Pediatric Dermatology

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background/Objectives</jats:title><jats:p>Efficacy and safety of roflumilast cream 0.15% were demonstrated in patients aged ≥ 6 years with atopic dermatitis (AD) in two Phase 3 trials. This Phase 3 parallel‐group, double‐blind trial (INTEGUMENT‐PED; NCT04845620) compared the efficacy and safety of roflumilast cream 0.05% and a vehicle in patients aged 2–5 years with AD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients aged 2–5 years with mild‐to‐moderate AD were treated with once‐daily roflumilast cream 0.05% or vehicle for 4 weeks. The primary efficacy endpoint was Validated Investigator Global Assessment for AD (vIGA‐AD) Success (0 [Clear] or 1 [Almost Clear] plus ≥ 2‐grade improvement from baseline) at Week 4. Other endpoints included ≥ 75% improvement in Eczema Area and Severity Index (EASI‐75) and Worst Itch‐Numeric Rating Score (WI‐NRS) Success (≥ 4‐point improvement in patients with baseline ≥ 4). Safety and tolerability were also assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Among 437 and 215 patients treated with roflumilast and vehicle, respectively, significantly greater proportions of the roflumilast group achieved Week‐4 vIGA‐AD Success (25.4% vs. 10.7%; <jats:italic>p</jats:italic> &lt; 0.0001), EASI‐75 (39.4% vs. 20.6%; <jats:italic>p</jats:italic> &lt; 0.0001), and WI‐NRS Success (35.3% vs. 18.0%; nominal <jats:italic>p</jats:italic> = 0.0002). Improvement in pruritus was observed within 24 h after the first application (nominal <jats:italic>p</jats:italic> = 0.0014). Treatment‐emergent adverse event (TEAE) rates were low in both groups, and 98.9% were mild or moderate. At all timepoints, stinging/burning that caused definite discomfort was reported by ≤ 0.7% of caregivers of patients in the roflumilast group.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In this Phase 3 trial, once‐daily roflumilast cream 0.05% improved AD signs/symptoms in patients aged 2–5 years, with early pruritus improvement, low AE rates, and local tolerability comparable with vehicle.</jats:p><jats:p>
<jats:bold>Trial Registration:</jats:bold> <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://clinicaltrials.gov">ClinicalTrials.gov</jats:ext-link>: NCT04845620</jats:p></jats:sec>

publication_history

received

accepted

published

Long‐Term Safety and Effectiveness With Roflumilast Cream 0.15% in Patients ≥ 6 Years of Age With Atopic Dermatitis: A Phase 3 Open‐Label Extension Trial

Dermatitis

Efficacy and safety of roflumilast cream 0.15% were demonstrated in patients aged ≥ 6 years with atopic dermatitis (AD) in two Phase 3 trials. This Phase 3 parallel-group, double-blind trial (INTEGUMENT-PED; NCT04845620) compared the efficacy and safety of roflumilast cream 0.05% and a vehicle in patients aged 2-5 years with AD.
Patients aged 2-5 years with mild-to-moderate AD were treated with once-daily roflumilast cream 0.05% or vehicle for 4 weeks. The primary efficacy endpoint was Validated Investigator Global Assessment for AD (vIGA-AD) Success (0 [Clear] or 1 [Almost Clear] plus ≥ 2-grade improvement from baseline) at Week 4. Other endpoints included ≥ 75% improvement in Eczema Area and Severity Index (EASI-75) and Worst Itch-Numeric Rating Score (WI-NRS) Success (≥ 4-point improvement in patients with baseline ≥ 4). Safety and tolerability were also assessed.
Among 437 and 215 patients treated with roflumilast and vehicle, respectively, significantly greater proportions of the roflumilast group achieved Week-4 vIGA-AD Success (25.4% vs. 10.7%; p < 0.0001), EASI-75 (39.4% vs. 20.6%; p < 0.0001), and WI-NRS Success (35.3% vs. 18.0%; nominal p = 0.0002). Improvement in pruritus was observed within 24 h after the first application (nominal p = 0.0014). Treatment-emergent adverse event (TEAE) rates were low in both groups, and 98.9% were mild or moderate. At all timepoints, stinging/burning that caused definite discomfort was reported by ≤ 0.7% of caregivers of patients in the roflumilast group.
In this Phase 3 trial, once-daily roflumilast cream 0.05% improved AD signs/symptoms in patients aged 2-5 years, with early pruritus improvement, low AE rates, and local tolerability comparable with vehicle.
ClinicalTrials.gov: NCT04845620.

Efficacy and Safety of Once-Daily Roflumilast Cream 0.05% in Pediatric Patients Aged 2-5 Years With Mild-to-Moderate Atopic Dermatitis (INTEGUMENT-PED): A Phase 3 Randomized Controlled Trial.

