Dupilumab in adolescents with uncontrolled moderate-to-severe atopic dermatitis: results from a phase IIa open-label trial and subsequent phase III open-label extension.

BACKGROUND: Dupilumab (monoclonal antibody inhibiting IL-4/IL-13 signalling) is approved for use in adolescents aged ≥ 12 years with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16-week, randomised, placebo-controlled phase III trial in adolescents (NCT03054428). OBJECTIVES: To characterize the pharmacokinetics of dupilumab, and long-term safety and efficacy in adolescents. METHODS: This was a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study with a phase III open-label extension (OLE) in adolescents with moderate-to-severe AD. In the phase IIa study, patients received one dupilumab dose (2 mg kg-1 or 4 mg kg-1 ) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8-week safety follow-up. Patients then enrolled in the OLE, continuing 2 mg kg-1 or 4 mg kg-1 dupilumab weekly. Primary end points were dupilumab concentration-time profile and incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI). RESULTS: Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, target-mediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg L-1 and 161 ± 60 mg L-1 for 2 mg kg-1 and 4 mg kg-1 , respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kg-1 ], 47% [4 mg kg-1 ]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction -34% ± 20% (2 mg kg-1 ) and -51% ± 29% (4 mg kg-1 )]. With continuing treatment, EASI scores improved further [week 52: -85% ± 12% (2 mg kg-1 ) and -84% ± 20% (4 mg kg-1 )]. CONCLUSIONS: In adolescents with moderate-to-severe AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52-week safety and efficacy data support long-term use of dupilumab in this patient population. What's already known about this topic? Adolescents with moderate-to-severe atopic dermatitis (AD) have high unmet medical need, with significant disease burden and limited treatment options. Dupilumab (monoclonal antibody against interleukin-4 receptor α) is approved for the treatment of adolescents with moderate-to-severe AD who are inadequately responsive to standard of care (U.S.A.) or candidates for systemic therapy (European Union). A 16-week, randomized, placebo-controlled phase III trial in adolescents demonstrated significant improvements in AD signs/symptoms with an acceptable safety profile. What does this study add? These studies demonstrate the long-term safety and efficacy of dupilumab in adolescents with moderate-to-severe AD for up to 52 weeks of treatment, thus extending and reinforcing the findings from the 16-week dupilumab phase III trial. The data from these studies also support the use of dupilumab in combination with current standard of care (topical corticosteroids), which was not evaluated in the 16-week phase III monotherapy trial.

Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME).

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.

Effects of 2 inhaled corticosteroids on growth: results of a randomized controlled trial.

OBJECTIVE: To compare the long-term effect of treatment with fluticasone propionate or beclomethasone dipropionate on growth in asthmatic children. DESIGN: Prospective, multicenter, randomized, double-blind, parallel-group study. SETTING: Children requiring regular treatment with inhaled corticosteroids and with a sexual maturity rating of Tanner stage 1 (prepubertal). PATIENTS: Three hundred forty-three children aged 4 to 11 years with asthma. The growth population (excluding patients with protocol violations likely to affect growth measurements) included 277 patients. INTERVENTIONS: Fluticasone propionate or beclomethasone dipropionate, both at a dosage of 200 microg administered twice daily via a dry powder inhaler (Diskhaler) for 12 months. MAIN OUTCOME MEASURES: Growth velocity, lung function, and serum and urinary cortisol levels. RESULTS: The adjusted mean growth velocity in the fluticasone group was significantly greater than that in the beclomethasone group (5.01 [SE, 0.14] vs 4.10 [SE, 0.15] cm/y; difference, 0.91 cm; 95% confidence interval, 0.63-1.20 cm; P<.001). Both treatments improved lung function, with significant differences in favor of fluticasone. Adverse events were similar in both groups, and there were no significant differences in effect on serum and urinary cortisol levels. CONCLUSIONS: The more favorable risk-benefit ratio of fluticasone indicates that this agent is preferable to beclomethasone for the long-term treatment of children with asthma, especially if moderate doses are required.

Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis.

