FormalPara Key Summary Points

Why carry out this study?

Topical corticosteroids (TCSs) are only recommended to treat infants with atopic dermatitis (AD) aged < 2 years according to the clinical practice guidelines for the management of atopic dermatitis 2021 by the Japanese Dermatological Association.

Because local adverse reactions such as skin atrophy and telangiectasia have been reported in the long-term use of TCSs, a new topical treatment option usable for a long time without safety concerns is required for the treatment of infants with AD aged < 2 years.

A phase 3, long-term, open-label study of difamilast 0.3% or 1% ointment is ongoing to evaluate efficacy and safety in Japanese infants with AD aged 3 to < 24 months.

What was learned from the study?

This ongoing study suggests that difamilast 0.3% or 1% ointment applied to infants with AD aged 3 to < 24 months twice daily is effective and well tolerated as of the interim report in the study period, although it is an open-label study.

Difamilast 0.3% or 1% ointment is expected to be a new long-term treatment option for AD in this population because of its efficacy and safety profiles.

Introduction

Atopic dermatitis (AD) is a common chronic and relapsing inflammatory skin disease characterized by pruritus and eczema. Pruritus is the most troublesome symptom to control in AD, and it promotes scratching and excoriation, which can further aggravate inflammation, increase infection risk, and cause crusting and lichenification [1, 2]. Patients with AD experience sleep disturbance, functional impairment, anxiety, depression, anger, and reduced health-related quality of life [3,4,5].

Treatment strategies for AD in Japan include (1) use of topical corticosteroids (TCSs), tacrolimus ointment (a topical calcineurin inhibitor), and delgocitinib ointment (a Janus kinase inhibitor) [6] to suppress inflammation; (2) use of topical emollients and moisturizers to repair skin barrier function; (3) avoidance of aggravation factors. Thus, the principal goal of AD treatment is to achieve and maintain a state of no or minor clinical symptoms that do not disturb patients’ daily activities [7].

In mild to moderate AD, the use of topical therapies is advantageous compared with systemic treatments because they have a minimum risk of adverse events (AEs) [2]. TCSs, tacrolimus ointment, and delgocitinib ointment are recommended as treatments for patients with AD in Japan. However, the safety of tacrolimus has not been established in infants aged < 2 years. Recently, the package insert of delgocitinib has covered Japanese infants aged 6 to < 24 months based on results of a phase 3, open-label, long-term study [8]. Therefore, TCSs are only recommended to treat patients with AD, including infants aged < 2 years, according to the Clinical Practice Guidelines for the Management of Atopic Dermatitis 2021 issued by the Japanese Dermatological Association [7]. However, local adverse reactions such as skin atrophy and telangiectasia occur with long-term use of TCSs [9,10,11]. Hence, a new topical treatment option that can be used for a long term without safety concerns is required for the treatment of AD in infants aged < 2 years.

AD is a chronic relapsing inflammatory skin disease. Although AD symptoms commonly develop in childhood, most of them resolve with the age, while some may persist into adulthood [4]. AD is well known to be associated with other atopic disorders, including food allergy, asthma, and allergic rhinitis, with the allergic progression termed as atopic march [12, 13]. Thus, initiation of a suitable intervention for AD from an early stage of childhood is required to prevent the persistence of symptoms and subsequent development of atopic march. Non-adherence to TCSs owing to safety concerns by parents or guardians can result in treatment failure in infants [14].

Difamilast is a selective phosphodiesterase 4 (PDE4) inhibitor developed by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan) [15]. PDE4 inhibition has been reported as a therapeutic strategy for inflammatory diseases, including AD [16,17,18]. Previous clinical studies conducted in Japan demonstrated the efficacy and safety of difamilast 1% ointment in adults (aged ≥ 15 years) and difamilast 0.3% or 1% ointment in children (aged 2–14 years) for the treatment of AD [19,20,21,22,23]. Difamilast is the first PDE4 inhibitor to receive manufacturing and marketing approval for the indication of AD in adult and pediatric patients (aged ≥ 2 years) in Japan in September 2021. Subsequently, a phase 3, long-term, open-label study was initiated to evaluate the efficacy and safety of topical difamilast in Japanese infants with AD aged 3 to < 24 months. Here, we report the interim results of the ongoing study.