Efficacy and Safety of Once‐Daily Roflumilast Cream 0.05% in Pediatric Patients Aged 2–5 Years With Mild‐to‐Moderate Atopic Dermatitis (<scp>INTEGUMENT</scp>‐<scp>PED</scp>): A Phase 3 Randomized Controlled Trial

JAMA Dermatology

<jats:sec><jats:title>Importance</jats:title><jats:p>Atopic dermatitis (AD) and plaque psoriasis are inflammatory skin diseases with unmet need for effective topical treatments with few application site reactions.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To assess the efficacy and safety of the topical phosphodiesterase 4 inhibitor PF-07038124 in patients with AD and plaque psoriasis.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>This phase 2a, randomized, double-blind clinical trial was conducted from December 21, 2020, to August 18, 2021, at 34 sites across 4 countries. Eligible patients (aged 18-70 years) had mild to moderate AD (covering 5%-20% body surface area) or plaque psoriasis (covering 5%-15% body surface area). Data were analyzed until December 15, 2021.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients were randomized (1:1) to PF-07038124, 0.01%, topical ointment or vehicle once daily for 6 weeks.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>The primary end point was the percent change from baseline (CFB) in the Eczema Area and Severity Index (EASI) total score among patients with AD and in the Psoriasis Area and Severity Index (PASI) score among patients with plaque psoriasis at week 6. Safety measures included treatment-emergent adverse events, including application site reactions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Overall, 104 patients were randomized (mean [SD] age, 43.0 [15.4] years; 55 [52.9%] women; 4 [3.8%] Asian, 13 [12.5%] Black, and 87 [83.7%] White), including 70 with AD (41 women [58.6%]; mean [SD] ages, 41.4 [16.6] years in the PF-07038124 group and 36.1 [13.9] years in the vehicle group) and 34 with plaque psoriasis (20 men [58.8%]; mean [SD] ages, 51.8 [12.3] years in the PF-07038124 group and 51.2 [10.8] years in the vehicle group). Baseline characteristics were generally balanced. At week 6, the PF-07038124 groups showed significantly greater improvements compared with vehicle groups in EASI (least-squares mean CFB,  −74.9% vs −35.5%; difference, −39.4% [90% CI, −58.8% to −20.1%]; <jats:italic>P</jats:italic> &amp;amp;lt; .001) and PASI scores (CFB, −4.8 vs 0.1; difference, −4.9 [90% CI, −7.0 to −2.8]; <jats:italic>P</jats:italic> &amp;amp;lt; .001). The number of patients with treatment-emergent adverse events was comparable between treatment groups in patients with AD (PF-07038124, 9 [25.0%]; vehicle, 9 [26.5%]) and plaque psoriasis (PF-07038124, 3 [17.6%]; vehicle, 6 [35.3%]). There were no application site reactions with PF-07038124 treatment.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>Topical PF-07038124 was well tolerated and demonstrated superior efficacy compared with vehicle in patients with mild to moderate AD and plaque psoriasis.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/study/NCT04664153">NCT04664153</jats:ext-link></jats:p></jats:sec>

National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study.

Atopic dermatitis epidemiology and unmet need in the United Kingdom.

J Dermatolog Treat

Tolerability of topical treatments for atopic dermatitis.

Dermatol Ther (Heidelb)

Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures.

J Am Acad Dermatol

Guidelines of care for the management of atopic dermatitis: section 2: management and treatment of atopic dermatitis with topical therapies.

Comparison of moisturizing creams for the prevention of atopic dermatitis relapse: a randomized double-blind controlled multicentre clinical trial.

Acta Derm Venereol

The pathology of type 2 inflammation–associated itch in atopic dermatitis.

Diagnostics (Basel)

The cytokine mediated molecular pathophysiology of psoriasis and its clinical implications.

Int J Mol Sci

Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases.

Front Pharmacol

Effect of roflumilast cream vs vehicle cream on chronic plaque psoriasis: the DERMIS-1 and DERMIS-2 randomized clinical trials.

JAMA

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1).

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease.

Nat Rev Drug Discov

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.

The International Conference on Harmonization Good Clinical Practice guideline.

Qual Assur

Test-based exact confidence intervals for the difference of two binomial proportions.

Biometrics

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.

The safety and efficacy of roflumilast cream 0.15% and 0.05% in atopic dermatitis: phase 2 proof-of-concept study.

J Drugs Dermatol

Umbrella and basket trials in oncology: ethical challenges.

