INDIVIDUAL ARTICLE: Real-World Evidence on the Use of Calcipotriene and Betamethasone Dipropionate Aerosol Foam 0.005%/0.064% in the Treatment of Psoriasis: A Review of Investigator-Initiated Studies Around the Globe

September 2023 | Volume 22 | Issue 9 | Copyright © September 2023


Published online September 1, 2023

Kathryn Lee BAa, Leon Kircik MDb, April W. Armstrong MD MPHc

aSaint Louis University School of Medicine, Saint Louis, MO  bIcahn School of Medicine at Mount Sinai, New York, NY; Physicians Skin Care, PLLC Louisville, KY;  DermResearch, PLLC Louisville, KY; Skin Sciences, PLLC Louisville, KY cDepartment of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 

Abstract
Topical medications are commonly used to manage mild-to-moderate psoriasis and serve as adjunct therapies used in combination with phototherapy and systemic treatments. Fixed-dose calcipotriene (Cal) 0.005%/betamethasone dipropionate (BD) 0.064% aerosol foam is a safe, efficacious topical therapy approved for the treatment of psoriasis vulgaris in the United States and European Union. Several investigator-initiated studies (IISs) have been conducted to provide real-world evidence related to the safety, effectiveness, and therapeutic indications of Cal/BD foam and are relevant to clinicians' every-day practice. This paper summarizes the findings of the IISs around the globe published to date and presents the real-world data related to the effectiveness and clinical considerations of Cal/BD foam as a treatment for psoriasis. J Drugs Dermatol. 2023;22:9(Suppl 2):s5-14.

INTRODUCTION

Psoriasis is a chronic inflammatory disease that affects approximately 8 million adults in the United States.1 It is characterized by sharply demarcated, erythematous plaques with overlying scales that can involve a large percentage of one's body surface area.1-2 Itching, pain, and scaling of the skin are among the most frequently reported symptoms.2 Without adequate treatment, patients may face considerable quality-of-life impairment.
Topical agents may be used to manage mild-to-moderate psoriasis or serve as adjunct therapies used in combination with phototherapy and systemic treatments. Fixed-dose combination calcipotriene (Cal) 0.005%/betamethasone dipropionate (BD) 0.064% aerosol foam (Enstilar; LEO Pharma, Ballerup, Denmark) is a topical therapy approved for the treatment of plaque psoriasis (hereinafter "psoriasis") in the United States and European Union.3,4 Several investigator-initiated studies (IISs) have been conducted globally to better understand the role of Cal/BD foam in treating psoriasis. These studies provide real-world evidence related to the safety, effectiveness, and therapeutic indications relevant to clinicians' every-day practice. Clinicians around the world have examined various aspects of treatment with fixed-dose combination Cal/BD aerosol foam, such as the drug's mechanism of action, impact on patient outcomes, and effectiveness in managing moderate-to-severe psoriasis. This paper summarizes the findings of the IISs around the globe published to date and presents the real-world data related to Cal/BD foam as a treatment for psoriasis.
 
Summary of Phase III Pivotal Studies 
PSO-ABLE (NCT02132936) was an international, prospective, parallel-group, investigator-blinded Phase III clinical trial that evaluated the efficacy and safety of fixed-combination Cal/BD foam with Cal/BD gel.5 Enrolled patients were randomized in a 4:4:1:1 manner to either once-daily Cal/BD aerosol foam, Cal/BD gel, foam vehicle, or gel vehicle treatment for 12 weeks. Enrolled patients had 2% to 30% of body surface involvement and underwent washout if receiving treatment prior to randomization. The study compared the proportion of participants who achieved a equal to/greater than 2-point improvement in Physician's Global Assessment (PGA) score (clear or almost clear status) at week 4 for Cal/BD aerosol foam vs those at week
 
8 for Cal/BD gel. Significantly more patients treated with Cal/BD  aerosol foam attained clear or almost clear status at week 4 compared to patients treated with Cal/BD gel at week 8.5 
 
Difference in treatment efficacy was observed as early as week 1 and maintained throughout the 12 weeks of treatment. Study findings showed that treatment with Cal/BD aerosol foam was safe and well-tolerated.5
 
