Novel Psoriasis Therapies and Patient Outcomes, Part 1: Topical Medications
In recent years, advances in our understanding of inflammatory mediators and the underlying pathogenesis of psoriasis and psoriatic arthritis have shed light on potential therapeutic targets, which has led to the development of several new promising treatments. In this article, key clinical trials, mechanisms of action, patient outcomes, and relevant safety information for these novel topical medications will be evaluated. This article is the first in a 3-part series on treatments presently in the pipeline for the management of psoriasis and psoriatic arthritis including topical agents, biologic treatments, and systemic therapies in phase 2 and phase 3 clinical trials. With novel approaches to the disease process, these therapies may afford more targeted individualized treatment regimens and offer hope to patients with psoriasis and psoriatic arthritis who have reported a suboptimal therapeutic response to conventional therapies.
Practice Points
- Topical therapies are the cornerstone of treating patients with mild to moderate psoriasis. Commercially available medications approved by the US Food and Drug Administration for use in patients with psoriasis include corticosteroids, vitamin D3 analogues, calcineurin inhibitors, retinoids, anthralin, and tar-based formulations.
- Recent developments in our understanding of inflammatory mediators and the underlying pathogenesis of psoriasis have revealed new potential therapeutic targets, leading to the discovery of many promising treatments.
- Novel topical therapies currently in phase 2 and phase 3 clinical trials for patients with mild to moderate psoriasis may offer hope to patients who have reported a suboptimal therapeutic response to conventional treatments.
LAS41004 (Proprietary Steroid and Retinoid Combination)
LAS41004 (Almirall, SA) is an ointment containing the corticosteroid betamethasone dipropionate and the retinoid bexarotene that is being evaluated for treatment of mild to moderate psoriasis. Five phase 2 studies (NCT01119339, NCT01283698, NCT01360944, NCT02111499, NCT01462643) have been completed; results were not available at the time of publication. A randomized, double-blind, phase 2a study (NCT02180464) with a left-right design assessing clinical response to LAS41004 versus control in patients with mild to moderate psoriasis was actively recruiting at the time of publication.
LEO 80190 (Vitamin D3 Analogue and Steroid Combination)
LEO 80190 (LEO Pharma) is a combination of the vitamin D3 analogue calcipotriol and the corticosteroid hydrocortisone. It was developed as a treatment for sensitive areas such as the face and intertriginous regions. A randomized, investigator-blind, phase 3 trial (NCT00640822) of LEO 80190 ointment versus tacalcitol ointment and placebo once daily for 8 weeks demonstrated controlled disease of the face in 56.8% (183/322) of patients in the LEO 80190 group, 46.4% (147/317) in the tacalcitol group, and 36.3% (37/102) in the placebo group.14 Another phase 2 study (NCT00704262) and 2 phase 3 studies (NCT00691002, NCT01007591) have been completed; results were not available at the time of publication.
LEO 90100 (Vitamin D Analogue and Steroid Combination)
LEO 90100 (LEO Pharma) contains the vitamin D3 analogue calcipotriol and the corticosteroid betamethasone. Three phase 2 studies (NCT01347255, NCT01536886, NCT01536938) and a phase 3 study (NCT01866163) examining the efficacy and safety of various vehicles and formulations of LEO 90100 have been completed; results were not available at the time of publication. Another phase 3 study (NCT02132936) is ongoing but not recruiting participants. Other completed studies whose results were not yet available include a phase 1 pharmacodynamic study (NCT01946386), a phase 1 study that used patch testing to assess the degree of skin irritation and sensitization associated with LEO 90100 (NCT01935869), and a phase 2 study examining the impact of LEO 90100 on calcium metabolism and the hypothalamic-pituitary-adrenal axis (NCT01600222).
M518101 (Vitamin D Analogue)
M518101 (Maruho Co, Ltd) is a novel topical vitamin D3 analogue. Phase 1 (NCT01844973) and phase 2 (NCT01301157, NCT00884169) trials evaluating the safety, pharmacokinetics, and efficacy of M518101 have been completed; results were not available at the time of publication. A phase 3 study (NCT01989429) assessing the safety and therapeutic efficacy of M518101 according to changes in the modified psoriasis area and severity index over an 8-week treatment period also has been completed; results were not yet available. Three phase 3 studies assessing the safety and therapeutic efficacy of M518101 are ongoing: one is currently closed to recruitment (NCT01908595) and 2 are actively recruiting participants at the time of publication (NCT01878461, NCT01873677).