BMC Med Ethics

Atopic dermatitis (AD) and plaque psoriasis are inflammatory skin diseases with unmet need for effective topical treatments with few application site reactions.
To assess the efficacy and safety of the topical phosphodiesterase 4 inhibitor PF-07038124 in patients with AD and plaque psoriasis.
This phase 2a, randomized, double-blind clinical trial was conducted from December 21, 2020, to August 18, 2021, at 34 sites across 4 countries. Eligible patients (aged 18-70 years) had mild to moderate AD (covering 5%-20% body surface area) or plaque psoriasis (covering 5%-15% body surface area). Data were analyzed until December 15, 2021.
Patients were randomized (1:1) to PF-07038124, 0.01%, topical ointment or vehicle once daily for 6 weeks.
The primary end point was the percent change from baseline (CFB) in the Eczema Area and Severity Index (EASI) total score among patients with AD and in the Psoriasis Area and Severity Index (PASI) score among patients with plaque psoriasis at week 6. Safety measures included treatment-emergent adverse events, including application site reactions.
Overall, 104 patients were randomized (mean [SD] age, 43.0 [15.4] years; 55 [52.9%] women; 4 [3.8%] Asian, 13 [12.5%] Black, and 87 [83.7%] White), including 70 with AD (41 women [58.6%]; mean [SD] ages, 41.4 [16.6] years in the PF-07038124 group and 36.1 [13.9] years in the vehicle group) and 34 with plaque psoriasis (20 men [58.8%]; mean [SD] ages, 51.8 [12.3] years in the PF-07038124 group and 51.2 [10.8] years in the vehicle group). Baseline characteristics were generally balanced. At week 6, the PF-07038124 groups showed significantly greater improvements compared with vehicle groups in EASI (least-squares mean CFB, -74.9% vs -35.5%; difference, -39.4% [90% CI, -58.8% to -20.1%]; P < .001) and PASI scores (CFB, -4.8 vs 0.1; difference, -4.9 [90% CI, -7.0 to -2.8]; P < .001). The number of patients with treatment-emergent adverse events was comparable between treatment groups in patients with AD (PF-07038124, 9 [25.0%]; vehicle, 9 [26.5%]) and plaque psoriasis (PF-07038124, 3 [17.6%]; vehicle, 6 [35.3%]). There were no application site reactions with PF-07038124 treatment.
Topical PF-07038124 was well tolerated and demonstrated superior efficacy compared with vehicle in patients with mild to moderate AD and plaque psoriasis.
ClinicalTrials.gov Identifier: NCT04664153.

Efficacy and Safety of PF-07038124 in Patients With Atopic Dermatitis and Plaque Psoriasis: A Randomized Clinical Trial.

Efficacy and Safety of PF-07038124 in Patients With Atopic Dermatitis and Plaque Psoriasis

Journal of the European Academy of Dermatology and Venereology

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>There remains an unmet need for oral medications that are safe and efficacious for long‐term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro‐inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>The objective of this study was to examine the PDE4 enzymatic activity and anti‐inflammatory effects of orismilast in vitro<jats:italic>,</jats:italic> ex vivo<jats:italic>,</jats:italic> and in vivo.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The PDE1‐11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone‐induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T‐helper (Th)1 (TNFα and IFNγ), Th17 (IL‐22 and IL‐23), and Th2 (IL‐4, IL‐5, and IL‐13) related cytokines in PBMC. In vivo<jats:italic>,</jats:italic> 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (<jats:italic>p</jats:italic> &lt; 0.0001, respectively).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Orismilast displayed selective and potent PDE4 inhibition and broad‐spectrum anti‐inflammatory activity in several pre‐clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.</jats:p></jats:sec>

New and emerging topical therapies for psoriasis and atopic dermatitis

J Clin Aesthet Dermatol

Manifestations and management of difficult‐to‐treat psoriasis

JDNA

Cyclic adenosine monophosphate signalling in inflammatory skin disease

J Clin Exp Dermatol Res

Crisaborole 2% ointment (Eucrisa) for atopic dermatitis

Skin Therapy Lett

Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD

Drug dDes Devel Ther

There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.
The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo.
The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.
Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively).
Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Orismilast is a high‐potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first‐generation immediate‐release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)‐related adverse events (AEs) observed with the first‐generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In a phase 2a prospective, randomized, double‐blind, placebo‐controlled trial, patients with moderate‐to‐severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single‐site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open‐label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high‐fat meal or low‐fat meal (open‐label) and (3) participants received up to 60 mg orismilast MR twice‐daily or a placebo for 17 days (double‐blind).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI‐related AEs than those receiving orismilast IR (16.7% vs. 33.3%).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Orismilast IR displayed higher efficacy compared to placebo in patients with moderate‐to‐severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation.</jats:p></jats:sec>

Novo Nordisk Fonden

The risk of depression, anxiety, and suicidality in patients with psoriasis: a population‐based cohort study

Arch Dermatol

Orismilast is a high-potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes.
The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first-generation immediate-release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)-related adverse events (AEs) observed with the first-generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo.
In a phase 2a prospective, randomized, double-blind, placebo-controlled trial, patients with moderate-to-severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single-site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open-label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high-fat meal or low-fat meal (open-label) and (3) participants received up to 60 mg orismilast MR twice-daily or a placebo for 17 days (double-blind).
In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI-related AEs than those receiving orismilast IR (16.7% vs. 33.3%).
Orismilast IR displayed higher efficacy compared to placebo in patients with moderate-to-severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation.

Oral orismilast: Efficacy and safety in moderate-to-severe psoriasis and development of modified release tablets.

Oral orismilast: Efficacy and safety in moderate‐to‐severe psoriasis and development of modified release tablets

Papers