Difamilast for the treatment of atopic dermatitis

Abstract

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease. The pathogenesis of AD is complex and still not fully understood. Despite recent therapeutic developments, the current therapeutic arsenal of AD remains limited and is associated with long-term efficacy and safety issues. Therefore, new topical therapies with different mechanisms of action are required to overcome the limitations of existing treatments. Difamilast is a phosphodiesterase 4 inhibitor currently in phase 3 studies. Difamilast shows antipruritic and anti-inflammatory properties and a rapid onset of action, with significant differences in some parameters from the vehicle within 1 week of treatment. Phase 2 and 3 clinical trials have shown that difamilast ointments are effective and well tolerated in adult and pediatric patients with AD, and are expected to be used for long-term AD treatment. In 2021, difamilast was the first phosphodiesterase 4inhibitor to acquire manufacturing and marketing approval in Japan for the treatment of adult and pediatric patients (2 years of age and older) with AD. This article is a narrative review of the current literature on difamilast in the management of AD.

Introduction

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease characterized by xerosis and pruritus. ¹ The prevalence of AD ranges from 15% to 30% in children and from 2% to 10% in adults in developed countries. ² Despite the enormous clinical heterogeneity, pruritus is a hallmark of AD. Some features of patients, such as the ethnic background, age at disease onset and morphology, distribution, and severity of the lesions, influence the clinical phenotype. ² AD is associated with other atopic diseases in the “atopic march”, and they include AD, asthma, food allergy, allergic rhinoconjunctivitis, and eosinophilic esophagitis. ³ Additionally, patients with AD complain about functional impairment and the burden of sleep disturbance, leading to anxiety, depression, and reduced health-related quality of life. ⁴ The pathogenesis of AD is complex and multifactorial, including environmental and genetic factors, skin barrier dysfunction, and immunological abnormality. ⁵ Current guidelines for managing AD advise a multifaceted approach. ⁶ Topical treatments are the mainstay of AD treatment. ⁷ The most commonly used treatments are moisturizers and emollients to repair the skin’s barrier function and topical anti-inflammatory agents to suppress inflammation. ⁶ Despite the effectiveness of topical corticosteroids (TCSs) in most patients with mild to moderate AD, their long-term daily use is not recommended because of their cutaneous (cutaneous atrophy) and systemic (e.g., suppression of the hypothalamic–pituitary–adrenal axis, mainly in children) adverse effects (AEs). ⁸ Topical calcineurin inhibitors (TCIs), which are steroid-sparing anti-inflammatory agents, are generally less effective than TCSs and are considered second-line treatment. ⁶ In addition, TCIs carry boxed warnings, despite increasing evidence from long-term studies that dispute the theoretical risk of malignancy. ⁹ Despite recent developments, the current therapeutic arsenal for AD remains limited and related to long-term efficacy and safety issues. Therefore, there is a demand to develop new topical therapies with different mechanisms of action that can overcome the limitations of existing treatments. Ruxolitinib (2021, FDA), which is a dual Janus kinase (JAK)1/JAK2 inhibitor, and delgocitinib, which is a pan-JAK inhibitor (2020, Japan), were recently approved for the treatment of AD.^10,11 Recently, studies have suggested that phosphodiesterase 4 (PDE4) inhibition may be an alternative for long-term treatment of AD. In AD, the increase in activity of PDE4 and the consequent reduction in intracellular cyclic adenosine monophosphate (cAMP) lead to the production of pro-inflammatory mediators and an increase in cytokines involved in inflammation from AD.^12,13 Crisaborole is the first PDE4 inhibitor approved for AD treatment (since 2020 for ages >3 months). ¹⁴ Difamilast is a new selective PDE4 inhibitor currently used in phase 3 studies. In 2021, difamilast was the first PDE4 inhibitor to acquire manufacturing and marketing approval in Japan for the treatment of adult and pediatric patients (≥2 years of age) with AD. ¹⁵

This article is a narrative review of the current literature on difamilast in the management of AD. A review of the published literature was conducted (up until October 2022) using the PubMed database, published abstracts, and virtual presentations from scientific meetings, data from industry press releases, and results published on ClinicalTrials.gov. Manuscripts with trial results, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on the topic of the article were selected.