Methods

This ongoing, phase 3, multicenter, open-label study was initiated on May 23, 2022, to evaluate the efficacy and safety of topical difamilast in infants with AD at five study sites in Japan. Parents or guardians of all included infants provided written informed consent before participation in the study. The study was approved by the institutional review board at each study site and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline, and the applicable local laws and regulatory requirements in Japan.

Patients

Male and female infants aged 3 to < 24 months with a diagnosis of AD according to the Japanese Dermatological Association criteria [7], an Investigator’s Global Assessment (IGA) score of 2 or 3 (on a 5-point scale ranging from 0 [clear] to 4 [severe/very severe]; Table S1 in Supplementary Material) [24], and a total affected body surface area (BSA; excluding the scalp) of 5–40% were included.

Infants with an AD or contact dermatitis flare-up within 28 days before baseline, a complication or history of a skin disease other than AD, an active viral skin infection or clinically significant abnormal laboratory test results, blood pressure or pulse rate were excluded. The full exclusion criteria are summarized in Table S2 in Supplementary Material.

Study Design

The study consisted of a screening period (2–30 days), a 4-week primary evaluation period, and a 48-week long-term extension period (Fig. 1). The investigational medicinal products (IMPs) were difamilast 0.3% and 1% ointments. The vehicle used for the IMPs was white petrolatum. Difamilast 0.3% ointment was applied twice daily to infants in the primary evaluation period. In the long-term extension period, infants could receive difamilast 1% ointment twice daily based on existing clinical conditions at the investigator’s discretion if they had an IGA score of at least 2 and no concerns about unacceptable tolerability. Subsequently, the IMP could be changed back to difamilast 0.3% ointment if improvements in symptoms were observed. Interruption or restarting of IMP application in the long-term extension period was permitted based on existing clinical conditions.

Fig. 1
figure 1

Study design

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Efficacy and safety were evaluated during study site visits at weeks 1, 2, and 4 in the primary evaluation period and, in principle, every 4 weeks in the long-term extension period. If the IMP was first changed to difamilast 1% ointment in the long-term extension period, the next visit was scheduled 2 weeks after the change (Fig. 1). Investigators instructed parents or guardians to apply the IMPs to the currently affected BSA (excluding the scalp) including the application range (%) and total application amount (g) by using a human body diagram at each visit. The amount of IMPs per application was calculated using the following formula: total BSA (m2) × percentage of treatment area (%) × 10 g/m2.

Infants who completed the 4-week primary evaluation period entered the 48-week long-term extension period. The day when evaluations were completed for all infants at week 8 (4 weeks after initiation of the long-term extension period) or at discontinuation was designated as the cut-off day (January 25, 2023). All data of difamilast immediately before the cut-off day were collected for the interim report.

Concomitant topical anti-inflammatory agents as a rescue medication were used for worsening of symptoms at the investigator’s discretion in the long-term extension period with the minimum dose and duration of use that did not interfere with efficacy assessments of IMPs. However, concomitant application of difamilast and anti-inflammatory agents to the same site was prohibited. Prohibited concomitant medications and therapies are summarized in Table S3 in Supplementary Material.

Treatment could be discontinued if investigators judged that the continuation of treatment with IMPs would be an undue risk for infants, for example, safety concerns related to IMPs or serious AEs.

Evaluations

Efficacy and safety of difamilast were assessed for the first time in this study in infants aged 3 to < 24 months. The response rate in the IGA score, defined as the percentage of infants who achieved an IGA score of 0 or 1 with at least a 2-point improvement from baseline, was primarily evaluated for the efficacy evaluation. The response rates in Eczema Area and Severity Index (EASI) 50, 75, and 90 [25], defined as the percentages of infants who achieved, respectively, at least 50%, 75%, and 90% improvement in EASI total score from baseline, were also evaluated. Missing data were handled as non-response.

Efficacy evaluations also included mean percentage changes in EASI total score and each subscale (erythema, induration/papulation, excoriation, and lichenification) score [25] and mean changes in patient-oriented eczema measure (POEM) score [26] and total affected BSA (%) from baseline.

Safety evaluations were based on the incidence and severity of AEs, clinical laboratory tests, physical examinations, and vital signs. AEs were classified by system organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 25.1.

Plasma concentrations of difamilast were measured after application of 0.3% or 1% ointment twice daily for 4 weeks. Data for difamilast 0.3% ointment were collected at week 4 in the primary evaluation period, while data for difamilast 1% ointment were obtained 4 weeks after the IMP was first changed to difamilast 1% ointment in the long-term extension period. Blood samples to determine plasma concentrations were collected 4 (± 2) h after application of the IMPs. The time to maximum plasma concentration was estimated 4 (± 2) h after application.

