A novel, fixed-dose calcipotriol and betamethasone dipropionate cream for the topical treatment of plaque psoriasis: Direct and indirect evidence from phase 3 trials discussed at the 30th EADV Congress 2021.

Four posters about the novel, fixed-dose calcipotriol and betamethasone dipropionate cream (CAL/BDP cream) based on Poly-Aphron Dispersion (PAD) Technology were presented at the 30th European Academy of Dermatology and Venereology (EADV) Congress 2021 and are summarized here. CAL/BDP cream was compared in two randomized, phase 3 trials to vehicle and active comparator (CAL/BDP gel/topical suspension [TS]) in adults with plaque psoriasis (NCT03802344 and NCT03308799). Pooled data from both trials demonstrated significant greater efficacy in favour of CAL/BDP cream for all efficacy endpoints, including PGA treatment success, mPASI, and mPASI75 compared to CAL/BDP gel/TS. CAL/BDP cream was well tolerated and comparable to CAL/BDP gel/TS with no adverse drug reactions with a frequency >1%. In the NCT03308799 study, CAL/BDP cream demonstrated a substantial improvement in the proportion of participants achieving a minimum 4-point improvement on the peak pruritus numeric rating scale (NRS) score compared with vehicle at Weeks 1, 4 and 8. CAL/BDP cream also improved quality of life (QoL), as assessed through the Dermatology Life Quality Index (DLQI), and the EQ-VAS at Week 8 compared with active comparator. Treatment convenience of CAL/BDP cream, as measured by the Psoriasis Treatment Convenience Scale, was superior to CAL/BDP gel/TS at all studied timepoints, including questions addressing formulation's greasiness and overall treatment satisfaction. Finally, an indirect comparison following the Bucher's method of adjusted indirect comparison and the difference-in-differences method was conducted to compare CAL/BDP cream and CAL/BDP foam, as both therapies have been compared to CAL/BDP gel/TS. Indirect evidence showed that treatment with CAL/BDP cream was associated with a trend for greater QoL improvement than CAL/BDP foam when DLQI improvement was assessed at the recommended treatment duration of 8 weeks for CAL/BDP cream and 4 weeks for CAL/BDP foam. CAL/BDP cream was statistically superior versus CAL/BDP foam in four out of five treatment satisfaction domains.

Efficacy, quality of life, and treatment satisfaction: an indirect comparison of calcipotriol/betamethasone dipropionate cream versus foam for treatment of psoriasis.

OBJECTIVE: To assess how the use of calcipotriol and betamethasone dipropionate (Cal/BDP) cream impacted efficacy, patients' quality of life (QoL), and treatment satisfaction versus Cal/BDP foam. METHODS: Data from clinical trials of Cal/BDP cream and foam were analyzed, by applying the common anchor Cal/BDP gel. Efficacy was assessed by Physician Global Assessment (PGA) treatment success and ≥75% reduction in Psoriasis Area and Severity Index (PASI75 response); QoL by Dermatology Life Quality Index (DLQI); treatment satisfaction by Psoriasis Treatment Convenience Scale (PTCS) and Topical Product Usability Questionnaire (TPUQ). RESULTS: Treatment with Cal/BDP cream was on par with foam on PGA treatment success (risk ratio (RR) for Cal/BDP cream versus foam: 0.80; 95%CI: 0.56, 1.14; p = .21) and PASI75 response (RR for Cal/BDP cream vs. foam: 0.85; 95%CI: 0.64, 1.13; p = .27) when assessed at the treatment duration of 8 weeks for Cal/BDP cream and 4 weeks for Cal/BDP foam. Treatment with Cal/BDP cream was associated with significantly greater treatment satisfaction versus foam on the domains: overall treatment satisfaction (p = .01), "ease of application" (p < .001), "lack of greasiness" (p < .001), "moisturizing effect" (p = .01), and almost significantly greater improvement on the domain "easily incorporated into daily routine" (p = .07). Furthermore, there was a trend for greater DLQI improvement with cream versus foam when assessed at recommended treatment duration [mean difference (MD) for Cal/BDP cream vs. foam: -1.00; 95%CI: -2.20, 0.20; p = .10]. CONCLUSIONS: Indirect comparison analyses showed that Cal/BDP cream significantly improves treatment satisfaction and tends to improve QoL versus foam. Cal/BDP cream is on par with foam on efficacy.

