The Evolution of Topical Formulations in Psoriasis (Family Practice)

Bonnie Kuehl, PhD¹ and Neil H. Shear, MD, FRCPC, FACP^2,3

¹Scientific Insights Consulting Group Inc., Mississauga, ON, Canada
²Sunnybrook Health Sciences Centre, Toronto, ON, Canada
³University of Toronto, Toronto, ON, Canada

Conflicts of interest: Bonnie Kuehl has consulted for and accepted consulting fees from Aralez Pharmaceuticals and LEO Pharma Canada; Neil Shear has consulted and spoken on behalf of AbbVie, Celgene, Valeant, Lilly, Novartis, Janssen, LEO Pharma, Sanofi Genzyme.

Introduction

Most people with mild-to-moderate psoriasis manage their disease with topical therapies. However, adherence to topical treatment remains a challenge as the daily application creates a significant treatment burden. New topical therapeutic options need to offer a combination of higher efficacy and better patient acceptability, including easier application, to reduce treatment burden and enhance patient adherence. Topical spray foam vehicles are innovative alternatives to creams and ointments, addressing many patient challenges with traditional vehicles. Well-designed spray foam vehicles are easily spread over large areas of the skin, while importantly not leaving a greasy or oily film on the skin after application. Calcipotriol/betamethasone diproprionate spray foam is a new psoriasis treatment option that is rapidly effective, offers greater efficacy versus ointment and gel formulations, and has been shown to increase patient treatment satisfaction. Hence, by addressing the several crucial unmet clinical needs in patients with mild-to-moderate psoriasis, this optimized spray foam formulation is poised to improve treatment follow-through.

Background

• Psoriasis is an immune-directed disorder that most commonly manifests itself with visible plaques on the skin, resulting in cosiderable morbidity for those affected. The World Health Organization characterizes psoriasis as “a chronic, noncommunicable, painful, disfiguring and disabling disease for which there is no cure.”¹
• The majority of patients are classified as having mild-moderate disease with an estimated 20% having moderate-severe disease.²
• In a multinational survey (US, Canada, France, Germany, Italy, Spain, UK), dermatologists acknowledged that psoriasis is undertreated with an ongoing unmet treatment need for patients with psoriasis.³
• The MAPP survey (population-based survey of psoriasis and/or psoriatic arthritis patients in North America and Europe) revealed that the majority of psoriasis patients are undertreated; more than 80% of patients with ≥4 palms body surface area (BSA ≥4) were receiving no treatment or topical treatment only.⁴
• Patient adherence to topical psoriasis therapy is low. The high burden of treatment and the substantial effort required to maintain ongoing therapy leads to treatment fatigue.
• Data supports that about 75% of patients³ with plaque psoriasis,
  regardless of severity, manage their disease with topical therapies,
  which may lead to quicker treatment fatigue as the daily treatment
  regimen can be cumbersome and time consuming.²
• Studies in medication adherence in psoriasis have shown that 39-73% of patients do not use their medication as prescribed.^5-7
• Factors influencing adherence include patient specific characteristics, disease-related characteristics, treatment satisfaction, cosmetic acceptability and complexity of treatment protocols.⁸
• Studies also report that cosmetic acceptability is a key contributor to adherence, with adherence being reduced if treatments are perceived as messy to apply and sticky on the skin.⁹
• Evidence suggests that low adherence to psoriasis therapies may be related to insufficient instruction on how to use the drug, misperceptions regarding possible adverse events (AEs) and mistaken expectations about the speed and degree of improvement.¹
• A challenge to the use of currently available topical therapies is the failure of many patients to achieve complete or almost complete clearance of their psoriasis.¹⁰
• Increasing awareness of the burden of psoriasis and the psychosocial impact of the disease have underscored the clinical need for a topical therapy that is easy to use, cosmetically appealing, and rapidly efficacious with short-term use, as well as be able to induce sustained efficacy for long-term maintenance.^8,10