PSO-FAST (NCT01866163) was a national, multicenter, prospective, randomized, double-blinded Phase III clinical trial.6 The study aimed to compare treatment efficacy and safety of Cal/BD aerosol foam with aerosol foam vehicle in patients with mild-to-severe psoriasis vulgaris on the body. Study participants were randomized in a 3:1 fashion to apply Cal/BD foam or vehicle once daily for 4 weeks.6 The study's primary efficacy endpoint was to assess the proportion of patients with psoriasis who achieved treatment success (defined as clear skin PGA rating in mild disease patients and clear/almost clear skin status in moderate-to-severe disease patients) at week 4.6 A significant proportion of patients with psoriasis using Cal/BD foam achieved treatment success when compared to the vehicle group. Overall, once-daily Cal/BD dosing was found to be a well-tolerated and safe treatment with few medication-related adverse reactions.6
 
Mechanism of Action of Cal/BD Foam and Clinical Features of Treatment-Response 
Combination Cal/BD foam has demonstrated superior efficacy and safety compared to treatment with individual betamethasone and calcipotriene components.7 In consideration of these findings, Heim et al conducted a prospective, randomized double-blind trial to examine the impact of Cal/BD treatment on cellular inflammation and cytokine production in active psoriasis lesions.8
 
Thirty patients with mild psoriasis (defined as PASI score <10) who had a minimum of two 2 cm2 symmetric lesions located on the elbows were randomized. Patients were randomized to apply either betamethasone foam, clobetasol propionate ointment, or placebo foam (emollient) to the elbows on one side of the body; all study participants applied Cal/BD aerosol foam to their elbows on the opposite side of their body. Topical therapies were applied to the same sites once daily for a 4-week period.8 Photographic images of the lesions were obtained and evaluated using the targeted Psoriasis Area and Severity Index (t-PASI) score pre- and posttreatment. Punch biopsies were taken from non-lesional and lesional skin in each patient, and immunofluorescence was utilized to examine cellular infiltrate, interferon gamma (IFN-gamma), and interleukin (IL)-17. Changes in cutaneous inflammation were studied alongside changes in epidermal thickness and t-PASI scores.8
 
Observed characteristics of lesional skin included increased epidermal thickness and increased counts of IL-17 and IFN-gamma producing CD8+ T cells, natural killer cells, and neutrophils.8 While all topical therapies were found to reduce epidermal thickness and improve t-PASI scores, Cal/BD foam was the only treatment to completely suppress CD8+ T-cell influx in the epidermis and dermis. Cal/BD therapy was also unique in its ability to reduce CD8 + IFN-gamma+ cell counts and significantly reduce the number of IL-17 expressing, myeloperoxidase (MPO) + neutrophils. Thus, treatment with Cal/BD aerosol foam displayed superior efficacy in decreasing cellular influx into active psoriatic lesions compared to emollient or betamethasone alone.8
Errichetti et al investigated the clinical and dermoscopic features of psoriasis plaques pre-Cal/BD foam therapy and in treatment-respondent plaques. Investigators also characterized residual dermoscopic findings associated with clinically improved and post-treatment relapse lesions.9 Patients equal to/greater than 18 years old with moderate-to-severe psoriasis were treated with once-daily Cal/BD aerosol foam for 4 weeks and seen at baseline, week 4 (end of therapy), and week 8.
Patients refrained from applying anything other than emollient on the treated areas between week 4 and week 8.9
 
At baseline, 3 target psoriasis lesions were randomly selected from each participant and observed throughout the study. Investigators assessed clinical improvement using the Local Psoriasis Severity Index (LPSI) to grade lesional erythema, scaling, and induration.9
Dermoscopic evaluation of lesions was also performed. Upon completion of the 4-week treatment period, investigators assessed for clinical improvement, which was categorized as limited response (LPSI improvement < 50%), partial response (LPSI improvement of 50%-75%), or optimal response (LPSI improvement > 75%); therapeutic outcome was then correlated with clinical and dermoscopic features first observed at baseline.9
A total of 105 lesions were included in the study analysis. Poor treatment outcomes were associated with degree of lesion infiltration at baseline; lesions localized to the legs were also associated with diminished outcomes. The presence of globular vessels at baseline dermoscopy and no/limited treatment response was found to be significantly correlated.9 Globular vessels were also significantly associated with psoriasis lesions localized to the legs. Analyses specific to leg lesions revealed that the presence of globular vessels was significantly more common in nonresponding plaques than in treatment-responding lesions. In contrast, the dermoscopic presence
 
of dotted vessels, which were significantly more common in truncal lesions, was associated with partial/optimal treatment response. Post-treatment follow-up at week 8 showed that 58.7% of lesions classified as treatment-respondent at week 4 had relapsed. Lesional recurrence was found to be significantly associated with dermoscopic vessel persistence at the end of therapy.9
 