MOL4239 and MOL4249 (Phosphorylated Signal Transducer and Activator of Transcription 3 Inhibitors)
MOL4239 (Moleculin, LLC) is a novel topical agent for use in mild to moderate psoriasis that acts via phosphorylated signal transducer and activator of transcription 3 (p-STAT3) inhibition.15 The p-STAT3 protein has increased expression in psoriasis.16 A phase 2 trial of MOL4239 ointment (NCT01826201) has been completed, showing a greater mean (standard deviation) change in the psoriasis severity score in lesions treated at 28 days with MOL4239 ointment 10% (−1.9 [1.45]) versus lesions treated with placebo ointment (−1.5 [1.87]).17
MOL4249 (Moleculin, LLC) is more potent than MOL4239 with better lipid solubility. In the MOL4249 subset of a placebo-controlled, double-blind, phase 2a study of 16 patients with mild to moderate psoriasis, 10% (1/10) of patients experienced complete clearance of psoriatic plaques, 30% (3/10) of patients experienced 75% or greater improvement, and 50% (5/10) of patients experienced 50% or greater improvement compared to 17% (1/6) in the placebo group. Currently, a phase 2a contralateral study, a phase 2b psoriasis area and severity index trial, and a phase 3 pivotal trial are planned, according to the manufacturer.18
MQX-5902 (Dihydrofolate Reductase Inhibitor)
MQX-5902 (MediQuest Therapeutics) is a topical preparation of methotrexate for the treatment of fingernail psoriasis. Methotrexate is a dihydrofolate reductase inhibitor and antimetabolite that inhibits folic acid metabolism, thereby disrupting DNA synthesis.19 A phase 2b dose-ranging trial (NCT00666354) was designed to assess the therapeutic efficacy and safety of MQX-5902 delivered via a proprietary drug delivery formulation in fingernail psoriasis; the outcome of this trial was not available at the time of publication.
PH-10 (Xanthine Dye)
PH-10 (Provectus Biopharmaceuticals, Inc) is a topical aqueous hydrogel derived from rose bengal disodium that may be beneficial in treating skin conditions such as atopic dermatitis and mild to moderate psoriasis. Rose bengal disodium is a hydrophilic xanthine dye with diagnostic utility in ophthalmology and gastroenterology as well as projected use as a melanoma treatment as demonstrated in phase 1 and phase 2 clinical trials of PV-10 (Provectus Biopharmaceuticals, Inc).20 Two phase 2 studies assessing the safety and therapeutic efficacy of PH-10 in psoriasis (NCT01247818, NCT00941278) have been completed; results were not available at the time of publication.
STF115469 (Vitamin D Analogue)
STF115469 (GlaxoSmithKline) is a calcipotriene foam. At the time of publication, a randomized, placebo-controlled, double-blind, phase 3 trial (NCT01582932) of this vitamin D3 analogue with a projected enrollment of 180 participants was actively recruiting patients aged 2 to 11 years with mild to moderate plaque psoriasis to study the efficacy, safety, and tolerability of STF115469, as well as its pharmacokinetics and pharmacodynamics.
WBI-1001 (Proprietary Product)
WBI-1001 (Welichem Biotech Inc), or 2-isopropyl-5-[(E)-2-phenylethenyl] benzene-1, 3-diol, is a novel proprietary agent that inhibits proinflammatory cytokines (eg, IFN-γ, TNF-α). A randomized, placebo-controlled, double-blind, phase 1 trial (NCT00830817) assessing the efficacy, safety, tolerability, and pharmacokinetics of WBI-1001 has been completed; results were not available at the time of publication. Another randomized, placebo-controlled, double-blind, phase 2 trial (NCT01098721) evaluating its efficacy and safety according to the physician’s global assessment demonstrated a therapeutic benefit of 62.8% in patients treated with WBI-1001 cream 1% versus 13.0% in those treated with a placebo after a 12-week treatment period (P<.0001).21 WBI-1001 may offer a novel approach in the treatment of mild to moderate psoriasis.
Conclusion
Enhanced knowledge of the underlying pathogeneses of psoriasis and psoriatic arthritis has identified new therapeutic targets and enabled the development of exciting novel treatments for these conditions. The topical agents currently in phase 2 and phase 3 clinical trials show promise in enhancing the way physicians treat psoriasis. There is hope for more individualized treatment regimens with improved tolerability and better safety profiles with increased therapeutic efficacy. As our understanding of the molecular underpinnings of psoriasis continues to deepen, it will afford the development of even more innovative therapeutics for use in the management of psoriasis.