Pooled Analysis Demonstrating Superior Patient- Reported Psoriasis Treatment Outcomes for Calcipotriene/ Betamethasone Dipropionate Cream Versus Suspension/Gel.

BACKGROUND: Calcipotriene and betamethasone dipropionate (CAL/BDP) cream is a novel treatment of plaque psoriasis based on PAD™ Technology (PAD-cream) designed to improve patient reported treatment satisfaction and quality of life (QoL). METHOD: A pooled analysis of patient reported outcomes from two phase 3, multicenter, randomized, investigator-blind, active, and vehicle-controlled trials evaluating a total of 1271 patients with mild to moderate plaque psoriasis according to the Physician Global Assessment (PGA) scale. Products were applied once daily for 8 weeks. RESULTS: The proportion of patients evaluating their treatment to have improved by 2 grades to clear or very mild disease on the 5-grade Subject Global Assessment (SGA) scale, defined as SGA Success, was significantly higher in the CAL/BDP PAD-cream group compared to active comparator (CAL/BDP suspension/gel) (week 8, 44.2% vs 27.9%, P<0.0001). A Dermatology Life Quality Index (DLQI) score of 0 or 1, indicating no impact of disease on the patient's life, was obtained by 43.8% of patients at week 8 in the CAL/BDP cream group versus 34.2% in the CAL/BDP suspension/gel group (P=0.0005). CAL/BDP PAD-cream demonstrated significantly greater psoriasis treatment convenience compared to CAL/BDP suspension/gel at all studied time points, including questions addressing greasiness of the formulation and overall satisfaction of treatment. CONCLUSION: CAL/BDP PAD-cream is a novel topical treatment for psoriasis, which through PAD™ Technology offers substantial improvement in QoL and treatment satisfaction for patients. Given these data, CAL/BDP PAD-cream may lead to better adherence to treatment, which ultimately could result in better treatment outcomes in clinical practice. CLINICALTRIALS: gov: NCT03308799 and NCT03802344. J Drugs Dermatol. 2022;21(3):242-248. doi:10.36849/JDD.6611.

Validation of the Self-Reported Psoriasis Treatment Convenience Scale (PTCS).

INTRODUCTION: Adherence to topical treatments for psoriasis is reported to be poor. One key contributing factor is the inconvenience associated with formulations that may be greasy, time consuming to apply, and slow to absorb. There is a paucity of patient-reported outcome measures that evaluate psoriasis patients' perceptions of treatment convenience. The Psoriasis Treatment Convenience Scale (PTCS) was therefore developed and validated. METHODS: Following a literature review of issues relating to convenience of topical treatments, important items were identified and a draft version of the PTCS was developed and underwent content validity testing (n = 20). The revised scale was included in a clinical trial of topical therapy (n = 794; NCT03308799), and psychometric testing was performed. RESULTS: The final questionnaire included five core items and one overall satisfaction question. In psychometric testing, the scale demonstrated stability across trial population, and good validity, reliability, and sensitivity. CONCLUSION: The PTCS is a new, reliable, sensitive, validated tool for the assessment of patient-reported treatment convenience. Use of the PTCS will facilitate evaluation of convenience as part of the clinical development of topical therapies, and thus may help to improve patient adherence and, therefore, treatment outcomes.

A Phase 3, Randomized Trial Demonstrating the Improved Efficacy and Patient Acceptability of Fixed Dose Calcipotriene and Betamethasone Dipropionate Cream.

BACKGROUND: The fixed dose combination of calcipotriene and betamethasone dipropionate (CAL/BDP) is a well-established, efficacious, and safe topical treatment of psoriasis. METHOD: A Phase 3, multicenter, randomized, investigator-blind, active, and vehicle-controlled trial enrolling 796 patients with moderate to severe psoriasis according to the Physician Global Assessment (PGA) scale. Products were applied once daily for 8 weeks. RESULTS: The proportion of patients achieving PGA treatment success after 8 weeks was statistically significantly greater for CAL/BDP cream (37.4%) compared to CAL/BDP TS (22.8%, P<0.0001), and vehicle (3.7%, P<0.0001). A similar statistically significant difference in favor of CAL/BDP cream at week 8 was demonstrated for the percentage change in mPASI from baseline and the proportion of patients obtaining mPASI75. Patient reported treatment convenience for CAL/BDP cream was rated superior to CAL/BDP TS. Safety assessments during the trial demonstrated that CAL/BDP cream was well-tolerated with no adverse reactions with a frequency greater than 1%. CONCLUSION: CAL/BDP cream is a novel topical treatment of psoriasis, which in a single product, offers a unique combination of high efficacy combined with favorable safety and excellent treatment convenience. For these reasons, CAL/BDP cream offers a distinctive advantage for the topical treatment of plaque psoriasis. ClinicalTrials.gov: NCT03308799J Drugs Dermatol. 20(4):420-425. doi:10.36849/JDD.5653.