Another IIS, led by Yelamos et al, evaluated the clinical and microscopic features in psoriasis target lesions treated with clobetasol cream compared to those treated with Cal/BD foam.10 Patients were randomized in a 1:1 manner to receive either clobetasol cream 0.5 mg/g applied once daily for 2 to 4 weeks (depending on clinical response) or Cal/BD foam once daily for 4 weeks. Study visits occurred at baseline (week 0), week 2, week 4, and week 8 (1 month without treatment).10
 
Investigators employed high-resolution photography to document each patient's most severe plaque at baseline and throughout the study. The Total Clinical Score (TCS), was used to grade erythema, induration, and scaling from the high-resolution clinical images; dermoscopic images of the target lesion center were also taken. The study's primary objective was to attain a lesional TCS score equal to/less than 1 at week 4.10 Investigators found that a significantly greater proportion of patients treated with Cal/BD foam achieved TCS equal to/less than 1 compared to those treated with clobetasol cream. Cal/BD treatment also resulted in significantly greater reductions in microscopic epidermal thickness by week 4 compared to clobetasol treatment. Furthermore, fewer telangiectasias were observed in Cal/BD-treated lesions than clobetasol-treated lesions.10
 
Special Considerations in Patient Outcomes 
Patient Treatment Adherence  
Patient adherence to topical therapies depends on multiple variables related to both the medication and patient. Lack of treatment adherence may contribute to unsatisfactory treatment outcomes. An open-label, prospective single-center study conducted by Navarro-Trivino et al examined adherence to treatment with Cal/BD foam of patients with psoriasis in addition to their satisfaction with the medication.11 Eligible patients were diagnosed with psoriasis on the trunk and extremities and had affected body surface area (BSA) <10%, PASI score <10, and a Dermatology Life Quality Index (DLQI) score <10. Patients receiving psoriasis treatment prior to the study underwent a washout period.11
Sixty-five study participants were enrolled and asked to apply Cal/BD foam on psoriasis plaques along the trunk and upper extremities once daily for no more than 4 weeks. Complete skin clearance was a criterion for treatment discontinuation; if psoriatic lesions relapsed, patients resumed treatment. Treatment adherence and medication satisfaction questionnaires were administered at week 4 and week 12. Strong patient adherence to treatment was observed, with 73.8% of patients demonstrating high adherence at week 12. Patients also notably reported high levels of satisfaction with Cal/BD therapy. By week 4, the majority of participants (70.8%) reported being completely satisfied with Cal/BD foam as their psoriasis treatment.11 Additionally, enrolled patients experienced improvements in quality of life (QoL), as the average DLQI score of participants by week 4 was 2.41 (SD = 3.87) compared to the mean baseline score of 10.67 (SD = 4.96).11 
Similarly, Svendsen et al investigated medication adherence by examining the impact of a smartphone application (app) in improving short-term adherence with once-daily Cal/BD foam therapy.12 The study was a single-center, Phase IV randomized controlled trial; adult patients with mild-to-moderate psoriasis received once-daily treatment with Cal/BD foam and were randomized to no app or app study arms. Patient visits occurred at 4 weeks, 8 weeks, and 26 weeks. An electric monitor chip placed on the dispensed foam canisters registered the day and time the canister was used. Treatment adherence rates were collected at week 4 by measuring the number of treatment applications as recorded by the electronic monitor chip, change in medication canister weight before and after use, and patient self-reporting measures; adherence rates obtained by chip and medication weight that were above 80% were considered adherent. Secondary study outcomes were short-term (week 4) and long-term (weeks 8 and 26) disease severity based on Lattice System Physician's Global Assessment (LS-PGA) and DLQI scores.12
 
