Superior efficacy and comparable safety of calcipotriol plus betamethasone dipropionate foam vs. ointment in Chinese patients with plaque psoriasis: A randomized phase 3 trial

To the Editor: Psoriasis, a chronic inflammatory disease affecting people of all ages, is a serious health burden in China and worldwide.[1] The most common form, plaque psoriasis, causes red, scaly, and itchy skin lesions. A widely recommended topical treatment is the combination of a vitamin D analog (calcipotriol; Cal) and a corticosteroid (betamethasone dipropionate; BD).[2] The fixed-dose combination of 50 µg/g Cal and 0.5 mg/g BD (Cal/BD) exists in different formulations: ointment, gel, cream, and aerosol foam. Widely used in many countries, the innovative Cal/BD aerosol foam formulation is changing the psoriasis treatment approach and represents a “game-changer” for both mild and moderate-to-severe cases.[3] Here, we report the results from the first clinical trial with Cal/BD foam in China (NCT05919082, https://clinicaltrials.gov/). This was a randomized, investigator-blind, active-controlled, parallel-group, multicenter phase 3 trial to compare the efficacy and safety of Cal/BD foam vs. ointment used once daily for 4 weeks to treat Chinese adults with stable plaque psoriasis of at least mild severity according to the Physician’s Global Assessment (PGA). Conducted between June 2023 and March 2024, the trial included a 4-week screening/washout period, a 4-week treatment period, and a 2-week safety follow-up period. An independent ethics committee at each trial site reviewed and approved the clinical trial protocol. All patients provided written informed consent. Detailed methods are presented in Supplementary Methods, https://links.lww.com/CM9/C712. A total of 604 patients were randomized 1:1 to Cal/BD foam or ointment. The participant flowchart is shown in Supplementary Figure 1, https://links.lww.com/CM9/C712. Of these, 438 (72.5%) of the patients were males, and the median age was 46 years. Baseline demographics and disease characteristics were similar in both treatment groups [Supplementary Table 1, https://links.lww.com/CM9/C712]. Ninety-one percent of the patients complied fully with the trial treatment; >99% had received previous antipsoriatic treatment [Supplementary Results, https://links.lww.com/CM9/C712]. Noninferiority was confirmed for Cal/BD foam on the primary endpoint, PGA score of 0 (clear) or 1 (almost clear) at week 4 with ≥2-point reduction from baseline. Following the hierarchical testing, which besides noninferiority also enabled superiority testing, superiority was demonstrated for Cal/BD foam vs. ointment on the primary endpoint (50.0% [151/302] vs. 42.4% [128/302], P = 0.0438) and both secondary efficacy endpoints, ≥75% reduction from baseline in modified Psoriasis Area and Severity Index (mPASI-75) at week 4 (63.6% [192/302] vs. 53.6% [162/302], P = 0.0108) and mPASI-90 at week 4 (33.1% [100/302] vs. 24.5% [74/302], P = 0.0199; Supplementary Figure 2, https://links.lww.com/CM9/C712). The adverse event (AE) incidence from baseline to week 6 was similar with both treatments (Cal/BD foam: 77 patients [25.7%], Cal/BD ointment: 68 patients [22.6%], Supplementary Table 2, https://links.lww.com/CM9/C712). Most AEs were nonserious, mild or moderate, and did not lead to permanent treatment discontinuation. Three serious AEs were reported during the treatment period (appendicitis, patella fracture, gastrointestinal hemorrhage), and one serious AE (psoriasis) was reported during safety follow-up; all four events occurred in the Cal/BD foam group and were considered not treatment-related by the investigator. The most frequently reported AEs (in ≥1% of patients) were similar with both treatments and included upper respiratory tract infection, folliculitis, and decreased cortisol [Supplementary Table 3, https://links.lww.com/CM9/C712]. Mean values for serum cortisol and urinary calcium: creatinine ratio were within normal range at baseline and week 4, as were individual values for the majority of patients. Mean changes from baseline to week 4 were small with both treatments and not considered clinically relevant. For albumin-corrected serum calcium, no patients had values above the normal range at any time, and there was no/negligible change in mean values from baseline to week 4. This Chinese randomized clinical trial (RCT), comparing Cal/BD foam head-to-head with Cal/BD ointment, a standard-of-care treatment for plaque psoriasis in China and worldwide, demonstrated superiority of Cal/BD foam on the primary and secondary efficacy endpoints. The differences between treatment groups of 8–10% points are comparable with those observed in an overseas phase 2 RCT with Cal/BD foam vs. ointment,[4] which are considered clinically relevant.