Early Response to Calcipotriol and Betamethasone Dipropionate PAD-Cream at Week 4 in Patients with Mild-to-Moderate Plaque Psoriasis: A Post-Hoc Pooled Analysis of Two Phase III Trials

Abstract

Introduction

Topical therapy plays an essential role in psoriasis management. However, lack of rapid improvement may negatively impact adherence. The calcipotriol and betamethasone dipropionate (CAL/BDP) cream based on polyaphron dispersion (PAD) technology has demonstrated high efficacy, favorable safety, and convenience compared with CAL/BDP gel in phase III trials. This post-hoc analysis aims to assess early treatment response to CAL/BDP PAD-cream at Week (W) 4.

Methods

This was a post-hoc pooled analysis of adults with mild-to-moderate psoriasis from two multicenter, investigator-blind, phase III trials (MC2-01-C2 and MC2-01-C7). Patients were randomized 3:1:3 to CAL/BDP PAD-cream (N = 551), PAD-cream vehicle (N = 178), or CAL/BDP gel (N = 542) once daily for 8 weeks. Physician’s Global Assessment (PGA) and Subject’s Global Assessment (SGA) were assessed at W1 and W4. At W4, early responders were defined as patients achieving PGA controlled disease (i.e., any improvement from baseline to a PGA score of 0–1), while PGA success was defined as a PGA score of 0–1 combined with a minimum 2-point improvement from baseline. SGA controlled disease and SGA success were also assessed. Comparisons between groups were performed by logistic regression models using multiple imputation. Rates of PGA/SGA concordance were assessed by simple percent agreement.

Results

At W4, CAL/BDP PAD-cream was associated with a significantly higher proportion of patients achieving early response compared with CAL/BDP gel (32.1% vs 21.4%, P < 0.0001). Differences were already significant at W1 (7.8% vs 4.8%, P = 0.0410). PGA success at W4 was also higher with CAL/BDP PAD-cream than with CAL/BDP gel (23.6% vs 14.8%, P < 0.0001). Rates of SGA controlled disease and success were also statistically significantly higher for CAL/BDP PAD-cream at W4. Concordance between PGA/SGA assessments at W4 was observed in 65.5% (controlled disease) and 69.5% (success) of patients treated with CAL/BDP PAD-cream.

Conclusion

CAL/BDP PAD-cream was associated with significantly higher early response rates at W4 than CAL/BDP gel, suggesting earlier clinical improvements.

Key Summary Points

Why carry out this study?

Early perceived treatment benefit is important for persistence with topical psoriasis therapies.

This study assessed the proportion of early responders to calcipotriol and betamethasone dipropionate cream based on polyaphron dispersion technology (CAL/BDP PAD-cream) according to the achievement of Physician Global Assessment (PGA) controlled disease at Week 4 and compared the concordance of results with patient-reported outcomes (PROs).

What was learned from the study?

CAL/BDP PAD-cream was associated with significantly higher early response rates at Week 4 than CAL/BDP gel and vehicle.

About seven out of ten patients treated with CAL/BDP PAD-cream showed concordance between their assessments and physician’s assessment of controlled disease or treatment success.

These findings support the clinical relevance of early treatment response and the complementary value of PROs, which may help improve treatment satisfaction and adherence in psoriasis management.

Introduction

Psoriasis is a common inflammatory skin disease that typically presents as raised, scaly, erythematous plaques and is associated with a substantial physical and psychological burden for patients [1]. Topical therapy plays an essential role in the management of psoriasis, as approximately 70–80% of patients present with mild-to-moderate disease and can achieve adequate control with these treatments. However, treatment ineffectiveness, patient dissatisfaction, and poor adherence remain major barriers to topical treatment success [2].

The calcipotriol and betamethasone dipropionate cream based on polyaphron dispersion technology (CAL/BDP PAD-cream) was developed as a novel formulation for a more convenient topical psoriasis treatment [3]. The PAD technology permits stable formulation of CAL/BDP in a water-based cream by encapsulating these molecules in oil droplets (aphrons), which enhances skin penetration, absorption speed, and cosmetic acceptability [3, 4]. Two phase III clinical trials conducted in Europe and in the United States (USA) demonstrated high efficacy, favorable safety, and improved convenience of CAL/BDP PAD-cream compared with CAL/BDP gel [5].