Role of PDE4 in the pathogenesis of AD

The pathogenesis of AD involves environmental factors, host genetics, immunological abnormalities, epidermal barrier dysfunction, and dysbiosis. ¹⁶ Depending on the subtype, several immune cytokine pathways, such as T helper (Th) 2, Th22, Th17, and Th1, are amplified. ¹⁷ Recent studies have suggested a role of PDE4 in a wide group of immune-related diseases including AD. ¹⁸ PDEs are enzymes that degrade cAMP or cyclic guanosine monophosphate. ¹⁹ cAMP plays a role in immune and inflammatory regulation responses, with increased levels of cAMP suppressing monocytes and T cells. ²⁰ Diverse PDE isoenzymes are expressed in specific tissue. PDE3 is preferentially expressed in the lungs, liver, heart, adipose tissue, inflammatory cells, and platelets, and PDE7 is in the kidneys, heart, pancreas, brain, skeletal muscle, and T lymphocytes. ²⁰ There are 20 variants in the PDE4 gene families of PDE4A, PDE4B, PDE4C, and PDE4D. ¹⁸ In AD, PDE4 is found in inflammatory and immune cells, such as B and T lymphocytes, neutrophils, monocytes, basophils, eosinophils, mast cells, and endothelial cells. ²¹ Increased cAMP-PDE activity has been documented in mononuclear lymphocytes from patients with AD, even those in whom the disease was in remission. ²² In unstimulated cells from patients with AD, to maintain a homeostatic steady state, there may be an increase in PDE activity in mononuclear lymphocytes owing to the upregulation of adenylate cyclase and increased cAMP levels. ¹⁸ When stimulated, a further increase in cAMP production fails to overcome the already increased PDE levels, and adequate cAMP levels are not maintained. ¹⁸ Furthermore, augmented PDE activity in monocytes results in raised production of prostaglandin E2, with a consequent increase in interleukin (IL)-10 and IL-6 levels, both of which contribute to the characteristic Th1/Th2 imbalance. ¹⁸ Mononuclear lymphocyte cultures from patients with AD have shown that PDE4 inhibition diminishes prostaglandin E2, IL-4, and IL-10 levels. ¹⁸ Based on this possibility to switch the overall imbalance in immune responses without using corticosteroids, PDE4 inhibition is considered a potential target for AD treatment. Although PDE4’s effects on AD are not yet fully understood, the selective inhibition of PDE4 allows for a more in-depth understanding of the immunological markers and cytokines involved. PDE4 inhibitors have the ability to affect various cytokines similarly to TCSs and TCIs. ¹⁸ Currently, there is still a lack of evidence regarding PDE4 inhibition and dysbiosis of AD. ¹⁸

Difamilast

Difamilast (OPA-15406) is a non-steroidal, selective, topical PDE4 inhibitor. This drug exhibits highly selective inhibition of PDE4 subtype B (half maximal inhibitory concentration=11.2 nmol/L), although it also exerts inhibitory outcomes on PDE2. Besides the rapid absorption of difamilast, on day 1 of dosing, there are low plasma difamilast concentrations in 0.3% (weight/weight) and 1% (wt/wt) formulations (maximum plasma concentration after administration = 3.18 and 4.74 ng/mL; time to reach Cmax = 4.01 and 4.06 hours, respectively). ²³

Difamilast is being investigated for the treatment of mild to moderate AD. Phase 2 and 3 trials have exhibited favorable efficacy and safety profiles in pediatric and adult patients. ⁷ We describe phase 2 and 3 clinical trial data in detail below (Table 1).

Table 1.

Difamilast results in the treatment of AD.