A total of 122 out of 134 patients completed the study. Intention-to-treat analyses showed that a statistically greater proportion of patients in the app treatment arm were adherent to Cal/BD cutaneous foam compared to those in the no-app group at week 4. At week 4, the app intervention group demonstrated a greater decrease in reported LS-PGA than the nonintervention group. A similar effect was observed at weeks 8 and 26, though it did not reach statistical significance.
Psoriasis Disease Burden and Impact on Patient Quality of Life  The signs and symptoms of psoriasis can contribute to profound physical and psychosocial disease burden, resulting in diminished patient QoL.13 Two studies performed by da Silva et al investigated the impact of psoriasis disease burden on patient QoL. One study evaluated the degree and directionality of patient-physician (dis)agreement on psoriasis BSA ratings.14 Patients utilized a high resolution grid to document total psoriasis BSA and the regional BSA percentage affecting the head, trunk, arms, and legs; the regional BSA % was used
 
in PASI calculations. Patient-physician disagreement was calculated from the absolute difference between the patient's and physician's total BSA % reports. Directionality of the disagreement was determined by the difference between patient-assigned PASI regional BSA % and physician-assigned PASI regional BSA % (patient-report -- physician-report).14
 
No significant differences between patients' and physicians' total BSA reports were detected; however, significant differences for the PASI regional scores for the head, trunk, arms, and legs were found to exist. Analyses examining the directionality of patient-physician (dis)agreement found that physicians were more likely to record a lower BSA percentage than patients. Additionally, a greater degree of patient-physician disagreement was significantly associated with greater QoL impairments and higher levels of depression.14,15
 
Another study conducted by da Silva et al assessed the effect of pruritus and anogenital psoriasis on disease burden and patient mental health.15 Investigators also sought to identify variables associated with clinically significant depression/anxiety symptoms and body dysmorphia concerns. A total of 107 adult psoriasis patients completed the study. Approximately 40% of patient participants reported moderate-severe pruritus, and 29% reported anogenital involvement.15 Patients with moderate-severe pruritus reported greater skin-related and pruritus-specific QoL impairment; they also reported more profound depression and anxiety symptoms along with greater concerns related to body dysmorphia. Moderate-severe pruritus patients also reported experiencing fewer treatment benefits than patients who reported no-mild pruritus. Additionally, moderate-severe pruritus had a detrimental effect on depression and perceived stigmatization for those without anogenital involvement. Patients who reported few treatment benefits were found to be more likely to experience clinically significant depression/anxiety symptoms.15
 
Sommer et al conducted a similar study to compare disease burden and patient needs between psoriasis patients with no-mild itch vs moderate-severe chronic pruritus.16 This cross sectional, observational study also examined the effect of disease severity and intrapersonal burden on patients' sexual relationships and perceptions of stigmatization. Psoriasis patients equal to/greater than 18 years completed questionnaires about pruritus severity, general skin-related and pruritus-specific QoL, anxiety/depression symptoms, body dysmorphia concerns, patient needs, treatment benefits, sexual dysfunction, and perceptions of stigmatization.16
A total of 107 psoriasis patients were included in the final study analysis: 60% reported having no-mild itch while 40% reported moderate-severe pruritus. Like da Silva et al, investigators found that patients with moderate-severe pruritus reported greater QoL impairment, depression and anxiety symptoms, and concerns about body dysmorphia.16 Moderate-severe pruritus patients also reported fewer treatment benefits than those with no-mild pruritus. Younger age, degree of disease involvement, increased scratching behaviors, body dysmorphia concerns, and perceived treatment benefits were factors significantly associated with higher levels of patient stigmatization.16 Disease severity, difficulty sleeping, and general skin-related QoL impairments were shown to have a statistically significant positive association with sexual dysfunction. Finally, study participants in both the no-mild and moderate-severe pruritus groups most frequently rated be[ing] healed of all skin defects and be[ing] free of itching as very important and quite important.16
 