Although most endpoints were mainly assessed by physicians at Week 8, in accordance with the recommended treatment duration of CAL/BDP PAD-cream, some findings suggested that superior clinical improvement compared with the active comparator may be observed earlier due to a faster onset of action of CAL/BDP PAD-cream [5]. Early perceived treatment benefit is an important factor for persistence with topical therapies, as lack of rapid improvement may lead to treatment discontinuation [6]. Moreover, evaluation of patient-reported outcomes (PROs) along with physician-reported outcomes is warranted. Considering that discrepancies between physicians’ and patients’ assessments of disease severity have been reported, alignment of treatment goals and expectations is important, as it may help to improve treatment satisfaction and adherence [7, 8].

In psoriasis, the Physician Global Assessment (PGA) is a well-established scale that evaluates treatment response by assessing key lesion characteristics and categorizing the disease as clear, almost clear, mild, moderate, or severe [9]. The Subject’s Global Assessment (SGA) is a PRO that classifies the disease in similar categories but from the patient’s perspective [10, 11]. Further evidence is needed to determine whether the PGA assessments show concordance with the SGA assessments in the context of topical psoriasis treatment with CAL/BDP PAD-cream.

Therefore, the objectives of this post-hoc analysis were to assess the proportion of early responders to CAL/BDP PAD-cream based on achievement of PGA controlled disease at Week 4 and to compare the concordance of results with PROs.

Methods

Study Design

This was a post-hoc pooled analysis of the two previously published phase III trials: MC2-01-C7 (NCT03802344) and MC2-01-C2 (NCT03308799) [12, 13]. Both studies were multicenter, randomized, investigator-blind, active, and vehicle-controlled. Although the two studies shared a nearly identical design, their primary endpoints were not the same. The trial performed in Europe (MC2-01-C7) primarily measured the percentage change in modified Psoriasis Area and Severity Index (mPASI) to Week 8, while the study performed in the USA (MC2-01-C2) focused on the percentage of patients achieving PGA treatment success by Week 8. The primary endpoint in each study was included as a secondary endpoint in the other study. The study protocols of the two phase III studies were reviewed and approved by ethics committees or local institutional review boards (independent ethics committee for trial MC2-01-C7: Ethikkommission der Ärztekammer, Hamburg, Weidestraße 122b, 22083 Hamburg, Germany; central institutional review board for trial MC2-01-C2: Quorum, 1501 Fourth Ave, Ste 800, Seattle, WA 98101). Both studies were conducted according to the 1964 Declaration of Helsinki and its subsequent amendments. All patients provided written informed consent to participate in the phase III studies.

Patients and Treatments

In both studies, adults with mild-to-moderate psoriasis were randomized in a 3:1:3 ratio to receive CAL/BDP PAD-cream, PAD-cream vehicle, or CAL/BDP gel once daily for 8 weeks. The MC2-01-C7 allowed the inclusion of patients with scalp psoriasis and required a minimum mPASI score ≥ 3, while in the MC2-01-C2 trial psoriasis was limited to the trunk and/or limbs and the mPASI score had to be ≥ 2 [3, 5].

Outcomes

PGA (0, clear; 1, almost clear; 2, mild; 3, moderate; and 4, severe) and SGA (0, clear; 1, very mild; 2, mild; 3, moderate; and 4, severe) were assessed at baseline, Week 1, and Week 4. The proportion of patients achieving PGA controlled disease (defined as any improvement from baseline to a PGA score of 0–1) and PGA success (defined as a PGA score of 0–1 with a ≥ 2-point improvement from baseline) was evaluated at each timepoint. Corresponding PROs, including SGA controlled disease and SGA success, were assessed using analogous definitions as PGA. Early responders were defined as patients achieving PGA controlled disease at Week 4.

Statistical Analysis

Rates of PGA controlled disease, PGA success, SGA controlled disease, and SGA success were compared between treatment arms at each timepoint by logistic regression models using multiple imputation. P values were not adjusted for multiplicity. The concordance between PGA and SGA assessments was evaluated by simple percent agreement. Assessment of between-study heterogeneity was not performed, as both phase III trials were highly comparable in design and exhibited consistent treatment effects.

All analyses were performed for the modified intention-to-treat (mITT) population, which includes all patients who were treated and had at least one assessment of efficacy after treatment initiation [5].

Results

Patients

The mITT population included 1271 patients, of which 551 patients were treated with CAL/BDP PAD-cream, 542 with CAL/BDP gel, and 178 with vehicle. Table 1 shows main baseline demographic and disease characteristics of patients included in the mITT population.

