Dataset Information

Difamilast Ointment in Japanese Adult and Pediatric Patients with Atopic Dermatitis: A Phase III, Long-Term, Open-Label Study.

ABSTRACT:

Introduction

Phosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD.

Methods

Adult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA.

Results

During therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75.

Conclusions

This study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD.

Clinical trial registration

Clinical Trials.gov identifier: NCT03961529.

SUBMITTER: Saeki H

PROVIDER: S-EPMC9276884 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 ?) 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.

Project description:BackgroundChildren aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking.ObjectivesTo report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD.MethodsChildren (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score.ResultsOf 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively.ConclusionsThese safety and efficacy results support the use of dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

Project description:BackgroundFor children aged 6-11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management.ObjectivesThis analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914).MethodsEnrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator's Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required.ResultsData for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response.ConclusionsConsistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6-11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit.Trial registrationClinicalTrials.gov Identifier NCT02612454.