Study	Phase	Study design	Primary endpoints	Results	Main adverse effects
Study to evaluate the effectiveness and safety of topical OPA-15406 ointment to treat participants with atopic dermatitis (NCT02068352) 24	2	Randomized,PC, DB121 patientsTreatment period of 8 weeksTopical administrationPatients aged between 10 and 70 years Randomized 1:1:10.3% difamilast ointment (n = 41) 1% difamilast ointment (n = 43) Vehicle (n = 37) Twice daily, with applications occurring approximately 12 hours apartThirty dermatology specialty research centers from the United States, Australia, and Poland participated in the trial	Percentage of successful responses on the IGA (IGA score: 0 or 1 with at least a 2-grade reduction from the baseline score) at week 4)	Success rate at week 4: - 0.3% difamilast: 14.6% (P = 0.0690 vs vehicle)- 1% difamilast: 20.9% (P = 0.0165 vs vehicle) - Vehicle: 2.7%	AEs: 51% (62/121) of patients- 0.3% difamilast: 59% (24/41) - 1% difamilast: 42% (18/43) - Vehicle: 54% (20/37) The most frequent AE in each treatment group was worsening of AD (26/121): - 0.3% difamilast: 20% (8/41) - 1% difamilast: 5% (2/43) - Vehicle: 8% (3/37)
Study of OPA-15406 ointment in patients with atopic dermatitis (NCT02914548) 5	2	Randomized, PC, DBScreening period of 2–30 days, treatment period of 8 weeks, and post-treatment observation period of 2 weeks200 patientsTopical administrationPatients aged between 15 and 70 years Randomized 1:1:10.3% difamilast ointment (n = 67) 1% difamilast ointment (n = 67) Vehicle (n = 67) Twice daily, with applications occurring approximately 12 hours apartAt 14 sites in Japan	Percentage of successful responses on the IGA at week 4	Success rate at week 4: - 0.3% difamilast: 14.93% (P = 0.0782 vs vehicle) - 1% difamilast: 22.39% (P = 0.0328 vs vehicle) - Vehicle: 9.09%	AEs: 39.0% (78/200) of patients- 0.3% difamilast: 46.3% (31/67) - 1% difamilast: 29.9% (20/67) - Vehicle: 40.9% (27/66) The most frequent AEs were worsening of AD, followed by viral upper respiratory tract infection and pruritusWorsening of AD: - 16.4% (11/67) of patients on 0.3% difamilast, 9.0% (6/67) on 1% difamilast, and 18.2% (12/66) on the vehicleViral upper respiratory tract infection: - 10.4% (7/67) of patients on 0.3% difamilast, 6.0% (4/67) on 1% difamilast, and 10.6% (7/66) on vehiclePruritus: - 7.5% (5/67) of patients on 0.3% difamilast, 1.5% (1/67) on 1% difamilast, and 6.1% (4/66) on the vehicle
Phase 2 Study of OPA-15406 ointment in pediatric patients with atopic dermatitis (NCT03018691) 25	2	Randomized, PC, DBScreening period of 2–30 days, treatment period of 8 weeks, and post-treatment observation period of 2 weeks73 patientsTopical administrationJapanese pediatric patients aged 2–14 yearsRandomized 1:1:10.3% difamilast ointment (n = 24) 1% difamilast ointment (n = 25) Vehicle (n = 24) Twice daily, with applications occurring approximately 12 hours apart	Number of patients who experienced AEs	IGA success rates at weeks 1, 2, and 4: - 0.3% difamilast: 4.17%, 33.33%, and 37.50%, respectively- 1% difamilast: 16.00%, 32.00%, and 40.00% respectively- Vehicle: 0.00%, 4.17%, and 8.33%, respectivelyDifferences between vehicle and: - 0.3% difamilast: 28% (P = 0.3055), 29.49% (P = 0.0104), and 30.39% (P = 0.0114), respectively- 1% difamilast: 16.91% (P = 0.0331), 29.79% (P = 0.0071), and 31.95% (P = 0.0113), respectively	AEs: 50.7% (37/73) of patients- 0.3% difamilast: 45.8% (11/24) - 1% difamilast: 56.0% (14/25) - Vehicle: 50.0% (12/24) TEAEs observed in at least 5% of patients: - 0.3% difamilast: worsening of AD (8.3%) and influenza (8.3%)- 1% difamilast: upper respiratory tract inflammation (24.0%) and increased blood alkaline phosphatase concentrations (8.0%)- Vehicle: worsening of AD (16.7%), viral infection, and upper respiratory tract inflammation (each 8.3%)
Comparison trial of OPA-15406 ointment in adult patients with atopic dermatitis syndrome (NCT03908970) 7	3	Randomized, PC, DBScreening period of 2–30 days and a 4-week assessment period364 patientsTopical administrationJapanese patients aged 15–70 yearsRandomized 1:11% difamilast ointment (n = 182) Vehicle (n = 182) Twice daily, with applications occurring approximately 12 hours apart	Percentage of successful responses on the IGA at week 4	Success in the IGA scoreAt week 1: - 1% difamilast: 10.99% (P < 0.001) - Vehicle: 0.55%At week 2: - 1% difamilast: 23.08% (P < 0.001) - Vehicle: 6.04%At week 4: - 1% difamilast: 38.46% (P < 0.001) - Vehicle: 12.64%	TEAEs: - 1% difamilast: 17.6% (32/182) - Vehicle: 28.0% (12/182) Most frequent TEAEs: - Worsening of AD (3.8% of patients on 1% difamilast and 12.1% on vehicle), followed by nasopharyngitis (4.9% of patients on 1% difamilast and 3.8% on vehicle)
Long-term trial of OPA-15406 ointment in adult and pediatric patients with atopic dermatitis (NCT03961529) 26	3	Long-term, open-labelScreening period (2–30 days) and a treatment period (52 weeks) 366 patientsTopical administrationJapanese adult (aged 15–70 years) and pediatric patients (aged 2–14 years) Adults: 1% difamilast ointment (n = 166) Pediatric patients: 0.3% difamilast ointment (n = 144) and 1% difamilast ointment (n = 56) Twice daily, with applications occurring approximately 12 hours apart	Number of patients who experienced TEAEs	Cumulative success rates in the EASI-75At week 4: 9.6% and 32.0% in adult and pediatric patients, respectivelyAt week 24: rates increased to 33.1% in adult patients and to 60.5% in pediatric patientsAt week 52: rates increased to 55.4% in adult patients and to 73.5% in pediatric patientsCumulative success rates in the IGA scoreAt week 4: 3.6% and 15.5% in adult and pediatric patients, respectively At week 24: 18.7% and 38.5% in adult and pediatric patients, respectivelyAt week 52: 34.9% and 52.5% in adult and pediatric patients, respectively	TEAEs: - Adult patients: 72.3%- Pediatric patients: 89.0%Most frequent AEs: - Adult patients: worsening of AD (21.1%), followed by nasopharyngitis (14.5%)- Pediatric patients: nasopharyngitis (32.0%), followed by worsening of AD (23.5%) and impetigo (15.5%)
Comparison trial of OPA-15406 ointment in pediatric patients with atopic dermatitis (NCT03911401) 23	3	Randomized, PC, DBScreening period of 2–30 days and a 4-week assessment period251 patientsTopical administrationJapanese pediatric patients aged 2–14 yearsRandomized 1:1:10.3% difamilast ointment (n = 83) 1% difamilast ointment (n = 85) Vehicle (n = 83) Twice daily, with applications occurring approximately 12 hours apart	Percentage of successful responses on the IGA at week 4	IGA score success rate at week 4: - 0.3% difamilast: 44.6% (P < 0001 vs vehicle) - 1% difamilast: 47.1% (P < 0001 vs vehicle) - Vehicle: 18.1%	TEAEs: - 0.3% difamilast: 33.0%- 1% difamilast: 34.0%- Vehicle: 34.0%Most frequent TEAEs: - Treatment groups: nasopharyngitis, followed by worsening of AD and impetigo

AD, atopic dermatitis; PC, placebo-controlled; DB, double-blind; AEs, adverse events; TEAEs, treatment-emergent adverse events; IGA, Investigator’s Global Assessment (score of 0 or 1: “free/almost free”); EASI, Eczema Area and Severity Index; EASI-75, improvement ≥75% in the EASI from baseline.