Statistical Analyses

As this is a long-term open-label study, no statistical tests were prespecified for comparison. All infants who received IMPs at least once were included in both efficacy and safety analysis sets. Of these, infants who had at least one pharmacokinetic assessment after treatment initiation were included in the pharmacokinetic analysis set. Variables were analyzed descriptively using all observed data.

The sample size was set at 40 to evaluate the efficacy and safety of difamilast based on the results of a previous phase 3 study in pediatric patients [22].

Results

Patients

All 41 included infants completed treatment in the primary evaluation period, and no discontinuations were reported at the time of the interim report in the long-term extension period either.

At baseline, 13 infants (31.7%) had an IGA score of 2, and 28 (68.3%) had a score of 3. The mean age was 10.0 months. Mean EASI total score was 9.6, mean POEM score was 7.4, and mean total affected BSA was 27.1%. Based on the Japanese AD severity index [7], AD in 9 infants (22.0%) was assessed as mild, 30 (73.2%) as moderate, and 2 (4.9%) as severe (Table 1).

Table 1 Patient demographics and baseline characteristics
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As of the interim report in the study period, the mean treatment duration was 135.7 days and the mean total dose of IMPs applied was 340.1 g. The maximum treatment duration was 222 days, and the minimum treatment duration was 53 days. The maximum total dose of IMPs applied was 820.7 g, and the minimum total dose of IMPs applied was 68.1 g. In the long-term extension period, 28 infants received difamilast 1% ointment.

As of the interim report, infants completed evaluations at weeks 8 (n = 8), 12 (n = 5), 16 (n = 7), 20 (n = 6), 24 (n = 1), 28 (n = 8), and 32 (n = 6) (Table S4 in Supplementary Material).

TCSs were only used as a rescue medication in this study. As of the interim report, 12 infants (29.3%) received the concomitant TCSs. TCS used most frequently as a rescue medication was dexamethasone valerate.

One infant who developed Kawasaki disease unrelated to the IMP as a serious AE (as described below) experienced interruption for about 2 weeks and then restarting of IMP application in the long-term extension period. No infants experienced interruption and restarting of IMP application except for this serious AE.

Efficacy

The response rate in the IGA score was 45.0% at week 1, which was maintained at 56.1% at week 4 and 63.4% at the interim report (Fig. 2).

Fig. 2
figure 2

Response rate in Investigator’s Global Assessment (IGA) score at each time point. The data represent the percentage of patients who achieved an IGA score of 0 or 1 with at least a 2-point improvement from baseline. Number of patients: 40 (Week 1); 39 (Week 2); 41 (Week 4); 41 (Interim report)

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The response rate in EASI 50 was 80.0% at week 1 and was maintained at 92.7% at week 4 and 92.7% at the interim report. The response rate in EASI 75 was 47.5% at week 1 and was maintained at 82.9% at week 4 and 78.1% at the interim report. Furthermore, the response rate in EASI 90 was 17.5% at week 1 and was maintained at 46.3% at week 4 and 58.5% at the interim report (Fig. 3).

Fig. 3
figure 3

Response rate in Eczema Area and Severity Index (EASI) 50, 75, and 90 at each time point. The data represent the percentage of patients who achieved at least 50%, 75%, and 90% improvements in EASI total score from baseline, respectively. Number of patients: 40 (Week 1); 39 (Week 2); 41 (Week 4); 41 (Interim report)

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The mean percentage change from baseline in EASI total score was − 67.0% at week 1, and the same degree of improvement was maintained at − 78.6% at week 4 and − 82.8% at the interim report (Fig. S1 in Supplementary Material). The mean percentage change from baseline in each EASI subscale (erythema, induration/papulation, excoriation, and lichenification) score also showed considerable reductions at week 1, and the improvement was maintained as of the interim report (Fig. S2 in Supplementary Material). The mean changes from baseline in POEM score and total affected BSA (%) showed the same trend (Figs. S3 and S4 in Supplementary Material).

Of the infants who have never achieved an IGA response under treatment with difamilast 0.3% ointment and whose dose was increased to difamilast 1% ointment from week 4 onward, 11 infants had no dose interruption and underwent IGA assessment after dose increase. In 54.6% of these infants (in 6/11 infants), an IGA response was achieved at atleast one time point after dose increase before data cut-off for the interim report.

