15%. Dupilumab is a human monoclonal antibody against the interleukin-4 receptor alpha, inhibiting the signalling of interleukin-4 and interleukin-13. The drug has been shown to be effective for adults with moderate to severe disease.
For example, in two identical randomised, placebo-controlled trials, where the primary outcome was the proportion of achieving a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in their score from baseline at week 16, this occurred in 36% of those who received dupilumab every other week and in 36% who received dupilumab weekly.
As mentioned earlier, whilst licensed from age 6, to date, there is limited data on the effectiveness in children under 6 years of age apart from one phase 2, open-label study, which found that a single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of eczema.
The present study was the first, large scale, randomised, placebo-controlled trial of dupilumab in children as young as 6 months old. The US team recruited children aged 6 months to under 6 years with moderate to severe atopic eczema (investigator’s Global assessment, IGA score of 3 – 4) with an inadequate response to topical corticosteroids. These children were then randomised 1:1 to either subcutaneous placebo or dupilumab 200 mg (body weight > 5 kg to < 15 kg) or 300 mg (> 15 kg but less than 30 kg) every 4 weeks in addition to a low-potency topical corticosteroid (hydrocortisone acetate 1%) for a total of 16 weeks.
The primary endpoint at week 16 was the proportion of patients who achieved an IGA score of 0 or 1 (indicating that their skin was either clear or almost clear). For the secondary endpoint, the team assessed the proportion achieving an EASI75, i.e., a 75% improvement in their eczema area and severity index also at week 16.
Dupilumab and improvement in disease severity
A total of 162 children with a mean age of 4 years (61% male) were randomised to dupilumab (83) or placebo. Among those assigned to dupilumab, 76% had an IGA score of 4 and both groups received hydrocortisone.
At week 16, a significantly higher proportion of patients taking dupilumab achieved the primary outcome (28% vs 4%, p < 0.0001) and this also occurred for the secondary endpoint of an EASI75 (53% vs 11%, p < 0.0001).
A similar proportion of patients had at > 1 treatment-emergent adverse event (64% vs 74%, dupilumab vs placebo).
The authors concluded that dupilumab with concomitant low potency topical steroids significantly improved disease severity compared to placebo in children under 6 years of age and that the drug was well tolerated.
Citation
Paller AS et al. Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial Lancet 2022
21st December 2021
Add-on dupilumab treatment in children with uncontrolled moderate-to-severe asthma produced a significant reduction in the number of exacerbations over a 52-week period, according to results of a Phase III, randomised, double-blind, placebo-controlled trial by researchers from the Division of Allergy, Immunology, and Pulmonary Medicine, Monroe Carell Jr. Children’s Hospital Nashville, US.
The global prevalence of asthma in children varies across the world with an estimated 10.8% of 6–7-year-old children having the disease although rates are lower rates in Northern and Eastern Europe (4.5%) but much higher in North America (20.0%) and Oceania (29.2%). While there are differences in the definition of ‘severe’ asthma, it has been suggested that prevalence of severe childhood asthma may be up to 5% and there is more concerning evidence indicating that childhood asthma increases the risk of COPD in adults.
Asthma appears, in part, to be a Th2-driven inflammatory process, characterised by the release of the cytokines interleukin (IL)-4, IL-5 and IL-13 and higher levels of Th2 inflammation are associated with greater airway hyper-responsiveness and more severe disease though only around 50% of patients have this endotype. The monoclonal antibody, dupilumab, blocks the action of IL-4 and IL-13 and has been approved for the treatment of adults and adolescents with asthma.
In Europe, the EMA has approved add-on dupilumab (brand name Dupixent) to ‘treat severe asthma in patients aged 12 years or over whose asthma is not properly controlled by a combination of high-dose corticosteroids taken by inhalation plus another medicine used for the prevention of asthma. Dupixent is only for use in patients with a type of inflammation of the airways called ‘type 2 inflammation’.
For the present study, the US team recruited children aged 6 to 11 years with physician diagnosed moderate-to-severe asthma. Children were defined as those with type 2 inflammatory asthma phenotype defined by an eosinophil count of > 150 cells/cubic/ml or at least 300 cells/cubic/ml at baseline.
These children were randomised 2:1 to receive subcutaneous dupilumab (or matching placebo) every two weeks for 52 weeks at a dose of 100 mg (if their weight was <30 kg) or 200 mg (if weighing >30 kg). The primary endpoint was the annualised rate of severe exacerbations during the treatment period, defined as a deterioration of asthma control requiring systemic glucocorticoids for at least 3 days, hospitalisation or an emergency department visit that resulted in systemic glucocorticoid use. A key secondary outcome was the change from baseline to week 12 in the percentage of predicted prebronchodilator FEV1 (ppFEV1).
Findings
A total of 408 children with type 2 inflammatory asthma and a mean age of 8.9 years (66.4% male) were randomised to add-on dupilumab therapy or placebo. Among these children, 43% used high-dose inhaled glucocorticoids and had an average of 2.2 severe asthma exacerbations in the past year. An additional 259 children with an eosinophil count > 300 were similarly matched to dupilumab and placebo.
