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Dupilumab provides favourable longāterm safety and efficacy in children aged ā„ 6 to < 12 years with uncontrolled, severe atopic dermatitis: results from an openālabel phase IIa study and subsequent phase III openālabel extension study
Background
Children aged ā„ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16āweek, randomized, placeboācontrolled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)ā4/ILā13 signalling, significantly improved signs and symptoms with acceptable safety; longerāterm safety and efficacy data are lacking.
Objectives
To report the pharmacokinetic profile and longāterm safety and efficacy of dupilumab in children (aged ā„ 6 to < 12 years) with severe AD.
Methods
Children (aged ā„ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, openālabel, ascendingādose, sequential cohort study and subsequent openālabel extension (OLE) study. Patients received singleādose dupilumab 2 or 4 mg kgā1 followed by 8āweek pharmacokinetic sampling, then 2 or 4 mg kgā1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentrationātime profile and treatmentāemergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PPāNRS) score.
Results
Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, targetāmediated pharmacokinetics characterized dupilumab concentrations (week 24ā48 mean serum concentrations: 2 mg kgā1, 61ā77 mg Lā1; 4 mg kgā1, 143ā181 mg Lā1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kgā1, 47%; 4 mg kgā1, 56%) and AD exacerbation (29% and 13%, respectively). Singleādose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PPāNRS improved by ā37%/ā33% and ā17%/ā20% at week 2 (phase IIa) and ā92%/ā84% and ā70%/ā58% at week 52 (OLE), respectively.
Conclusions
These safety and efficacy results support the use of dupilumab as a continuous longāterm treatment for children aged ā„ 6 to < 12 years with severe AD
Infections in Dupilumab Clinical Trials in Atopic Dermatitis : A Comprehensive Pooled Analysis
Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649
Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.
Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE.
We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety.
The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group).
In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052
Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.
BACKGROUND
Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits
signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important
drivers of atopic or allergic diseases such as atopic dermatitis.
METHODS
In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1
and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose
disease was inadequately controlled by topical treatment. Patients were randomly
assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg)
or placebo weekly or the same dose of dupilumab every other week alternating
with placebo. The primary outcome was the proportion of patients who had both
a score of 0 or 1 (clear or almost clear) on the Investigatorās Global Assessment
and a reduction of 2 points or more in that score from baseline at week 16.
RESULTS
We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary
outcome occurred in 85 patients (38%) who received dupilumab every other week and
in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received
placebo (P<0.001 for both comparisons with placebo). The results were similar in
SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab
every other week and in 87 (36%) who received dupilumab weekly, as compared
with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition,
in the two trials, an improvement from baseline to week 16 of at least 75% on the
Eczema Area and Severity Index was reported in significantly more patients who received
each regimen of dupilumab than in patients who received placebo (P<0.001 for
all comparisons). Dupilumab was also associated with improvement in other clinical
end points, including reduction in pruritus and symptoms of anxiety or depression
and improvement in quality of life. Injection-site reactions and conjunctivitis were
more frequent in the dupilumab groups than in the placebo groups.
CONCLUSIONS
In two phase 3 trials of identical design involving patients with atopic dermatitis,
dupilumab improved the signs and symptoms of atopic dermatitis, including
pruritus, symptoms of anxiety and depression, and quality of life, as compared
with placebo. Trials of longer duration are needed to assess the long-term effectiveness
and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals;
SOLO 1 ClinicalTrials.gov number, NCT02277743; SOLO 2 ClinicalTrials
.gov number, NCT02277769.
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Dupilumab in adolescents with uncontrolled moderateātoāsevere atopic dermatitis : results from a phase IIa openālabel trial and subsequent phase III openālabel extension
Background
Dupilumab (monoclonal antibody inhibiting ILā4/ILā13 signalling) is approved for use in adolescents aged ā„ 12 years with inadequately controlled moderateātoāsevere atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16āweek, randomised, placeboācontrolled phase III trial in adolescents (NCT03054428).
Objectives
To characterize the pharmacokinetics of dupilumab, and longāterm safety and efficacy in adolescents.
Methods
This was a global, multicentre, phase IIa, openālabel, ascendingādose, sequential cohort study with a phase III openālabel extension (OLE) in adolescents with moderateātoāsevere AD. In the phase IIa study, patients received one dupilumab dose (2 mg kgā1 or 4 mg kgā1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8āweek safety followāup. Patients then enrolled in the OLE, continuing 2 mg kgā1 or 4 mg kgā1 dupilumab weekly. Primary end points were dupilumab concentrationātime profile and incidence of treatmentāemergent 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, targetāmediated pharmacokinetics. Mean Ā± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 Ā± 19 mg Lā1 and 161 Ā± 60 mg Lā1 for 2 mg kgā1 and 4 mg kgā1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kgā1], 47% [4 mg kgā1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean Ā± SD reduction ā34% Ā± 20% (2 mg kgā1) and ā51% Ā± 29% (4 mg kgā1)]. With continuing treatment, EASI scores improved further [week 52: ā85% Ā± 12% (2 mg kgā1) and ā84% Ā± 20% (4 mg kgā1)].
Conclusions
In adolescents with moderateātoāsevere AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52āweek safety and efficacy data support longāterm use of dupilumab in this patient population
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 ā„ 12 years with moderate-tosevere 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 ā„ 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
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