BACKGROUND: Bronchiolitis obliterans (BO) is an uncommon and severe form of chronic obstructive lung disease in children that results from an insult to the lower respiratory tract. METHODS: A case-control study of children under the age of 3 years was performed in 109 cases and 99 controls to determine risk factors for the development of BO. Participants were evaluated by immunofluorescence viral tests, pulmonary function tests, and questions to assess tobacco and other exposures. RESULTS: Bronchiolitis due to adenovirus (odds ratio (OR) 49, 95% confidence interval (CI) 12 to 199) and the need for mechanical ventilation (OR 11, 95% CI 2.6 to 45) were strongly and independently associated with an increased risk for BO. Factors not associated with post-infectious BO included age of the child, sex, and environmental tobacco exposure (either in utero or during infancy). CONCLUSIONS: Adenovirus infection and need for mechanical ventilation are significant risk factors for developing BO in children. Further research is needed to determine why these risk factors are so strong and how they may contribute to the development of the disease.

Lung function in infants with chronic pulmonary disease after severe adenoviral illness.

OBJECTIVE: To evaluate pulmonary function and bronchodilator responses in young children with chronic pulmonary disease (CPD) after a severe adenoviral lower respiratory tract infection. METHODS: Pulmonary function tests were performed in 13 patients (mean age, 1.32 +/- 0.8 years) with CPD and were compared with a control group of 13 healthy infants (mean age, 1.16 +/- 0.4 years). RESULTS: Respiratory rate, peak tidal expiratory flow (PTEF), PTEF/tidal volume, absolute time up to PTEF, time percentage to PTEF, volume percentage for PTEF, and compliance and resistance of the respiratory system were significantly affected in the CPD group. Similarly, maximal flow at functional residual capacity (V'maxFRC) was 56.0 +/- 42 mL/s and 373 +/- 107 mL/s in the CPD and control groups, respectively (P =.001). No within-group differences with baseline values or between-group differences were noted in response to treatment with ipratropium bromide or albuterol. CONCLUSION: Young children with CPD caused by adenovirus have pulmonary function changes characterized by severe obstruction and diminished lung distensibility not responsive to the administration of inhaled ipratropium bromide or albuterol.

CpG oligodeoxynucleotides can reverse Th2-associated allergic airway responses and alter the B7.1/B7.2 expression in a murine model of asthma.

CpG oligodeoxynucleotides (CpG-ODN) administered during Ag sensitization or before Ag challenge can inhibit allergic pulmonary inflammation and airway hyperreactivity in murine models of asthma. In this study, we investigated whether CpG-ODN can reverse an ongoing allergic pulmonary reaction in a mouse model of asthma. AKR mice were sensitized with conalbumin followed by two intratracheal challenges at weekly intervals. CpG-ODN was administered 24 h after the first Ag challenge. CpG-ODN administration reduced Ag-specific IgE levels, bronchoalveolar lavage fluid eosinophils, mucus production, and airway hyperreactivity. We found that postchallenge CpG-ODN treatment significantly increased IFN-gamma concentrations and decreased IL-13, IL-4, and IL-5 concentrations in bronchoalveolar lavage fluids and spleen cell culture supernatants. Postchallenge CpG-ODN treatment also increased B7.1 mRNA expression and decreased B7.2 mRNA expression in lung tissues. These results suggest that CpG-ODN may have potential for treatment of allergic asthma by suppressing Th2 responses during IgE-dependent allergic airway reactions. The down-regulation of Th2 responses by CPG-ODN may be associated with regulation of the costimulatory factors B7.1 and B7.2.

The chinese herbal medicine formula MSSM-002 suppresses allergic airway hyperreactivity and modulates TH1/TH2 responses in a murine model of allergic asthma.