In the type 2 inflammation group, the adjusted annualised rate of severe asthma exacerbations was 0.31 (95% CI 0.22 – 0.42) in the add-on dupilumab group and 0.75 (95% CI 0.54 – 1.03) in the placebo group, giving a relative risk reduction, RR of 59.3% (p < 0.001). Similarly, among those with eosinophil counts > 300, the adjusted annualised rate of severe exacerbations was 0.24 (dupilumab) and 0.67 (placebo).
Overall, the percentage of participants who had no exacerbations during the 52-week study period was 77.1% in the dupilumab group and 59.6% in the placebo group and 79% vs 58.3% in the eosinophil vs placebo groups.
The changes in ppFEV1 were also significantly better for those in the add-on dupilumab group for both asthma phenotypes.
The authors concluded that dupilumab led to a meaningful improvement through asthma exacerbations and improvements in lung function in 6 to 11 year olds with moderate-to-severe asthma.
Citation
Bacharier LB et al. Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma. N Engl J Med 2021
9th December 2021
Patients with moderate-to-severe atopic eczema prescribed the monoclonal antibody dupilumab experienced less severe COVID-19 symptoms according to the results of a prospective study by researchers from the Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, US.
Atopic eczema is a chronic skin disease and is characterised by T helper 2 (Th2)-driven inflammation due to a Th1/Th2 imbalance. Moreover, cytokines released by Th2 cells including IL-4, IL-5 and IL-13 elevate production of IgE and increased inflammation in the skin and aggravate the skin barrier defect seen in atopic eczema. Interestingly, research suggests that infection with COVID-19 leads to an increased level of various interleukins, including IL-13. Since the mode of action for dupilumab involves blockage of the two interleukins, IL-4 and IL-13, it might be possible that the drug impacts on the severity of symptoms in those with COVID-19.
For the present study, the US researchers examined a disease registry within the department of dermatology at their hospital which included medication prescribed for patients with moderate-to-severe atopic eczema. They enrolled patients 9 years of age and older either at the time of a clinic visit or invited them to participate over the telephone. They included patients prescribed dupilumab, other systemic agents and either limited or no current treatment. Individuals were asked about the presence and duration of COVID-19 symptoms and based on their responses, categorised on a 1 – 5 scale ranging from mild disease (1), severe (3) through to 5 (fatal). The primary outcome was the presence of moderate-to-severe COVID-19 symptoms.
Findings
A total of 1237 patients were included, of which 632 with a mean age of 41.2 years (47% male), were prescribed dupilumab, 107 other systemic agents including oral JAK inhibitors, prednisolone, methotrexate and mycophenolate. The remaining 498 patients were on limited treatment or no treatment, with the majority (71%) prescribed only topical agents. In terms of COVID-19 severity, the majority (77%) of all individuals scored 0 on the 1 – 5 scale.
Among non-dupilumab treated patients, there was a nearly four-fold increased risk of experiencing moderate-to-severe COVID-19 symptoms (odds ratio, OR = 3.89, p = 0.01) compared to those prescribed dupilumab. Similarly, this risk was elevated for those with either limited or no treatment (OR = 1.95, p = 0.04).
In addition, when examining the relationship among those with a PCR confirmed COVID-19 diagnosis, non-dupilumab treated patients again had a significantly increased risk of moderate-to-severe COVID-19 symptoms compared to those prescribed dupilumab (OR = 13.79, p = 0.002), as did those with limited or no treatment (OR = 2.44, p = 0.05).
Commenting on their findings, the authors speculated that given the over-expression of Th2 cells in atopic eczema, patients were unable to mount a sufficient Th1 response to viral infections. With the use of dupilumab, which attenuated the Th2 response, the Th1/Th2 imbalance could be redressed allowing individuals to mount a greater Th1 response against the virus.
They concluded by suggesting that future studies should seek to understand the implications of their findings for other specific viral infections.
Citation
Ungar B et al. COVID-19 Symptoms Are Attenuated in Moderate-to-Severe Atopic Dermatitis Patients Treated with Dupilumab. J Allergy Clin Immunol Pract 2021
20th August 2021
Allergic rhinitis is characterised by several symptoms including sneezing, itching, nasal congestion and rhinorrhoea. It can be categorised as either seasonal allergic rhinitis, in which symptoms are evoked in response to season triggers such as pollen or perennial allergic rhinitis, where symptoms are continually present. Seasonal allergic rhinitis is a global health problem and has been reported to affect 15 to 25% of adults and children. Moreover, while localised symptoms are problematic for patients, the condition also has a more generalised effect upon sufferers leading to fatigue, mood changes and reduced cognitive function which can affect work and overall quality of life. Treatment involves the use of oral and intranasal antihistamines as well as intranasal corticosteroids. However, when such treatments fail to provide symptomatic relief, subcutaneous or sublingual allergen immunotherapy can be used with subcutaneous therapy appearing to be more effective. In fact, a recent review found that the benefits of allergen immunotherapy were sustained for at least 2 – 3 years after cessation of treatment.