Rationale for New Topicals in Psoriasis

• Topical treatment of skin conditions has been shown to impact the skin and offer systemic benefits.^11,12
• A new understanding of skin architecture, topical drug formulation and drug delivery has resulted in the development of a more directed delivery system for topical drugs.
• A growing knowledge on product formulation and consumer acceptability have led to the identification of criteria that constitute the “ideal” vehicle, which include properties such as easy application and removal, nonirritating/nonallergenic, chemically stable, homogenous, bacteriostatic, cosmetically acceptable, and ability to rapidly release the drug for enhanced, controlled or targeted absorption.^11,12
• New topical carrier/vehicles should be able to:
  • Influence the performance of the drug with targeted and enhanced skin absorption
  • Improve control of application and help with the maintenance of, or be able to improve the skin barrier.¹³
• Beyond this, compounds of active ingredients with new agents need to offer a combination of higher efficacy and better patient acceptability compared with currently available therapies in order to enhance patient adherence.¹⁰
• A simplified dosing schedule, such as once per day and rapid onset of observed effect are key factors that can improve adherence to topical therapies.^14,15
• The primary consideration is the active drug and its impact on the inflammatory process responsible for psoriasis.
• The immune pathogenesis of psoriasis involves dendritic cells, T-cells, keratinocytes and a diverse group of inflammatory mediators (chemokines, cytokines, antimicrobial peptides) that further amplify the inflammatory response and trigger the hyperproliferation of keratinocytes. Once activated, this inflammatory process results in the development of painful, itchy, erythematous plaques covered in silvery scales.¹⁶

Vitamin D Receptor Agonists and Glucocorticoids

• Vitamin D receptor agonists (e.g., calcipotriol) and glucocorticoids (e.g., betamethasone diproprionate) have shown benefit in treating psoriasis.
• Glucocorticoids are known potent anti-inflammatory agents that block multiple anti-inflammatory pathways.
• Vitamin D receptor agonists appear to enhance the immunosuppressive activity of regulatory T-cells. Calcipotriol has been shown to normalize the pro-inflammatory cytokine cascade in psoriasis, ultimately interrupting the pro-inflammatory feedback loop that drives disease pathogenesis.^17,18
• Recent data further supports the benefit of combining betamethasone with calcipotriol. The combination of the two agents showed additive effects, inhibiting the secretion of cytokines by dendritic cells and T-cells, as well as reducing the inflammatory response of stimulated keratinocytes. This cellular data supports the enhanced clinical efficacy observed with the combination product, compared to the respective mono-treatments in psoriasis patients.¹⁷

Vehicle – Getting it Right

• In clinical practice, the key question is which formulation types (e.g., creams, gels, ointments, spray foams or liposomes) are better at delivering a drug to the skin, promoting cutaneous absorption and potentially leading to enhanced clinical efficacy.
• Formulation impacts cosmetic acceptability (greasiness, messiness, stickiness, visibility on skin and tactile sensation); ease of use/convenience (spreadability, time required for application and drying, staining of clothes/bedding); and potency of the topical preparation.^12,19

Foams

• Foams are an easy to apply innovative alternative to creams and ointments.
• Foam vehicles were developed to more effectively deliver active ingredients as well as being able to be spread easily on large areas of the skin; not require excessive rubbing into already damaged sensitive skin; not leave a greasy or oily film or on the skin after
  application; and not impart a greasy feeling.
• Pharmaceutical spray foams are unique delivery vehicles as they have three transition states: liquid in the can, propellant/aerosol as it leaves the can and foam on the skin of the patient.²⁰
• Drug delivery is controlled by the vehicle excipients as these impact partitioning of the active ingredients (between transition states) permitting release from the vehicle and diffusion through.
• Excipients in the formulation are responsible for enhancing penetration/permeation of the active ingredients, skin hydration, occlusiveness and stability of the topical preparation.¹

Ointments and Gels

• In the treatment of psoriasis, the fixed combination of calcipotriol and betamethasone as dipropionate (Cal/BD), in either ointment or gel formulations, has shown superior efficacy and improved acceptability compared with the individual active ingredients.^21,22

• The fixed dose combination of Cal and BD (as dipropionate) allows the delivery of small amounts (0.005% and 0.05%, respectively) of two very potent drugs within a single formulation.