Treatment of Psoriasis Patients with Skin of Color 
There is limited data on the efficacy of topical medications in treating patients with skin of color. Liu et al conducted a single-center, double-blinded study to examine the efficacy of fixed-dose Cal/BD aerosol foam as a treatment of psoriasis vulgaris in patients with Fitzpatrick skin types IV to VI.17  Eligible adult psoriasis patients were randomized to Cal/BD foam or foam vehicle once-daily application for 4 weeks.
Approximately 21% (4/19) of patients randomized to the Cal/BD foam treatment arm reached clear/almost clear Investigator Global Assessment (IGA) status with equal to/greater than 2 point improvement by week 4. In comparison, 0% (0/5) of vehicle patients reached clear/almost clear status at this time.17 Investigators also found that a statistically greater proportion of Cal/BD foam patients achieved a 50% reduction in their PASI score at week 4 compared to vehicle patients (63% vs 0%; P=0.04). Average changes in melanin index observed at week 4 demonstrated a trend in increasing pigmentation in patients treated with  Cal/BD foam. In contrast, decreased pigmentation was observed in patients treated with vehicle foam.17
Treatment in Palmoplantar Psoriasis 
Mateu-Puchades et al led an observational, prospective study to investigate the effectiveness, and safety of Cal/BD foam as a treatment for non-pustular palmoplantar (PP) psoriasis.18 Investigators evaluated the effect once-daily Cal/BD foam had on patient QoL and treatment satisfaction. Eligible adult patients diagnosed with PP psoriasis were enrolled in the 4-week clinical study. Palmoplantar Psoriasis Area Severity Index (PPASI) and PGA scores were used to assess treatment effectiveness and safety. The DLQI and the 14-item Treatment Satisfaction Questionnaire for Medication were administered to evaluate patient QoL and treatment satisfaction.18
A total of 19 patient participants were included in the final
 
analysis. All enrolled study individuals had a BSA < 10%. Notably, study participants experienced a statistically significant reduction in PPASI (median reduction: 3.6, P=0.0284) and PGA scores (median reduction:1.0, P=0.0047).18 An improvement in QoL was observed in patients, though it did not reach statistical significance. No adverse reactions associated with treatment were recorded. Patient-reported treatment satisfaction with Cal/BD foam was high (score: 76.9/100, higher scores indicating greater satisfaction with treatment), implying patient satisfaction with the effectiveness, convenience, and side-effect profile of the medication.18
 
Treatment of Moderate-to-Severe Psoriasis 
Efficacy of Cal/BD Aerosol Foam in Patients With Moderate Psoriasis 
Topical treatments are the mainstay therapies used to treat mild and moderate psoriasis.19 They are also commonly used as adjunctive therapies in patients with moderate-to-severe disease who are receiving treatment with phototherapy, oral systemic, or biologic agents.20 Del Rosso et al conducted a 2-center, 4-week clinical study to examine the use of once-daily Cal/BD foam monotherapy to treat moderate-severity psoriasis.20 The study also examined the efficacy of Cal/BD foam treatment on plaques localized to the knees and elbows, which were two sites that had not been previously evaluated and treated as target lesions. The study enrolled patients with psoriasis who were equal to/greater than 18 years old with 3% to 20% BSA involvement and moderate disease (PGA score = 3) at baseline. All participants had bilateral, symmetric psoriasis plaques along the knees and/or elbows that measured 2 cm to 4 cm in diameter with a Target Lesion Severity Score equal to/greater than 6.20
 
The study protocol required patient visits at baseline, week 2, and week 4 to assess efficacy, safety, and tolerability. The observed therapeutic responses related to clinical efficacy and medication-related adverse events were similar to findings observed in the pivotal studies.5,6 Novel findings included statistically significant changes in absolute and percent target lesion size at week 4; significant reductions in target lesion erythema and induration from baseline to week 2 and from week 2 to week 4 were also observed.20
 
Adjunctive Cal/BD Foam with Oral Apremilast for Moderate Psoriasis 
Apremilast is an oral small-molecule phosphodiesterase 4 (PDE4) inhibitor that may be used in the treatment of psoriasis. The medication has demonstrated a well-established safety and efficacy profile throughout various clinical studies.21-22 Kircik et al conducted a 16-week, investigator-blinded study to better understand the efficacy and safety of using Cal/BD foam in combination with oral apremilast to treat moderate psoriasis.23
Patients equal to/greater than 18 years old diagnosed with moderate psoriasis (PGA score= 3) and who had been started on oral apremilast (30 mg twice daily) within 10 days of enrollment were deemed eligible. Study participants were randomized in a 1:1 manner to either once-daily Cal/BD foam and apremilast combination therapy or once-daily vehicle foam and apremilast combination therapy for 4 weeks. After the initial 4-week treatment period, those enrolled received 8 weeks of apremilast monotherapy, which was followed by re-initiation of once-daily Cal/BD foam or vehicle foam with apremilast for an additional 4 weeks.23
 