The role of interleukins (IL) in the pathophysiology of seasonal allergic rhinitis is uncertain although some evidence observed a trend towards higher levels of both IL-4 and IL-13. The monoclonal antibody dupilumab targets the IL-4 and IL-13 receptor and been recently shown to improve asthma and perennial allergic rhinitis symptoms. This led a team from the Department of Medicine and Paediatrics, David Geffen School of Medicine, California, US, to examine whether addition of dupilumab to subcutaneous immunotherapy would provide an additional benefit to patients with seasonal allergic rhinitis. They undertook a phase 2a, randomised trial with four arms, comparing subcutaneous immunotherapy (SCIT) either alone or combined with dupilumab verses placebo in patients with seasonal allergic rhinitis. The study involved a 12-week screening period, a 16-week treatment phase and an 8-week post-treatment follow-up in adult patients (aged 18 years and over but less than 55 years) with seasonal grass pollen allergy. The four treatment arms were: SCIT + placebo; SCIT + dupilumab 300mg every 2 weeks; Dupilumab alone; SCIT alone. The primary outcome as the percentage change from pre-baseline in the area under the curve for peak total nasal symptom score (TNSS), a composite of rhinorrhoea, nasal congestion, nasal itching, and sneezing and measured 0 – 1 hour following a nasal allergen challenge.
Findings
A total of 103 patients were enrolled and randomised to one of the four arms. The mean age of participants assigned to SCIT and dupilumab was 33 years (30.8% male) and the mean age across the study ranged from 33 to 40.3 years. At week 17 and following a nasal allergen challenge, there was no difference between SCIT and SCIT + dupilumab (least squares mean – 56.76% vs 52.03%). Similarly, there was no significant difference in the absolute change in TNSS scores. There was however, a slight, but significant improvement in the peak TNSS scores when dupilumab was added to SCIT (p = 0.026), suggesting that addition of the drug may help improve SCIT tolerability. The authors concluded that there was no benefit from adding dupilumab to SCIT in terms of reducing the response to an allergen challenge.
Citation
Corren J et al. Short-term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomised trial. J Asthma Allergy 2021
10th August 2021
Atopic eczema (AE) is a common, chronic, relapsing-remitting skin condition, characterised by inflammation and intense pruritus and which has a substantial impact on quality of life. It affects up to 22.6% of children, whereas the prevalence in adults varies between 1.2 to 17.1%. While the precise cause of AE remains to be clarified, it is driven by pro-inflammatory interleukins (IL) including IL-4 and IL-13. Evidence that these two cytokines have an important role in the pathophysiology comes from studies with the monoclonal antibody dupilumab.
Though dupilumab was the first biologic agent to be used in patients with moderate-to-severe atopic eczema, only just over a third of patients in two of the largest trials achieved the primary endpoint of clear or almost clear skin. Thus, other pathways are likely to be involved in AE and recent work has implicated the Janus Kinase pathway (JAK) in the signalling of several interleukins including IL-4 and IL-13. Upadacitinib is an oral JAK inhibitor which is currently licensed for use in rheumatoid arthritis.
Nevertheless, a recent phase 3 trial in patients with moderate-to-severe AE found that when combined with topical steroids, oral upadacitinib at a dose of either 15 or 30 mg, led to a significant improvement in disease severity in over 60% of patients. While such data highlights that upadacitinib is an effective treatment, what is less clear, is its position in the eczema treatment pathway.
This led a team from Oregon Medical Research Centre, Portland, US, to undertake a randomised trial, comparing upadacitinib with dupilumab. Eligible patients were adults aged 18 to 75 years, diagnosed with AE and who were candidates for systemic treatment, after a failure of topical therapy. All were randomised 1:1 to 30mg of upadacitinib given once daily until week 24 or 300mg dupilumab subcutaneously every 2 weeks (after a 600mg loading dose). The primary outcome was an EASI75, which represents a 75% improvement in disease severity at week 16.
Findings
A total of 348 participants with a mean age of 36.6 years (52.6% male) were randomised to upadacitinib and 344 with the same mean age (56.4% male) to dupilumab. After 16 weeks, 71% using upadacitinib and 61.1% given dupilumab achieved an EASI75 (p = 0.006). In addition, 27.9% using upadacitinib and 7.6% using dupilumab, achieved an EASI100 (p < 0.001), i.e., were completely clear of their eczema. There were also significantly better improvements in measure of itch severity using upadacitinib compared to dupilumab.
Based on these findings, the authors concluded that upadacitinib was well tolerated and provided superior efficacy to dupilumab.
Citation
Blauvelt A et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis. A Randomised Clinical Trial. JAMA Dermatol 2021
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