Evaluation the Topical Apremilast Nanoformulation in Treatment of Localized Plaque Psoriasis

Assiut University

Status: Begins enrollment in 2 months

Conditions: Psoriasis

Treatments: Drug: betamethasone valerate 0.1% cream; Drug: Apremilast Nanoformula 0.3٪

Study type: Interventional

Funder types: Other

Identifiers

NCT07366268

Nano Apremilast in psoriasis

Details and patient eligibility

About

This study is a comparative randomized clinical trial evaluating the efficacy and safety of topical apremilast nanoemulsion 0.3% in the treatment of localized mild to moderate plaque psoriasis.Clinical efficacy will be assessed using TES score, Physician Global Assessment (PGA), dermoscopy, and patient satisfaction, while safety is monitored through adverse effect reporting. In addition, histopathological and immunohistochemical evaluation of PDE4 expression will be performed before and after treatment to assess tissue-level responses.

The study aims to determine whether topical apremilast nano-formulation, alone or combined with corticosteroids, offers an effective and safer alternative to conventional topical therapy, with improved local efficacy and reduced corticosteroid-related adverse effects.

Full description

Psoriasis is a chronic immune-mediated inflammatory skin condition with a strong genetic predisposition and an autoimmune pathogenic characteristic . Its worldwide prevalence is up to 2% but this varies between different geographic regions . In Egypt, the prevalence of psoriasis ranges between 0.19% and 3% .

Individuals with psoriasis frequently endure marked psychological distress. This includes social embarrassment, reduced self esteem, anxiety, depression, and an increased tendency toward suicidal ideation and behavior .

Psoriasis Skin lesions are usually symmetrical, sharply demarcated, with red or pink raised plaques, and covered with silvery scales. These plaques reflect key pathological processes, including inflammation, keratinocyte hyperproliferation, and angiogenesis .

Cellular responses to environmental stimuli and intracellular signaling in various cell types-including myeloid, lymphoid, and other inflammatory cells-are mediated by intracellular "second messengers," particularly cyclic adenosine monophosphate (cAMP) .

Phosphodiesterase4 (PDE4) is one of the major cAMP-selective PDEs expressed in epithelial cells . It is also present in several mesenchymal cell types, including dermal keratinocytes, smooth muscle cells, vascular endothelial cells, and chondrocytes, By decreasing intracellular cAMP, PDE4 promotes production of pro-inflammatory mediators and decreases production of anti-inflammatory mediators. Conversely, inhibition of PDE4 increases the intracellular concentration of cAMP and selectively blocks pro-inflammatory cytokines, such as TNF-α, IFN-γ, and IL-2 production from peripheral blood monocytes and T cells.

PDE4 has four subtypes (A, B, C and D). These subtypes are encoded on separate genes. Expression of the PDE4A subtype increased in nearly all cell types of the skin of psoriasis patients. PDE4B is present in vessels and in immune cells, whereas PDE4D is expressed in fibroblasts and endothelial cells .

Management of mild to moderate psoriasis usually begins with topical therapies, including emollients, topical corticosteroids, calcipotriol, tar preparations, and dithranol. There is little evidence to guide the selection of topical treatments, so it can be based on patient and prescriber preference .

Topical glucocorticoids are the first-line therapy in mild to moderate psoriasis and areas where other topical treatments may cause irritation, such as joints or genitals . Corticosteroids bind to intracellular corticosteroid receptor and regulate gene transcription of numerous genes, particularly those that code for pro-inflammatory cytokines. They act as vasoconstrictive, antiproliferative, anti-inflammatory and immunosuppressive.

However, long-term application of topical corticosteroids may cause skin atrophy, striae, telangiectasia, adrenal suppression and hypopigmentation. Additionally, abrupt discontinuation can precipitate early disease relapse or rebound flares.

Apremilast is classified as a small-molecule phosphodiesterase4 (PDE4) inhibitor , It inhibits PDE4 isoforms from all four sub-families (A,B,C,D) Apremilast acts by hindering the conversion of cyclic adenosine monophosphate (cAMP) to AMP . further causing an intracellular accumulation of cyclic adenosine monophosphate (cAMP) causing a reduction in the production of inflammatory mediators such as CX-CL9, CX-CL10, IFN-γ, TNF-α, IL-2, IL-8, IL-12, and IL-23, thereby attenuating the inflammatory cascade .

Its oral form is FDA approved for plaque psoriasis in adult patients eligible for systemic therapy or phototherapy, as well as for adults with moderately to severely active psoriatic arthritis. . It is recommended that apremilast be titrated to the recommended dose of 30 mg twice daily, to be taken orally starting on day 6 .

The results of long-term, placebo-controlled study (ESTEEM 2) established the efficacy of oral apremilast in patients with plaque psoriasis, and are consistent with those reported in ESTEEM 1.The primary end point in this study was met, with a significantly greater proportion of patients treated with apremilast achieving a PASI 75 response at week 16 vs. placebo. Across different phases of study, PASI 75 responses at week 16 have ranged from 29% to 41%.

Apremilast is low soluble and low permeable classifying the drug as biopharmaceutical classification system (BCS) class 4 molecule with a poor solubility of 10-14 μg/mL. The oral medication of apremilast has systemic side effects such as diarrhea, nausea, vomiting, weight loss, and depression in some cases .

These limitations highlight the need for alternative routes of administration that enhance drug delivery to affected skin while minimizing systemic exposure. Topical delivery of apremilast represents a promising strategy to achieve localized therapeutic effects with fewer systemic side effects and improve patient outcomes .

Nevertheless, poor solubility and limited skin penetration restrict the effectiveness of topical apremilast, particularly in psoriatic skin, which is thickened and inflamed . Hence, the incorporation into nanotechnology-based drug delivery systems could be used as a strategy to improve its solubility and permeability in order to improve dermal bioavailability and consequently to achieve local anti-inflammatory efficacy .

Several ex vivo studies have demonstrated that apremilast loaded nanoparticles significantly increase skin retention compared with conventional gel formulations, resulting in improved therapeutic outcomes. Cytotoxicity and skin irritation studies further indicate that nano formulations are safe and well tolerated .

Enrollment: 36 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age: ≥18 years.
• Pattern: Patients with chronic plaque psoriasis not exceeding 10% of the body surface area.

Exclusion criteria

• History of phototherapy or systemic treatment in the previous 12 weeks, topical psoriasis treatment within the last 4 weeks.
• Renal, hepatic disease, cardiovascular, Immunosuppressive therapy, endocrine and blood disease or mental illness.
• Pregnancy, breast-feeding or women planning to become pregnant within 3 months.
• Psoriasis exceeding 10% of body surface area or other severe types of psoriasis requiring systemic treatment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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36 participants in 3 patient groups

Topical Apremilast Nanoformula

Experimental group

Description:

Participants will receive topical apremilast nanoformula 0.3% applied twice daily for 12 weeks.

Treatment:

Drug: Apremilast Nanoformula 0.3٪

Topical betamethasone valerate

Active Comparator group

Description:

Participants will receive topical betamethasone valerate 0.1% cream applied twice daily for 12 weeks.

Treatment:

Drug: betamethasone valerate 0.1% cream

Combination therapy

Experimental group

Description:

Participants will receive combined topical apremilast nanoformula 0.3% and topical betamethasone valerate 0.1% cream applied for 12 weeks.

Treatment:

Drug: Apremilast Nanoformula 0.3٪

Drug: betamethasone valerate 0.1% cream