BACKGROUND: Asthma is a major public health problem worldwide, and the morbidity and mortality of asthma have increased in the past two decades. The reputed efficacy, low cost, and relative absence of side effects of traditional Chinese medicines (TCMs) have led to increasing interest in the use of TCMs for the treatment of asthma in Western countries. However, there are few well-controlled scientific studies on the efficacy, safety, and mechanisms of action of TCMs used to treat asthma. OBJECTIVE: The goal of this study was to investigate the effects of the Chinese herbal medicine formula MSSM-002, derived from TCMs used to treat allergic asthma, on a well-characterized mouse model of allergic asthma. METHODS: Mice sensitized intraperitoneally and challenged intratracheally with conalbumin were treated with MSSM-002 24 hours after the first intratracheal challenge. Dexamethasone-treated, saline solution sham-treated, and naive mice served as controls. The effects of MSSM-002 on allergic airway hyperreactivity, inflammation, antigen-specific antibody production, lung histologic features, and cytokine profiles were evaluated. RESULTS: MSSM-002 treatment virtually eliminated airway hyperreactivity and markedly reduced the total number of cells and the percent eosinophils in bronchoalveolar lavage fluids compared with the sham-treated group. Lung histologic features showed that MSSM-002 reduced inflammation and mucus production. These effects were equivalent to the effects of dexamethasone, but in contrast to the overall immunosuppressive effects of dexamethasone MSSM-002 treatment decreased antigen-specific IgE, IL-4, IL-5, and IL-13 levels without suppressing IgG2a and IFN-gamma synthesis. CONCLUSION: MSSM-002 exhibits anti-airway hyperresponsiveness, anti-airway inflammation, and immunoregulatory effects on T(H)1/T(H)2 responses, which may be useful for treatment of allergic asthma.

Food Allergy Herbal Formula-1 (FAHF-1) blocks peanut-induced anaphylaxis in a murine model.

BACKGROUND: Peanut allergy is a major cause of fatal and near-fatal anaphylactic reactions to foods. There is no curative therapy for this condition. Traditional Chinese medicines have been reported to have antiallergic properties, which might be useful for treating peanut allergy. OBJECTIVE: The purpose of this study was to investigate the effects of a Chinese herbal formula, FAHF-1, on peanut anaphylactic reactions in a mouse model of peanut allergy. METHODS: Mice were sensitized with freshly ground whole peanut in the presence of cholera toxin and boosted 1 and 3 weeks later. FAHF-1 treatment was initiated 1 week later and continued for 7 weeks. After treatment, mice were challenged with peanut, and anaphylactic symptoms, body temperatures, and plasma histamine and IgE levels were measured. T-cell proliferative responses and cytokine production were also determined. RESULTS: FAHF-1 completely blocked peanut-induced anaphylactic symptoms and markedly reduced mast cell degranulation and histamine release. Peanut-specific serum IgE levels were significantly reduced by 2 weeks of treatment at the time of challenge, and they remained lower 4 weeks after discontinuation of treatment. FAHF-1 significantly reduced peanut-induced lymphocyte proliferation as well as IL-4, IL-5, and IL-13 synthesis but not IFN-gamma synthesis. No toxic effects on liver or kidney functions were observed, nor was there any overall immune suppression. CONCLUSION: FAHF-1 protected peanut-sensitized mice from anaphylactic reactions and significantly reversed established IgE-mediated peanut allergy. This suggests that FAHF-1 might prove valuable for the treatment of peanut allergy.

Montelukast added to budesonide in children with persistent asthma: a randomized, double-blind, crossover study.

OBJECTIVE: We tested the hypothesis that adding montelukast to budesonide would improve asthma control in children with inhaled glucocorticoid-dependent persistent asthma. STUDY DESIGN: In a multicenter, randomized, double-blind, crossover study, we compared the benefit of adding montelukast, 5 mg, or placebo once daily to budesonide, 200 microg, twice daily. RESULTS: After a 1-month run-in with budesonide, 200 microg, twice daily, 279 children were randomized to montelukast or placebo. The mean +/- SD age was 10.4 +/- 2.2 years, the mean forced expiratory volume in 1 second (FEV(1)) was 77.7% +/- 10.6% predicted, and reversibility was 18.1% +/- 12.9%. Compared with adding placebo to budesonide, adding montelukast produced significant improvements in mean percent change from baseline FEV(1) (P =.062 [P =.010 for per-protocol analysis]), mean absolute change from baseline FEV(1) (P =.040), mean increase from baseline in morning (P =.023) and evening (P =.012) peak expiratory flows, decrease in exacerbation days by approximately 23% (P <.001), decreased beta2-agonist use (P =.013), and reduced blood eosinophil counts (P <.001). The treatments did not differ significantly with regard to safety. CONCLUSIONS: Montelukast, 5 mg, added to budesonide improved asthma control significantly, indicated by a small additive effect on lung function and a clinically relevant decrease in asthma exacerbation days.