A total of 28 individuals completed the clinical study. At week 4, a statistically greater portion of patients in the Cal/BD foam plus apremilast treatment arm achieved improvement in skin clearance (equal to/greater than 75% reduction in PASI score and equal to/greater than 2 PGA score improvement) than the vehicle foam plus apremilast arm.23 The Cal/BD group also experienced statistically significant improvements in pruritus compared to the vehicle group. Disease severity (ie, PASI and PGA scores), pruritus, and patient QoL worsened after the 8-week Cal/BD foam treatment withdrawal period; however, improvements in these efficacy measures recovered after resuming Cal/BD foam therapy from week 12 to week 16.23 Overall, investigators found that Cal/BD foam was effective in clearing patients' skin and improving their QoL when used as an adjunct therapy alongside apremilast. Thus, treatment regimen of Cal/BD foam and apremilast was found to be safe and well-tolerated in the management of moderate psoriasis.
Ozyurekoglou et al sought to build upon Kircik et al's findings and examined the efficacy of twice-weekly maintenance dosing following treatment with 4 weeks of standard once-daily Cal/BD foam application in combination with apremilast.24 Twice-weekly application has been shown to prolong disease remission and reduce relapses in patients initially treated with standard once-daily Cal/BD foam dosing.7 However, previous studies had not evaluated the use of Cal/BD foam as a maintenance therapy used alongside apremilast.
A single-center, open-label pilot study was conducted and enrolled adult patients with moderate psoriasis who began treatment with oral apremilast (30 mg twice daily) within 10 days of their baseline visit. Study visits and assessments were performed at baseline, week 4, week 16, and week 20. Individuals who reached clear/almost clear PGA status at week 4 were instructed to reduce Cal/BD application to twice-weekly maintenance dosing through week 16 while continuing apremilast treatment. Treatment was stopped at week 16, and safety follow-up was conducted at week 20.24 
At week 4, 95% of patients treated with the combination regimen of apremilast plus Cal/BD achieved clear/almost clear
 
PGA status.24 Though the greatest reduction in PGA occurred at week 4, significant PGA score reductions were observed at each subsequent visit after baseline. A majority of patients (74%) were still clear/almost clear at week 16. Additionally, 90% of patients reported being somewhat to extremely satisfied with treatment overall at week 16, with the most common patient responses to the week-16 patient satisfaction questionnaire being mostly satisfied to extremely satisfied with Cal/BD foam's efficacy in treating and preventing symptoms. No adverse events were suspected to be due to the study medication, and no serious adverse events were reported.24
Adjunctive Cal/BD Foam Therapy Plus Biologic Treatment for Moderate-to-Severe Psoriasis 
Despite their high levels of efficacy, biologic agents do not always result in rapid and complete clearance in patients with moderate-to-severe psoriasis; topical treatments are commonly added as adjunct therapies in these instances.25 Bagel et al conducted two trials to obtain real-world data related to the safety and efficacy of Cal/BD foam as an adjunctive therapy to biologic treatment for moderate-to-severe psoriasis. One of the studies assessed the tolerability and effectiveness of once-daily Cal/BD foam in patients with psoriasis who may have failed to obtain adequate treatment responses with biologic therapy.26 The study employed a prospective, single-arm design; enrolled individuals were adult patients with psoriasis, a BSA equal to/less than 5%, and had been treated with a biologic equal to/greater than 24 weeks. All patients were asked to continue their biologic regimen and apply Cal/BD foam once daily for 4 weeks; this was followed by a 12-week maintenance dosing period where individuals applied Cal/BD foam on 2 consecutive days weekly.26
Combination therapy of biologic plus Cal/BD foam resulted in significant clinical improvement in disease. Over one-quarter of participants achieved total clearance (defined as 0% BSA and PGA=0) as early as week 4.26 Whereas only 12% reached
 