Phase 2 clinical trials

A phase 2 (NCT02068352), vehicle-controlled, randomized, double-blind, parallel-group, 8-week trial evaluated the effectiveness and safety of topical difamilast ointment in patients with mild to moderate AD. Thirty research centers participated in this trial from the United States, Australia, and Poland. A total of 121 patients were randomized 1:1:1 to receive 0.3% difamilast ointment (wt/wt) (n = 41), 1% difamilast ointment (n = 43), or vehicle (n = 37) on a double-blind basis, twice daily, with applications occurring approximately 12 hours apart. ²⁴ This trial included patients aged between 10 and 70 years with a history of AD longer than 3 years and an initial Investigator Global Assessment score of Disease Severity (IGA) of 2 (mild) or 3 (moderate). The total body surface area (BSA) affected at baseline was between 5% and 40%. The head, face, and neck were not included in the protocol. Patients on phototherapy or systemic therapy within 28 days or those who used TCIs or TCSs within 7 days of baseline were excluded from the trial. ²⁴ The primary endpoint was the proportion of successful responses on the IGA (IGA score of 0 or 1 with at least a 2-grade reduction from the baseline score) at week 4. ²⁴

At week 4 in this trial, the success rates of the IGA score were 14.6%, 20.9%, and 2.7% for 0.3% difamilast, 1% difamilast, and vehicle, respectively (P = 0.0690 vs vehicle and P = 0.0165 vs vehicle, respectively). There were no significant differences in the success rates of the subgroups when analyzed by BSA at baseline, age, or geographical region. ²⁴ An IGA of 0 or 1, with or without a 2-degree reduction from baseline, was achieved in 24.4%, 30.2%, and 10.0% of patients treated with 0.3% difamilast, 1% difamilast, and vehicle, respectively (P = 0.1287 vs vehicle and P = 0.0354 vs vehicle, respectively). In the group treated with 1% difamilast, there was a relatively rapid improvement (weeks 2–4), which was maintained until the end of treatment (week 8). The 1% difamilast group showed a rapid and sustained improvement in patients' pruritus compared with the vehicle group. As early as week 1, an improvement in the mean Visual Analog Scale pruritus score was observed from moderate (63.7 ± 20.3 mm) to mild (40.5 ± 27.1 mm) at 1 week, representing a 36.4% change from baseline. The improvement with 0.3% difamilast was less pronounced. ²⁴

During the study, AEs were observed in 51% (62/121) of patients, with rates of 59% (24/41) in those on 0.3% difamilast, 42% (18/43) in those on 1% difamilast, and 54% (20/37) in those on the vehicle. Of these, AEs were considered potentially therapeutically related in 9% (11/121) of patients, with rates of 12% (5/41) on 0.3% difamilast, 2% (1/43) on 1% difamilast, and 14% (5/37) on the vehicle. The most frequent AE in each treatment group was worsening of AD (26/121), with rates of 20% (8/41) on 0.3% difamilast, 5% (2/43) on 1% difamilast, and 8% (3/37) on the vehicle. However, the worsening was considered to be related to therapy in only 5% of patients, and none of them were in the 1% difamilast group. All AEs with a potential association with therapy were of mild to moderate intensity. Serious AEs were considered in five patients, and none were related to treatment. ²⁴

Another phase 2 (NCT02914548), vehicle-controlled, randomized, double-blind, parallel-group trial evaluated the effectiveness and safety of topical difamilast ointment in Japanese patients aged 15 to 70 years with mild to moderate AD. This study was conducted at 14 sites in Japan. The study consisted of three treatment periods as follows: a screening period (2–30 days), a treatment period (8 weeks), and a post-treatment observation period (2 weeks). If a patient discontinued therapy during the treatment period, the patient was immediately evaluated in the post-treatment period. ⁵ Of 223 patients screened, 200 were randomized 1:1:1 to receive 0.3% (w/w) (n = 67) or 1% (n = 67) difamilast ointment or vehicle (n = 66) on a double-blind basis, twice daily, with applications occurring approximately 12 hours apart. The trial included patients aged between 15 and 70 years with a history of AD for longer than 3 years and an initial IGA of 2 or 3. BSA affected at baseline was between 5% and 40%. The head, face, and neck were not included in the protocol. The following patients were excluded from the study: patients with a clinically significant complication or a history of any disorder; those with an abnormal and clinically significant laboratory value, pulse rate, blood pressure result, or electrocardiographic finding; those who could not stop using antihistamines, TCSs, retinoids, or immunomodulators from 7 days before the initial exam; those who required treatment with immunomodulators, systemic corticosteroids, antimetabolites, or biological retinoids from 28 days before the start of the study; those in whom ultraviolet phototherapy was required from 28 days before the trial; and those who were unable to stop using sodium cromoglycate, systemic antihistamines, suplatast tosilate, or tranilast within 7 days of the initial examination. Women who did not agree with birth control, were pregnant, or were breastfeeding were also excluded. ⁵ The primary endpoint of this trial was the same as that in the previous study (NCT02068352). ²⁴ Overall, 72.5% (145/200) patients completed the trial. Across all treatment groups, the main reported reasons for discontinuation were AEs (18.5%) and withdrawal by patients (5.5%). ⁵