Table 1.

Main baseline characteristics of patients included in the pooled mITT population of the CAL/BDP PAD-cream phase III trials

Baseline characteristic	CAL/BDP PAD-cream (N = 551)	CAL/BDP gel (N = 542)	PAD-cream vehicle (N = 178)	Total (N = 1271)
Age (years), mean (SD)	50.9 (14.1)	52.2 (14.2)	50.6 (13.8)	51.4 (14.1)
Male, n (%)	337 (61.2)	333 (61.4)	113 (63.5)	783 (61.6)
Female, n (%)	214 (38.8)	209 (38.6)	65 (36.5)	488 (38.4)
BSA affected (%), mean (SD)	8.0 (6.4)	8.7 (6.9)	8.7 (6.6)	8.4 (6.6)
mPASI, mean (SD)	7.5 (3.9)	7.8 (4.0)	7.6 (4.0)	7.7 (4.0)
PGA, mean (SD)	2.8 (0.4)	2.8 (0.4)	2.8 (0.4)	2.8 (0.4)
DLQI, mean (SD)	9.6 (6.0)	9.9 (6.7)	9.3 (6.2)	9.7 (6.3)

BDP betamethasone dipropionate, BSA body surface area, CAL calcipotriol, DLQI Dermatology Life Quality Index, mITT modified intention-to-treat, mPASI modified Psoriasis Area and Severity Index, PAD polyaphron dispersion, PGA Physician Global Assessment, SD standard deviation

Physician-Reported Outcomes (PGA Results)

A statistically significant higher proportion of early responders was observed in the CAL/BDP PAD-cream group (32.1%; 95% confidence interval (CI) [32.05, 32.20]) compared to both CAL/BDP gel (21.4%; 95% CI [21.34, 21.46]; Δ = + 10.7%; P < 0.0001) and vehicle (4.5%; 95% CI [4.48, 4.51]; Δ = + 27.6%; P < 0.0001) at Week 4 (Fig. 1a). Differences between groups were already statistically significant at Week 1, with a higher percentage of patients achieving PGA controlled disease in the CAL/BDP PAD-cream group (7.8%; 95% CI [7.78, 7.83]) compared to CAL/BDP gel (4.8%; 95% CI [4.78, 4.81]; Δ = + 3.0%; P = 0.0410) and vehicle (1.1%; 95% CI [1.12, 1.13]; Δ = + 6.7%; P = 0.0013) (Fig. 1a).

Fig. 1.

PGA controlled disease and success at Week 1 and Week 4. BDP betamethasone dipropionate, CAL calcipotriol, N number of patients achieving endpoint, PAD polyaphron dispersion, PGA Physician Global Assessment. P values represent comparison of CAL/BDP PAD-cream to CAL/BDP gel or vehicle using logistic regression models with multiple imputation. ^aPatients achieving any improvement from baseline to a PGA score of 0–1. ^bPatients achieving PGA controlled disease at Week 4 are considered early responders. ^cPatients achieving a PGA score of 0–1 with a ≥ 2-point improvement from baseline

At Week 4, a statistically significant higher proportion of patients achieved PGA success with CAL/BDP PAD-cream (23.6%; 95% CI [23.53, 23.66]) compared to both CAL/BDP gel (14.8%; 95% CI [14.71, 14.81]; Δ = + 8.8%; P < 0.0001) and vehicle (1.1%; 95% CI [1.12, 1.13]; Δ = + 22.5%; P < 0.0001) (Fig. 1b).

Patient-Reported Outcomes (SGA Results)

A statistically significant higher percentage of patients achieved SGA controlled disease at Week 4 with CAL/BDP PAD-cream (41.6%; 95% CI [41.47, 41.65]) than with CAL/BDP gel (31.5%; 95% CI [31.47, 31.63]; Δ = + 10.1%; P = 0.0006) or vehicle (14.0%; 95% CI [14.00, 14.09]; Δ = + 27.6%; P < 0.0001) (Fig. 2a). SGA success was also statistically significant higher with CAL/BDP PAD-cream (23.8%; 95% CI [23.71, 23.84]) than with CAL/BDP gel (16.6%; 95% CI [16.56, 16.66]; Δ = + 7.2%; P = 0.0021) and vehicle (7.9%; 95% CI [7.84, 7.89]; Δ = + 15.9%; P < 0.0001) at Week 4 (Fig. 2b).