Novel Spray Foam

• To address patient needs for an easy to apply topical vehicle offering efficacy in psoriasis – an innovative spray foam formulation containing calcipotriol and betamethasone in a fixed dose combination was developed.²⁵
• The Cal/BD spray foam is a pressurized formulation including an emollient vehicle base, with calcipotriol and betamethasone dissolved in a mixture of volatile propellants, butane and dimethyl ether.
• Dimethyl ether also acts as a solvent enhancing the solubility of the active ingredients allowing them to completely dissolve, in contrast to the ointment and suspension formats.
• Cal and BD in the Cal/BD spray foam have been shown to have significantly greater in vitro skin penetration and increased ex vivo skin permeation (penetration through all skin layers) compared with Cal and BD in the Cal/BD ointment. This is likely due to the
  development of the stable supersaturated solution, leading to greater solubility and skin penetration of the active ingredients.²⁵

Discussion

• Phase II and III studies have demonstrated significantly greater treatment success and at least a 75% reduction in modified psoriasis area and severity index (mPASI75) of the Cal/BD spray foam compared to foam vehicle, calcipotriol alone and betamethasone alone, Cal/BD ointment and Cal/BD gel (Table 1) in the treatment of adult patients with psoriasis on the body.
• The PSO-FAST study demonstrated an early (day 3) significantly greater itch relief and improvement in itch-related sleep loss compared with vehicle in patients receiving the Cal/BD spray foam, which was maintained for the remainder of the study.^26,27
• These findings are thought provoking as they demonstrate therapy alleviated common and distressing aspects of psoriasis, including scratching in response to itchiness that can aggravate lesions and cause sleep loss that can impact daily productivity.²⁸
• Cal/BD spray foam has been shown to be efficacious and well accepted in adult patients with psoriasis vulgaris for up to a 4-week treatment period. The safety profile is in alignment with the more established Cal/BD fixed combination ointment.
• Safety of the Cal/BD spray foam versus gel for up to 12 weeks treatment has been demonstrated in a Phase III trial. Pooled analysis of the Phase II/III clinical studies showed that the most common adverse drug reactions included application site pruritus,
  stinging/burning and pain (≤1%)^24,26,30
• The Phase II maximum use systemic exposure (MUSE) study in 35 patients with extensive psoriasis vulgaris (covering 15-30% BSA, with at least 30% scalp involvement), demonstrated that the Cal/BD spray foam had no clinically relevant impact on the hypothalamic-pituitary-adrenal (HPA) axis, calcium homeostasis
  or renal function, demonstrating low systemic absorption of Cal and BD.³¹
• Notably, the Cal/BD spray foam has a safety and tolerability profile similar to Cal/BD ointment and the individual active ingredients, demonstrating that the superior efficacy of the spray foam does not impact tolerability.¹⁰
• While long-term data for the Cal/BD spray foam is yet to come, 52-week data from the Cal/BD ointment demonstrated that no patients experienced HPA axis suppression and that the fixed dose combination is safe and well tolerated when used long-term.^32-34
• Skin atrophy remains a major concern with long-term topical corticosteroid use. The 52-week safety study reported atrophy, that resolved in most patients, in <2% (n=4) of patients in the Cal/BD group.³²

Adherence

• Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as therapy cost, patient self-image and QoL.^8,35
• Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload.
• Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.³⁶
• When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.⁸
• With topical dermatologic products, studies suggest that patients prefer, and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.³⁷

Conclusion

The efficacy of a fixed-dose Cal/BD combination is well established in patients with mild-to-moderate psoriasis. With the ongoing clinical challenge of achieving optimal control and adherence to treatment, the Cal/BD spray foam was developed to increase the therapeutic options available. The data supports that the Cal/BD spray foam offers enhanced efficacy due to improved skin penetration of the active ingredients after the formation of a stable supersaturated solution on the skin. With its further impact on itch and quality of
life, this foam formulation may help improve adherence to address the unmet need in patients with psoriasis.