Safety

AEs reported in the primary evaluation period are summarized in Table 2. In total, 22 infants (53.7%) experienced AEs, all of which were judged to be unrelated to the IMP and were mild or moderate in severity. No serious AEs or AEs leading to discontinuation were reported. AEs (classified by MedDRA PTs) that were observed in at least 5% of infants were nasopharyngitis (19.5%) and dermatitis contact (7.3%). These AEs were classified by SOC as infections and infestations (34.1%) or skin and subcutaneous tissue disorders (12.2%). No clinically relevant abnormalities were reported in clinical laboratory tests, physical examinations, and vital signs.

Table 2 Summary of adverse events (AEs) and AEs observed in at least 5% of patients in the 4-week primary evaluation period
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Table 3 summarizes AEs that were reported as of the interim report in the study period (AEs reported until the cut-off day). AEs were reported in 36 infants (87.8%) and were all judged to be unrelated to the IMPs. No AEs leading to discontinuation were reported. Regarding the severity, 26 (63.4%) were assessed as mild, 8 (19.5%) as moderate, and 2 (4.9%) as severe. The two events that were assessed as severe were respiratory syncytial virus infection [27] and Kawasaki disease [28]. Although these were judged to be serious events, the two infants recovered from the events.

Table 3 Summary of adverse events (AEs) and AEs observed in at least 5% of patients as of the interim report
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AEs (classified by MedDRA PTs) observed in at least 5% of infants as of the interim report in the study period were nasopharyngitis (70.7%), gastroenteritis (22.0%), COVID-19 (17.1%), otitis media acute (14.6%), hand-foot-and-mouth disease, impetigo, conjunctivitis bacterial (12.2% each), pharyngitis, respiratory syncytial virus infection (9.8% each), dermatitis contact (17.1%), dermatitis diaper (14.6%), and dermatitis atopic (7.3%). These AEs were classified by SOC as infections and infestations (87.8%) or skin and subcutaneous tissue disorders (39.0%). No clinically relevant abnormalities were reported in clinical laboratory tests, physical examinations, and vital signs.

Table 4 summarizes the AEs at application sites reported as of the interim report in the study period. In total, 11 infants (26.8%) experienced AEs at application sites, all of which were mild or moderate in severity. Furthermore, no clinically problematic events at application sites were reported. AEs at application sites (classified by MedDRA PTs) reported in at least two infants were impetigo (12.2%) and dermatitis atopic (4.9%). Of the AEs classified by SOC, infections and infestations were the most frequent (22.0%) followed by skin and subcutaneous tissue disorders (7.3%).

Table 4 Adverse events observed at application sites as of the interim report
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Pharmacokinetics

In infants who received difamilast 0.3% ointment (n = 36) and in those who received difamilast 1% ointment (n = 23), the mean plasma concentrations of the IMPs were 7.2 ng/ml and 12.7 ng/ml, respectively. Five infants who received only difamilast 0.3% ointment were excluded from the pharmacokinetic evaluation as they had not received the IMP within 7 days before blood collection; therefore, the plasma concentrations were considered not to have attained steady state.

Discussion

In this ongoing phase 3, 52-week, open-label study, we evaluated efficacy and safety of difamilast ointments in infants with AD aged 3 to < 24 months. Difamilast ointments demonstrated the efficacy and safety in phase 3, 4-week, randomized, double-blind, vehicle-controlled studies in adult and pediatric patients with AD (aged ≥ 2 years) [21, 22] and received manufacturing and marketing approval for the indication of AD in Japan. Because the present study was conducted in infants with AD aged 3 to < 24 months, we employed the open-label study without vehicle control by ethical considerations. The objective of the present study was to assess the improvements in AD symptoms and the long-term safety with difamilast ointments in this population. To evaluate the preventive effect of difamilast on atopic march will be a challenge in the future.

Response rates in IGA score and EASI 50, 75, and 90 at week 4 in this study were numerically higher than those reported in previous phase 3 studies in Japanese adult and pediatric patients [21, 22]. Innate immunity carried by basophils or group 2 innate lymphoid cells is thought to be mainly involved in the early-onset phase of AD [29, 30]. Difamilast has been reported to improve the symptoms of AD by suppressing interleukin-4 production in basophils [31]. These factors could account for the somewhat high response rates of difamilast ointments in infants with early-onset AD in this study. The clinical manifestations of AD are categorized into three stages according to age: infantile, childhood, and adult stages. It is known that treatment efficacy is likely to appear within a short time in infants and children [7, 32]. This trend was also reflected in the results of the response rates in IGA score and EASI 50, 75, and 90 at week 4 in this study. These response rates were maintained as of the interim report.