At week 4 in this trial, the IGA success rates were 14.93%, 22.39%, and 9.09% for 0.3% difamilast, 1% difamilast, and vehicle, respectively (P = 0.0782 vs vehicle and P = 0.0328 vs vehicle, respectively). There was a trend toward improvement in the primary endpoint in the 0.3% difamilast group. Furthermore, based on the revised responder analysis, the success rates at week 4 were 26.87%, 32.84%, and 12.12% for 0.3% difamilast, 1% difamilast, and vehicle, respectively (P = 0.0309 vs vehicle and P = 0.0045 vs vehicle, respectively). With regard to secondary endpoints, the rate of success on the IGA score was significantly higher in the 1% difamilast-treated group than in the vehicle group at week 8 (P = 0.0078). Both drug-treated groups showed a significant decrease as early as week 1 in the Eczema Area and Severity Index (EASI), patient-oriented eczema measure , and Visual Analog Scale pruritus scores compared with placebo, and the improved scores were generally maintained through week 8. ⁵

During this trial, AEs were observed in 39.0% (78/200) of patients, and they occurred in 46.3% (31/67) of those on 0.3% difamilast, 29.9% (20/67) on 1% difamilast, and 40.9% (27/66) on the vehicle. Of these, AEs were considered potentially therapeutically related in 11.9% (8/67) of patients on 0.3% difamilast, 7.5% (5/67) on 1% difamilast, and 10.6% (7/66) on the vehicle. The most frequent AE was worsening of AD, followed by viral upper respiratory tract infection and pruritus. A worsening of AD was observed in 16.4% (11/67) of patients on 0.3% difamilast, 9.0% (6/67) on 1% difamilast, and 18.2% (12/66) on the vehicle. Viral upper respiratory tract infection occurred in 10.4% (7/67) of patients on 0.3% difamilast, 6.0% (4/67) on 1% difamilast, and 10.6% (7/66) on the vehicle. Additionally, pruritus was observed in 7.5% (5/67), 1.5% (1/67) and 6.1% (4/66) of patients treated with 0.3% difamilast, 1% difamilast, and vehicle, respectively. The incidence rates of treatment-emergent AEs (TEAEs) leading to discontinuation were 22.4% (15/67), 10.4% (7/67) and 22.7% (15/66) in patients treated with 0.3%difamilast, 1% difamilast, and vehicle, respectively. Across all treatment groups, the TEAEs that most frequently led to discontinuation were worsening of AD and pruritus. No deaths or severe TEAEs were reported in this study. All TEAEs observed in the drug-treated groups were mild or moderate. ⁵

Another phase 2 (NCT03018691), vehicle-controlled, randomized, double-blind, parallel-group trial evaluated the efficacy and safety of topical difamilast ointment in Japanese pediatric patients aged 2 to 14 years with mild to moderate AD. This study was conducted at eight sites in Japan. The study also consisted of three treatment periods as follows: a screening period (2–30 days), a treatment period (4 weeks), and a post-treatment observation period (2 weeks). If a patient discontinued therapy during the treatment period, the patient was immediately evaluated in the post-treatment period. ²⁵ Of 74 patients who were screened, 73 were randomized 1:1:1 to receive 0.3% difamilast ointment (w/w) (n = 24), 1% difamilast ointment (n = 25), or vehicle (n = 24) on a double-blind basis, twice daily, with applications occurring approximately 12 hours apart. The trial included patients aged between 2 and 14 years with AD and an initial IGA score of 2 or 3. BSA affected at baseline was between 5% and 40%. The trial exclusion criteria were the same as those in the previously described phase 2 study (NCT02914548). ²⁵ Overall, 86.3% (63/73) patients completed the trial. Across all treatment groups, the main reported reasons for discontinuation were AEs (8.2%) and withdrawal by a parent/guardian (2.7%). ²⁵

At weeks 1, 2, and 4 in this trial, the success rates in the IGA score were 4.17%, 33.33%, and 37.50% in patients treated with 0.3% difamilast, 16.00%, 32.00%, and 40.00% in those treated with 1% difamilast, and 0.00%, 4.17%, and 8.33% in those treated with the vehicle, respectively. At weeks 1, 2, and 4, the differences in the IGA score between the 0.3% difamilast and vehicle groups were 4.28% (P = 0.3055), 29.49% (P = 0.0104), and 30.39% (P = 0.0114), respectively, and those between the 1% difamilast and vehicle groups were 16.91% (P = 0.0331), 29.79% (P=0.0071), and 31.95% (P = 0.0113), respectively. Both difamilast groups showed a more elevated incidence of success in the IGA score than that in the vehicle group over the 4-week trial. ²⁵ In addition, both drug-treated groups showed better improvement from baseline in the EASI, patient-oriented eczema measure, and Visual Analog Scale pruritus scores than that in the vehicle-treated group throughout the study. ²⁵