Fig. 2.

SGA controlled disease and success at Week 1 and Week 4. BDP betamethasone dipropionate, CAL calcipotriol, N number of patients achieving endpoint, PAD polyaphron dispersion, SGA Subject’s Global Assessment. P values represent comparison of CAL/BDP PAD-cream to CAL/BDP gel or vehicle using logistic regression models with multiple imputation. ^aPatients achieving any improvement from baseline to a SGA score of 0–1. ^bPatients achieving a SGA score of 0–1 with a ≥ 2-point improvement from baseline

PGA and SGA Concordance

Rates of PGA and SGA concordance are shown in Table 2. When comparing PROs (SGA) with physician-reported assessments (PGA) at Week 4, 65.5% of patients treated with CAL-BDP PAD-cream showed concordance in the assessment of controlled disease and 69.5% showed concordance for success. Similar rates were observed for CAL/BDP gel, whereas higher concordance rates were obtained with the vehicle (Table 2).

Table 2.

Rates of PGA and SGA concordance at Week 1 and Week 4

PGA/SGA concordance	CAL/BDP PAD-creama N = 551	CAL/BDP gela N = 542	Vehiclea N = 178
Controlled diseaseb
Week 1	433/543 (79.7)	420/531 (79.1)	151/174 (86.8)
Week 4	338/516 (65.5)	366/515 (71.1)	131/160 (81.9)
Successc
Week 1	481/541 (88.9)	477/528 (90.3)	170/174 (97.7)
Week 4	358/515 (69.5)	389/514 (75.7)	146/160 (91.3)

Concordance is given if PGA and SGA assessments of controlled disease and success are matching

BDP betamethasone dipropionate, CAL calcipotriol, PAD polyaphron dispersion, PGA Physician Global Assessment, SGA Subject’s Global Assessment

^aData are presented as n/m (%), where m is the number of non-missing observations in PGA and SGA

^bPatients achieving any improvement from baseline to a PGA or SGA score of 0–1

^cPatients achieving a PGA or SGA score of 0–1 with a ≥ 2-point improvement from baseline

Discussion

Patients with psoriasis expect to see rapid improvement with topical treatments. Otherwise, they may discontinue treatment [6]. The present post-hoc analysis assessed the proportion of early responders in the pooled population of the two phase III clinical trials of CAL/BDP PAD-cream by the achievement of PGA controlled disease at Week 4 [5, 12, 13]. The rates of concordance between physicians’ assessments (PGA) and patients’ assessments (SGA) were further investigated.

For the definition of early response, the PGA was used. In psoriasis, the PGA has shown reliability and strong correlation with the Psoriasis Area and Severity Index (PASI), as well as with measures of health-related quality of life [9, 14, 15]. In fact, the endpoint PGA controlled disease (i.e., any improvement from baseline to a PGA score of 0–1) was selected instead of PGA success (i.e., a PGA score of 0–1 with a ≥ 2-point improvement from baseline) to capture early clinically meaningful improvement at Week 4, because achieving clear or almost clear disease represents a patient-relevant treatment goal in real-world psoriasis management, regardless the minimum 2-point improvement [16]. As such, PGA controlled disease was considered a pragmatic measure for evaluating early treatment benefit, while PGA success was also assessed as a more stringent endpoint.

A higher proportion of patients achieved an early response at Week 4 with CAL/BDP PAD-cream than with the gel formulation (32.1% vs 21.4%, P < 0.0001), suggesting earlier clinical improvement. Differences in PGA controlled disease between the two formulations were already statistically significant after 1 week of treatment. This may be clinically relevant, as to get better skin quickly is among the most important treatment goals for patients [17]. These findings should, however, be interpreted cautiously given the exploratory nature of this post-hoc analysis and the lack of multiplicity adjustment. In addition, patients receiving CAL/BDP PAD-cream also showed a higher rate of PGA success at Week 4 (23.6% vs 14.8%, P < 0.0001), which is a more restrictive endpoint. Similar tendencies were observed based on patient-reported SGA scores, with a statistically significant higher percentage of patients in the CAL/BDP PAD-cream group than CAL/BDP gel achieving SGA controlled disease (41.6% vs 31.5%, P = 0.0006) and SGA success (23.8% vs 16.6%, P = 0.0021) at Week 4. Overall, CAL/BDP PAD-cream was consistently associated with significantly higher response rates than CAL/BDP gel at Week 4 across both physician- and patient-reported assessments. This may be particularly relevant because rapid clinical improvement is among the treatment outcomes most valued by patients with psoriasis [6].