Six infants who did not respond successfully to difamilast 0.3% ointment according to the IGA scores showed response with subsequent application of difamilast 1% ointment. Thus, infants in whom difamilast 0.3% ointment shows insufficient efficacy may experience therapeutic effect with difamilast 1% ointment.

Difamilast 0.3% ointment improved not only the EASI total score but also its subscale scores in the primary evaluation period, and the improvement was maintained as of the interim report. This indicates that difamilast is effective regardless of symptoms or area of the eruption in infants. The mean changes from baseline in the POEM score and total affected BSA (%) also showed beneficial results.

Thus, difamilast ointments applied twice daily to infants aged 3 to < 24 months improved clinical signs and symptoms, providing beneficial therapeutic effects to infants.

In the 4-week primary evaluation period, no notable safety concerns were reported. The most frequent AE was nasopharyngitis (19.5%) followed by dermatitis contact (7.3%). These symptoms are widely prevalent in children [33, 34]. Nevertheless, all AEs were judged to be unrelated to the IMP and were mild or moderate in severity; no AEs leading to discontinuation were reported. Thus, no new safety concerns were found in infants treated with difamilast 0.3% ointment in the primary evaluation period.

As of the interim report in the study period, no notable safety concerns were identified with the application of difamilast 0.3% or 1% twice daily. The incidence of AEs (87.8%) was similar to that reported in pediatric patients (89.0%) in the previous phase 3 long-term study of difamilast [23]. Among the AEs, hand-foot-and-mouth disease, impetigo, nasopharyngitis, respiratory syncytial virus infection, dermatitis contact, and dermatitis diaper are commonly prevalent in children. Infants aged < 2 years are thought to be at high risk of infections due to their premature skin barrier function and immature immune function, which result in a high exposure to pathogens [35].

The two IMP-unrelated severe AEs, respiratory syncytial virus infection [27] and Kawasaki disease [28], reported in one infant each as of the interim report, were judged to be serious events. These infants continued treatment without changing dosage and administration because they recovered from the symptoms with medical treatment by hospitalization. The latter continued treatment after interruption for about 2 weeks.

Skin atrophy and telangiectasia, which have been previously reported with TCSs [8,9,10], and burning or stinging sensations, which have been previously reported with tacrolimus ointment [9, 36], were not observed at the application sites in this study.

No IMP-related AEs and no AEs leading to discontinuation were reported. No new safety concerns were found in infants treated with difamilast 0.3% or 1% ointment as of the interim report in the study period.

No IMP-related systemic serious AEs were reported in this study. The systemic influence of topical difamilast may be limited considering the pharmacokinetic profile of minimal systemic absorption.

This study has some limitations. First, this study lacked a control group. The efficacy of the vehicle in infants with AD aged 3 to < 24 months is uncertain because of lack of a control group. The actual usage of a rescue medication is also uncertain when the vehicle is only applied to this population. The lack of the control group may limit the interpretation of the study results of difamilast in this population. Second, use of topical anti-inflammatory agents as a rescue medication was permitted for worsening of symptoms in the 48-week long-term extension period (to the cut-off day), and TCSs were used for 12 infants as of the interim report. However, TCSs as a rescue medication were actually used to treat many symptoms observed other than in the sites to be evaluated, including contact dermatitis, dermatitis diaper, impetigo, folliculitis, erythema multiforme exudativum, otitis externa, and insect bite. Therefore, the influence of TCSs as a rescue medication on the efficacy assessment is unknown in this study. The use of TCSs may also limit discussions on the long-term study results of difamilast in this population. Third, results from this study cannot be directly compared with those from the previous phase 3 studies in patients aged ≥ 2 years [21,22,23]. Fourth, because of the infants’ age range, some assessments relied on reports from parents or guardians. Finally, only Japanese infants were included; therefore, it is not clear whether the results are generalizable to non-Japanese infants.

Conclusions

Regardless of some limitations, based on the results of efficacy and safety observed as of the interim report in the study period, difamilast 0.3% or 1% ointment applied twice daily to infants with AD aged 3 to < 24 months is expected to be a new topical therapeutic option usable for a long-term treatment. The final result will be presented in the near future.