A dose-finding trial with a novel ingenol derivative (ingenol disoxate: LEO 43204) for field treatment of actinic keratosis on full face or 250 cm2 on the chest.

PURPOSE: Actinic keratoses (AKs) may progress to squamous cell carcinoma and can occur in cancerized fields as sub-clinical and clinically visible lesions. Ingenol disoxate gel is a topical field therapy for AK. This Phase I/II trial aimed to assess the safety and efficacy of ingenol disoxate on full face or chest in patients with AKs. MATERIALS AND METHODS: Part 1 was a phase-I, open-label, dose-escalation trial investigating the maximum tolerated dose of ingenol disoxate. Part 2 was a phase-II, randomized, double-blind, vehicle-controlled trial; patients were randomized 1:1:1:1 to ingenol disoxate 0.018%, 0.012%, 0.006% gel or vehicle for 2 consecutive days. RESULTS: Reduction in AK count from baseline at Week 8 was significantly higher than with vehicle for all doses of ingenol disoxate gel (0.018%, 79.0%; 0.012%, 73.4%; 0.006%, 69.7%; vehicle; 42.3%; p < .001). Local skin responses peaked at Day 3 for all doses, rapidly declined, and reached mild levels at Week 2. Most adverse events were mild or moderate in intensity, and were most commonly application site pain/pruritus. CONCLUSIONS: Ingenol disoxate gel is efficacious and well tolerated as field treatment for AKs on the full face or chest. Clinical Trial No.: NCT01922050.

Squamous cell carcinoma and keratoacanthomas are biologically distinct and can be diagnosed by light microscopy: a review.

Keratoacanthomas (KAs) are self-limiting squamoproliferative lesions usually seen on sun damaged skin. These tumours are in many ways enigmatic, and the relation between KAs and squamous cell carcinoma is still a contested topic. In this review the biology and histology of KAs will be discussed, and based on morphology, clinical outcome and recent genetic analysis of the tumour types, we conclude that KAs and SCCs are two distinct biological entities which can usually be distinguished by conventional microscopy. The sentinel observation of rapid and frequent appearance of KAs after BRAF treatment of malignant melanoma patients has paved the way for a more general understanding of the pathogenesis leading to the appearance of KAs in patients with inflammation in the skin. In BRAF treated patients, the KAs are a consequence of paradoxical activation of the MAP kinase pathway. Similarly, any external trauma or pharmaceutical interventions resulting in inflammation in the skin will activate the MAP kinase pathway. Such inflammation-mediated MAP kinase activation in the skin will result in the development of KAs through the same pathway as demonstrated for BRAF treated patients. It is characteristic that skin tumours following short acting inflammatory stimulation of severely sun damaged skin develop almost exclusively into KAs, whereas it is exceedingly rare that such inflammatory conditions lead to formation of SCCs. The understanding that inflammatory reactions in sun-damaged skin may activate pathways specifically leading to the formation of KAs may spare the patient the discomfort and disfigurement of needless overtreatment.

The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer's disease.

This review discusses current knowledge of the complex interactions between amyloid-beta (A beta) peptide, the receptor for advanced glycation endproducts (RAGE), and inflammatory mediators, focusing on the roles of such interactions in the pathogenesis of Alzheimer's disease. As a ubiquitous cell-surface receptor, RAGE demonstrates enhanced expression in an A beta-rich environment; the effects of RAGE on microglia, the blood-brain barrier and neurons are mediated through various signaling pathways. Relevant preclinical models illustrate that the A beta-RAGE interaction amplifies neuronal stress and the accumulation of A beta, impairs memory and learning, and exaggerates neuroinflammation. These findings suggest that RAGE may mediate a common proinflammatory pathway in neurodegenerative disorders.