Although patients tended to rate their disease severity higher, with approximately 17% categorizing their disease as severe at baseline, concordance between the patient- and physician-reported assessments of controlled disease and success at Week 4 was observed in the 65.5% and 69.5% of patients treated with CAL/BDP PAD-cream, respectively. Notably, higher concordance rates were shown in the vehicle group (81.9% and 91.3%, respectively). These findings suggest that patients may generally perceive the psoriasis status as more severe than physicians do. However, they appear to assess the direction and magnitude of disease evolution following treatment in a manner that is largely consistent with physician evaluations. Patient–physician discordance in disease perception is well documented in psoriasis. In a cross-sectional study of 1053 pairs of patients with psoriasis or eczema and physicians, 447 out of the 487 pairs who demonstrated discordance showed positive discordance (defined as patient-graded severity more than 2 points higher in severity than physicians) [18]. This tendency to rate the disease severity higher than physicians may occur because physicians focus on objective and visible clinical signs of psoriasis, which do not always correlate with the psychoemotional burden experienced by patients [19]. In contrast, patients consider also the impact on quality of life and the emotional burden when assessing disease severity [18, 20, 21].

Strengths of this analysis include the assessment of early treatment response, which represents a clinically relevant outcome for patients with psoriasis. In addition, the combined evaluation of physician-reported and PROs strengthens the robustness and clinical relevance of the findings. However, this analysis has some limitations. First, the population included in this post-hoc analysis was derived from phase III clinical trials conducted under strict and controlled conditions [5]. Patients’ characteristics and treatment adherence may differ in non-controlled real-world settings, potentially leading to different results [22]. Second, early response to CAL/BDP PAD-cream was assessed at Week 4. In routine clinical practice, some patients may experience a response earlier in time. Finally, all analyses were exploratory in nature and were unadjusted for multiplicity, which increases the risk of type I error and warrants cautious interpretation of statistical significance.

Conclusion

Overall, in this post-hoc exploratory pooled analysis, CAL/BDP PAD-cream was associated with a statistically significant higher percentage of early response compared to both CAL/BDP gel and vehicle in adults with mild-to-moderate psoriasis. However, these findings warrant cautious interpretation given the exploratory nature of the analysis and the lack of multiplicity adjustment. PROs assessed using comparable scales, such as SGA controlled disease and SGA success, were also higher with CAL/BDP PAD-cream. Despite patients tending to rate disease severity higher than physicians, approximately seven out of ten patients treated with CAL/BDP PAD-cream showed concordance between their assessments and physician’s assessment of controlled disease or treatment success at Week 4, supporting the clinical relevance of early treatment response in topical psoriasis management.

Author Contributions

Maria Esposito: Conceptualization, Investigation, Validation, Writing—review & editing; Juan Manuel Morón-Ocaña: Conceptualization, Investigation, Validation, Writing—review & editing; Aditya Gupta: Conceptualization, Investigation, Validation, Writing—review & editing; Jordi Galván: Funding acquisition, Project administration, Supervision, Writing—original draft; Ayoub Bentohami: Formal Analysis, Methodology, Writing—original draft; Frank Freischläger: Data curation, Formal Analysis, Methodology, Writing—original draft.

Funding

This work, as well as the journal’s Rapid Service Fee, were supported by Almirall S.A.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Maria Esposito declares to have served as speaker or board member for Abbvie, Almirall, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi-Regeneron, UCB. Juan Manuel Morón-Ocaña declares no conflicts of interest. Aditya Gupta is a consultant for Almirall S.A. Jordi Galván and Ayoub Bentohami are employees of Almirall S.A. Frank Freischläger is co-founder and co-owner of Estimondo GmbH.

Ethical Approval

The study protocols of the two phase III studies were reviewed and approved by ethics committees or local institutional review boards (independent ethics committee for trial MC2-01-C7: Ethikkommission der Ärztekammer, Hamburg, Weidestraße 122b, 22083 Hamburg, Germany; central institutional review board for trial MC2-01-C2: Quorum, 1501 Fourth Ave, Ste 800, Seattle, WA 98101). Both studies were conducted according to the 1964 Declaration of Helsinki and its subsequent amendments. All patients provided written informed consent to participate in the phase III studies.