 
the study's treat-to-target goal of equal to/less than 1% BSA from biologic monotherapy at baseline, 76% and 68% of patients achieved this status at weeks 4 and 16 respectively after receiving adjunctive treatment with Cal/BD foam (P<0.001). Significantly more patients achieved PGA equal to/less than 1 status with Cal/BD foam at both week 4 and week 16 compared with those treated with biologics alone at baseline.33 Furthermore, no serious adverse events or medication-related adverse events were reported throughout the duration of the study.26
Bagel et al conducted another 16-week, open-label study to assess the efficacy of Cal/BD foam in patients who failed to clinically respond to treatment with stable etanercept or adalimumab therapy.27 The clinical study had an additional aim of evaluating the potential cost savings of treatment with adjunctive Cal/BD compared to switching treatment to a different biologic therapy. Patient visits occurred at baseline and weeks 4, 8, 12, and 16. Failed clinical response to biologic therapy was defined as having BSA involvement of 2% to 10% and a PGA rating equal to/greater than 2 despite treatment with etanercept or adalimumab for equal to/greater than 24 weeks. Enrolled participants were treated with 4 weeks of once-daily Cal/BD foam adjunct therapy, followed by every-other-day Cal/BD foam dosing for an additional 12 weeks. Maintenance biologic dosing with either etanercept or adalimumab was continued throughout the duration of the 16-week study. For pharmacoeconomic evaluation, investigators calculated the cumulative cost of adjuvant Cal/BD therapy by adding the cost of 4 weeks of once-daily Cal/BD foam dosing followed by 12 weeks of once-every-other-day therapy to the cost of 16 weeks of maintenance etanercept or adalimumab dosing. This was compared to the cost of switching to a new biologic, which was determined by averaging the wholesale prices for commonly prescribed biologics multiplied by the FDA-approved induction and maintenance doses for up to 16 weeks of treatment.27
 
The study demonstrated clinical improvements in BSA involvement, PGA scores, and composite BSA x PGA scores within 4 weeks of initiating Cal/BD adjunct therapy.27 These improvements were maintained for an additional 12 weeks of Cal/BD every-other-day dosing combination therapy. Additionally, 75% of patients achieved treat-to-target status of BSA equal to/less than 1%. Investigators were less inclined to switch biologics by week 16, as their reported likelihood to switch decreased from 90.0% at baseline to 7.1%. Finally, pharmacoeconomic evaluation revealed that Cal/BD foam adjuvant therapy resulted in lower costs than switching biologic agents.27
 
The overall findings of the two clinical studies conducted by Bagel et al provided real-world evidence demonstrating the efficacy and cost-effectiveness of adjunctive Cal/BD foam therapy in patients who experience lack of clinical response despite treatment with biologics. Information related to the pharmacoeconomic considerations associated with biologic plus Cal/BD combination therapy was further examined by Haidari et al.28 Investigators conducted a systematic literature review using MEDLINE to identify articles discussing treatment approaches for moderate-to-severe psoriasis patients who failed to attain complete skin clearance (defined as 100% improvement in PASI score and/or PGA score=0) despite treatment with a biologic. The efficacy, cost, and safety associated with each therapeutic approach were reviewed.28
Of the treatment regimens reported in the literature, the therapeutic approaches most likely to induce complete clearance in patients who failed to reach clearance on a biologic were addition of Cal/BD foam to initial biologic therapy (28%), switching biologic therapy to guselkumab (20%), and switching to treatment with infliximab (15.8%).28 The cost of adjuvant therapy with Cal/BD foam plus existing biologic treatment was found to be $3,780 per patient cleared; this was less costly compared to the lowest-cost biologic dose escalation (guselkumab; $73,370 per patient cleared) or switching to the least expensive alternative biologic agent (infliximab; $88,250 per patient cleared).28