During this trial, AEs were observed in 50.7% (37/73) of patients, with 45.8% (11/24) on 0.3% difamilast, 56.0% (14/25) on difamilast 1% and 50.0% (12/24) on the vehicle. TEAEs were worsening of AD (8.3%) and influenza (8.3%) in the 0.3% difamilast group, upper respiratory tract inflammation (24.0%) and increased blood alkaline phosphatase (8.0%) in the 1% difamilast group, and worsening of AD (16.7%), viral infection, and upper respiratory tract inflammation (8.3% in each) in the vehicle group. The incidence rates of therapy-related TEAE were 4.2%, 16.0%, and 20.8% in the 0.3% difamilast, 1% difamilast, and vehicle-treated groups, respectively. The rates of worsening of investigational medical product-related AD were 4.2%, 4.0%, and 12.5% in the 0.3% difamilast, 1% difamilast, and vehicle-treated groups, respectively. Folliculitis treatment-related AEs (4.2%) were also found in the 0.3% difamilast group, increased blood alkaline phosphatase (8.0%) and urine protein were present (4.0%) in the 1% difamilast group, and pigmentation disorder (4.2%) and pruritus (4.2%) were found in the vehicle group. All TEAEs were mild or moderate. No severe TEAEs or deaths were observed. ²⁵

Phase 3 clinical trials

A phase 3 (NCT03908970), vehicle-controlled, randomized, double-blind, parallel-group, multicenter comparison trial of 1% difamilast ointment and its vehicle was performed in Japanese patients aged 15 to 70 years with mild to moderate AD. This trial had a screening period (2–30 days) and a 4-week assessment period. ⁷ Of 414 patients screened, 364 were randomized 1:1 to receive 1% difamilast ointment (w/w) (n = 182) or vehicle (n = 182) on a double-blind basis, twice daily, with applications occurring approximately 12 hours apart. The inclusion criteria and the primary endpoint were similar to those in a previous study (NCT02914548). ⁷ The exclusion criteria were the existence of activity or a history of other concomitant cutaneous diseases, the occurrence of an AD outbreak within 28 days before the initial examination, and an active viral cutaneous infection. ⁷ Overall, 82.4% (300/364) of patients completed the trial. Across all treatment groups, the main reported reason for discontinuation was withdrawal of consent, followed by AEs. ⁷

At weeks 1, 2, and 4 in this trial, the rate of success in the IGA score was significantly higher in patients treated with 1% difamilast than in those treated with the vehicle. At week 1, the success rates in IGA score in the 1% difamilast and vehicle groups were 10.99% and 0.55% (P < 0.001) those at week 2 were 23.08% and 6.04% (P < 0.001), and those at week 4 were 38.46% and 12.64% (P < 0.001), respectively. ⁷

During the study, TEAEs were observed in 17.6% (32/182) of patients in the 1% difamilast group, and in 28.0% (12/182) of patients in the vehicle group. TEAEs were mostly mild or moderate in severity. The most frequent TEAEs reported were worsening of AD (3.8% of patients with 1% difamilast and 12.1% with vehicle), followed by nasopharyngitis (4.9% of patients with 1% difamilast and 3.8% with vehicle). In this trial, no pain was observed at the application site in the 1% difamilast group. The percentage of patients who discontinued treatment owing to TEAEs was 3.8% in the 1% difamilast group and 11.5% in the vehicle group. TEAEs that were considered treatment-related occurred in 1 (0.5%) patient in the 1% difamilast group and in 16 (8.8%) patients in the vehicle group. The most frequent treatment-related TEAE was worsening of AD (0.5% of patients with 1% difamilast and 6.0% with vehicle). No serious AEs or deaths were reported in either treatment group. ⁷

A phase 3, long-term, open-label study (NCT03961529) was conducted at 37 study sites in Japan. This study had a screening period (2–30 days) and a treatment period (52 weeks). The efficacy and safety were examined on day 0 (baseline), at weeks 2 and 4, and every 4 weeks. ²⁶ Patients were allowed to discontinue treatment for any reason at any time. Adults received 1% difamilast and pediatric patients received 0.3% or 1% difamilast ointment on the basis of their AD severity, twice daily for 52 weeks. Of 381 patients screened, 366 (200 pediatric patients, and 166 adult patients) were included in the trial. In pediatric patients, 144 started with 0.3% difamilast and 56 with 1% difamilast. The adults were aged 15 to 70 years, and pediatric patients were aged 2 to 14 years, with an IGA score of at least 2 and BSA >5% at baseline. ²⁶ The following patients were excluded: those with active viral skin infection; those with a history of another cutaneous disease than AD; those with clinically significant abnormal blood pressure, pulse rate, or laboratory tests; those with an outbreak of AD or contact dermatitis within 28 days before starting the study; and those unable to withhold other treatments for AD. ²⁶ Overall, 82.5% (302/366) patients (178 pediatric patients and 124 adult patients) completed the trial. ²⁶

At week 4 of this study, the cumulative success rates in improvement ≥75% in the EASI from baseline (EASI-75) were 9.6% and 32.0% in adult and pediatric patients, respectively. These rates increased to 33.1% and 60.5% at week 24, and to 55.4% and 73.5% at week 52 in adult and pediatric patients, respectively. The cumulative success rates of the IGA score were 3.6% and 15.5% at week 4, 18.7% and 38.5% at week 24, and 34.9% and 52.5% at week 52 in adult and pediatric patients, respectively. ²⁶

Overall, 178 (89.0%) pediatric patients and 120 (72.3%) adult patients had TEAEs. The majority of TEAEs were mild or moderate. In adult patients, the most frequent AEs were worsening of AD (21.1%), followed by nasopharyngitis (14.5%). In pediatric patients, nasopharyngitis (32.0%) was the most frequent AE, followed by worsening of AD (23.5%) and impetigo (15.5%). Severe AEs were observed in one pediatric patient (bacterial pneumonia) and in two adult patients (diffuse large B-cell lymphoma and rhegmatogenous retinal detachment); none of these AEs were considered treatment-related. The percentage of discontinuations due to TEAEs was reported in 3.5% of pediatric patients and in 7.8% of adult patients. AEs were reported to be drug-related in 8.0% and 8.4% of pediatric and adult patients, respectively. In adult patients, the most frequent TRAEs were atopic dermatitis (1.8%) and acne (1.2%). In pediatric patients, the most frequent TRAEs were pigmentation disorder and aggravation of AD (each 2.0%). The incidence of infectious TRAEs was also low in both patient groups, with folliculitis reported in two pediatric patients. No deaths were reported. ²⁶

Another phase 3 (NCT03911401), vehicle-controlled, randomized, double-blind, parallel-group comparison trial included a screening period (2–30 days) and a 4-week assessment period. The study was performed at 30 investigational sites in Japan. If a patient discontinued therapy during the treatment period, a withdrawal examination was performed. ²³ Of 262 patients screened, 251 were randomized 1:1:1 to receive 0.3% difamilast ointment (w/w) (n = 83), 1% difamilast ointment (n = 85), or vehicle (n = 83) on a double-blind basis, twice daily, with applications occurring approximately 12 hours apart. The inclusion criteria established were the same as those in the above-mentioned phase 2 study (NCT03018691). ²³ The exclusion criteria of this trial were as follows: contact dermatitis or an AD outbreak within 28 days before a baseline examination; an inability to persist in the study without modifying the administration and dosage of systemic sodium cromoglycate, antihistamines, suplatast tosilate, or tranilast from 7 days before the initial examination through week 4; and receiving one of several prescribed treatments before the initial examination, including systemic or topical corticosteroids and ultraviolet light therapy. ²³ The primary endpoints were similar to those in previous studies (NCT02914548 and NCT03908970). ²³

At week 4, the IGA score success rates were 44.6%, 47.1%, and 18.1% for 0.3% difamilast, 1% difamilast, and the vehicle, respectively (P < 0001 vs vehicle and P < 0001 vs vehicle, respectively). Patients in both drug-treated groups also had highly significant IGA score success rates compared with the vehicle group at weeks 1 and 2. ²³ During the study, TEAEs were observed in 33.0% of patients on 0.3% difamilast, 34.0% of patients on 1% difamilast and 34.0% on the vehicle. TEAEs were mostly mild or moderate in severity, and no serious events or deaths were documented. The most frequent TEAEs observed in the treatment groups were nasopharyngitis, followed by worsening of AD and impetigo. TEAEs that were considered treatment-related occurred in 6%, 3%, and 5% of patients on 0.3% difamilast, 1% difamilast, and vehicle, respectively. The most frequent treatment-related TEAE was worsening of AD (1%, 4%, and 0.5% of patients on 0.3% difamilast, 1% difamilast, and vehicle, respectively), followed by folliculitis (1% and 1% of patients on 0.3% and 1% difamilast, respectively). ²³

Discussion

AD is a common skin disorder found mainly in children, which usually develops in the first years of life and sometimes persists into adulthood. AD has an enormous effect on the quality of life of pediatric and adult patients. Several drugs are under development for AD treatment to fill the current therapeutic gaps. Topical PDE4 inhibitors, including difamilast, have been evaluated for AD treatment in phase 2 and 3 trials.