CONCLUSION

The efficacy and safety of Cal/BD foam as a treatment for psoriasis have been well-studied in large-scale clinical trials and several IISs. Data from these studies add to the body of clinical evidence that aids physicians in selecting efficacious, cost-effective therapeutic approaches to improve patient treatment outcomes in psoriasis.
The results reported by Errichetti et al and Yelamos et al confirmed the efficacy of once-daily Cal/BD therapy in treating psoriasis.9,10 Their novel findings provide dermoscopic characteristics associated with treatment improvement (ie, lesions localized to the trunk and dermoscopic presence of dotted vessels) to aid physicians in clinical management. Svendsen et al and Navarro-Trivino et al examined medication adherence with once-daily Cal/BD foam; the real-world data obtained from their studies highlight the impact of treatment adherence and clinical efficacy of once-daily Cal/BD dosing.11,12 These findings demonstrate the need for clinicians to counsel patients on the importance of treatment adherence for clinical improvement. Navarro-Trivino et al's work also highlighted the high levels of patient satisfaction with Cal/BD foam, as most patients reported high levels of overall satisfaction in addition to satisfaction with the cosmetic quality and ease of application of the drug. Given the importance of patient treatment satisfaction on treatment adherence and overall treatment outcomes, this finding suggests that Cal/BD foam is an easy-to-use medication that psoriasis patients may be more likely to apply regularly and thereby improve their disease.
Additional studies provided insight into special treatment considerations. For example, the findings provided by da Silva et al and Sommer et al brought attention to the need to account for patients' perceived stigmatization and disease burden to better care for patients and increase treatment compliance.14-16 Their findings exhibit the importance of shared decision-making practices given the burden that visible areas of disease can have on psoriasis patients. Liu et al's clinical study also presented novel findings, documenting Cal/BD foam's safety and efficacy as a psoriasis treatment in patients with skin of color.17 The increased pigmentation of lesional skin observed in the Cal/BD treatment group may be due to pigmentary changes associated with clinical improvement of psoriasis in skin of color. Thus, clinicians may consider the therapeutic benefit of Cal/BD for psoriasis patients with skin of color. Finally, Mateu-Puchades et al's examination of Cal/BD foam as a potential treatment for PP psoriasis found that the medication is well-tolerated and clinically effective with high levels of patient satisfaction.18
Clinicians also investigated the role of Cal/BD foam in therapeutic management of moderate-to-severe psoriasis. Del Rosso et al notably documented the effectiveness and tolerability of once-daily Cal/BD aerosol foam as a treatment for moderate-severity plaques affecting the elbows and knees, which were target lesion sites that had not been previously studied.20 These findings suggest that patients with moderate-to-severe psoriasis plaques involving these anatomic sites would benefit from Cal/BD therapy. Other studies conducted by Kircik et al and Ozyurekoglou et al confirmed the safety and efficacy of Cal/BD plus apremilast combination therapy in treating moderate psoriasis while also substantiating the effectiveness of twice-weekly maintenance Cal/BD maintenance dosing.23,24 Furthermore, the studies led by Bagel et al and Haidari et al highlighted the efficacy and cost-effectiveness of
 
adjunct Cal/BD therapy.26-28 Given the clinical improvements and economic savings associated with biologic plus Cal/BD foam treatment reported in these studies, physicians may consider this regimen in patients with inadequate response to stable biologic treatment.
This report summarizes the real-world data regarding the unique clinical and therapeutic considerations of Cal/BD foam as presented in the IISs that have been conducted around the globe and have been published to date. These studies provide an abundance of strong, real-world evidence to guide clinicians' everyday practice.

DISCLOSURES

Leon Kircik MD has received research grants from AbbVie, Allergan, Almirall, Amgen, Arcutis, Boehringer Ingelheim, Breckinridge Pharma, Bristol Myers Squibb, Celgene, Cellceutix, Centocor, Combinatrix, Connetics, Coria, Dermavant, Dermira, Dow Pharma, Dr. Reddy's Laboratories, Eli Lilly, EPI Health, Galderma, Genentech, GlaxoSmithKline, Idera, Johnson & Johnson, Leo Pharma, Maruho, MC2, Merck, Medicis, Novan, Novartis AG, Pfizer, PharmaDerm, Promius, Stiefel, Sun Pharma, UCB, Valeant, and XenoPort; has received honoraria from AbbVie, Allergan, Almirall, Amgen, Arcutis, Biogen Idec, Bristol Myers Squibb, Celgene, Cipher, Connetics, Dermavant, Dermira, Dr. Reddy's Laboratories, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Johnson & Johnson, Leo Pharma, Merck, Novartis AG, PharmaDerm, Promius, Serono (Merck Serono International SA), Stiefel, Sun Pharma, Taro, UCB, and Valeant.
 
AWA has served as a research investigator, scientific advisor, and/or speaker to AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Mindera, Nimbus, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, and Pfizer.
 
All other authors report no disclosures.
IRB approval status: Exempt

REFERENCES

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AUTHOR CORRESPONDENCE

April W. Armstrong MD MPH armstrongpublication@gmail.com
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