Three phase 3 clinical trials with difamilast were published recently, and showed the efficacy and safety results consistent with previously published phase 2 studies.^5,24,25 All three studies showed the superiority of 1% difamilast compared with placebo regarding primary and secondary endpoints in pediatric and adult patients.^7,23,26 A phase 3 study that evaluated the efficacy and safety of difamilast in Japanese adult and pediatric patients >2 years of age with AD for longer than 52 weeks showed no new safety concerns beyond those identified in the other phase 2 and 3 studies. ²⁶ Discontinuation rates were 11.0% and 25.3% in pediatric and adult patients, respectively. Therefore, most patients completed difamilast treatment during the 52 weeks. In this trial, although 89.0% and 72.3% of pediatric and adult patients, respectively, had TEAEs, most were mild or moderate. This outcome is comparable to that documented in other published phase 2 and 3 trials.^5,7,23–26 Difamilast ointments may be used for long-term AD treatment. In contrast to the effects observed with other PDE4 inhibitors, in all clinical trials, difamilast at any concentration did not cause cutaneous burning or stinging sensations in pediatric patients. ²⁷ A treatment-related mild skin burning sensation was reported by an adult patient in one of these trials, ²⁶ although it was not reported in the other phase 2 and 3 trials.^5,7,23–26 The incidence of treatment-related infectious AEs was generally low in pediatric and adult patients (2.0% and 0.6%, respectively). ²⁶ Impetigo, which was not related to treatment, was mainly observed in pediatric patients, and is postulated to be associated with dry skin with AD in the pediatric population.^28,29 In the NCT03961529 trial, treatment-related folliculitis was observed in only two (1.0%) pediatric patients and in one adult (0.6%) patient, and all cases were mild. ²⁶ In contrast, folliculitis is frequently observed with the use of topical tacrolimus (reported incidence of 11.7%) and TCSs.^30–32 The oral PDE4 inhibitors apremilast and roflumilast, which were approved for the oral treatment of psoriasis and psoriatic arthritis, and exacerbation in severe chronic obstructive pulmonary disease, respectively, are associated with gastrointestinal AEs.^33–36 No treatment-related gastrointestinal AEs were observed in any of the phase 2 and 3 trials.^5,7,23–27 No serious TEAEs, deaths, or clinically significant changes in laboratory tests or vital signs were reported. All published phase 3 trials showed that 0.3% and 1% difamilast ointments were significantly superior to the vehicle regarding the primary endpoint, which was the success rate in the IGA score at week 4, in the pediatric and adult population. In addition, all studies reported significant success rates in the EASI-75 at week 4. An increase in the EASI-75 from weeks 4 to 52 in adult and pediatric patients was observed in the 52-week study (NCT03961529). At week 4, there was a substantial decrease in the mean EASI score from baseline in adult and pediatric patients across all trials, with continued improvement through week 52. Significant effects on the IGA and EASI were observed in the 1% difamilast group compared with the vehicle group from weeks 1 to 4, demonstrating this drug’s rapid onset of action. Additionally, across all trials, responses were numerically higher in patients treated with 1% difamilast vs 0.3% difamilast. An improvement in eczema severity and a decrease in the affected BSA were shown with 1% difamilast.^5,7,23–27 The efficacy and safety profiles of topical difamilast may be due to the degree of its cutaneous absorption and the stronger inhibitory activity against PDE4B than the other three PDE4 subtypes.^18,37 Depending on the severity of pruritus, the patients’ quality of life can be negatively affected. A significant improvement in the Visual Analog Scale pruritus score was observed in the 1% difamilast group as early as week 1 and sustained through week 4, which indicated effective and rapid relief of pruritus. ³⁸ Furthermore, at week 4, significant improvements in the patient-oriented eczema measure score and sleep disturbance indicated the additional benefits of 1% difamilast for patients with AD. At the pediatric age, AD guidelines specify that patients should be assessed for treatment effects once every 1 to 2 weeks, mainly to maximize drug effects and minimize any adverse effects. ⁸ Long-term adherence is critical in the management of chronic diseases such as AD. ⁸ A systematic review reported that a shorter time to the first follow-up visit appeared to improve adherence and treatment outcomes. ³⁹ Consequently, the rapid onset of action of difamilast, which is normally observed within 1 week, may be beneficial for patients, clinicians, and parents/guardians.

The main limitations of phase 3 studies are the inclusion of only Japanese patients, which may decrease the direct results’ generalizability to other patients. However, phase 2 studies did not show significant differences in the efficacy or safety of difamilast between Japanese and non-Japanese patients.^5,24 Similarly, the results of these studies were not directly compared with those of topical TCSs and TCIs. Additionally, patients aged <2 years with a higher prevalence of AD were not included.

Currently, two phase 3 trials (NCT05571943: Open-label Study to Assess the Long-term Safety of Difamilast Ointment 1% in Mild to Moderate Atopic Dermatitis; NCT05372653: A Long-term Trial of OPA-15406 in Infants With Atopic Dermatitis) are ongoing in the recruitment status (Table 2).^40,41 In 2021, difamilast obtained approval in Japan for the treatment of adult and pediatric patients (≥2 years of age) with AD. ¹⁵

Table 2.

Ongoing clinical trials investigating difamilast for the treatment of AD.

Clinical Trials.gov Identifier	Official title	Phase	Estimated enrolment (number of participants)	Status	Estimated study completion date
NCT05571943	A Open-label Study to Assess the Long-term Safety of Difamilast Ointment 1% in Mild to Moderate Atopic Dermatitis	3	500 (United States)	Recruiting	June 2024
NCT05372653	A Long-term Trial of OPA-15406 in Infants With Atopic Dermatitis	3	40 (Japan)	Recruiting	October 2023

Conclusion

Phase 2 and 3 clinical trials have shown that difamilast ointments are effective and well tolerated in adult and pediatric patients with AD, and are expected to be used for long-term AD treatment. Difamilast shows antipruritic and anti-inflammatory properties and a rapid onset of action, with significant differences from the vehicle in some parameters within 1 week of treatment. Based on available efficacy and safety data, mainly in the Japanese population, difamilast is currently approved in Japan and is a new therapeutic option in the treatment of AD.