[2] Thus, we confirm that Cal/BD foam is efficacious in Chinese adults with plaque psoriasis, inducing significant improvements in psoriasis signs and symptoms after 4-week once-daily treatment. The large sample size and multicenter trial design support the generalizability of results from this RCT to the Chinese patient population. The results are consistent with findings from overseas RCTs comparing Cal/BD foam with ointment, gel, and vehicle formulations.[2] The superior efficacy of Cal/BD foam over ointment and gel is linked to the increased skin bioavailability of the active pharmaceutical ingredients due to the aerosol foam formulation.[5] Given the high efficacy of Cal/BD foam, it may delay or even circumvent the need for systemic therapy. In the Chinese RCT, where ~75% of patients had moderate-to-severe psoriasis at baseline, it is noteworthy that 33.1% of patients receiving Cal/BD foam achieved mPASI-90 at week 4. If combined with systemic therapies, Cal/BD foam may accelerate disease improvement, enabling dosage reduction and consequently enhancing the tolerability of the systemic drug.[2] Furthermore, the combination of topical and systemic drugs may optimize treatment efficacy and improve quality of life.[6] As shown herein, the safety profile of Cal/BD foam in Chinese patients treated for 4 weeks is similar to that of Cal/BD ointment. The Chinese RCT included serum cortisol measurement as an indicator of the potentially suppressive effect of betamethasone on adrenal cortex function, if systemically absorbed. AEs of “cortisol decreased,” reported in 7 patients (2.3%) receiving Cal/BD foam and 6 patients (2.0%) receiving Cal/BD ointment, reflected serum cortisol values that were below the normal range at week 4 and deemed clinically significant by the investigator. Viewed in the context of the natural daily fluctuation of cortisol and the clinical laboratory data (showing negligible mean changes from baseline to week 4 and normal values for most patients), the AEs of “cortisol decreased” do not indicate any safety concerns regarding potential adrenal suppression after treatment with Cal/BD foam or ointment. This is consistent with the safety profile observed in overseas RCTs, none of which have shown higher risk of adverse reactions due to the greater skin penetration of Cal/BD foam compared with ointment/gel. This is also true for the 52-week overseas RCT (PSO-LONG), where no AEs of skin atrophy were reported and no clinically relevant adrenal suppression was detected,[7] indicating no increased concern for corticosteroid-induced local or systemic adverse reactions during long-term twice-weekly proactive maintenance treatment with Cal/BD foam. A limitation of this trial was the absence of a vehicle control, which might cause artificially high AE reporting in both treatment groups, since all patients knew they received active treatment, and the Cal/BD foam group knew they received the experimental treatment. This awareness might also cause perception bias due to different tactile and visual characteristics of the two formulations, potentially influencing subjective reporting of tolerability or efficacy-related outcomes. The absence of vehicle control and patient blinding is, however, unlikely to have biased the above-mentioned objective efficacy endpoints based on investigator-blind assessments, and Cal/BD foam and ointment have both been proven superior to vehicle in overseas RCTs. In conclusion, Cal/BD foam showed superior efficacy and similar tolerability compared with Cal/BD ointment in Chinese adults with plaque psoriasis, consistent with results previously reported for non-Chinese patients. Acknowledgments The authors thank all patients and site staff who participated in this clinical trial. Furthermore, they thank Georgios Pesiridis, Marie Yolande Jablonski Bernasconi, Martin Olesen, Michael Mao, and Xiaochen Li from LEO Pharma for contributing to the manuscript planning and review. Lillian Sandø from LEO Pharma contributed with manuscript writing and editing, according to Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). Conflicts of interest The clinical trial (including drug supply) and all analyses presented in this article were funded by LEO Pharma. Jianzhong Zhang has received consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer Investment Co. Ltd., Novartis Pharmaceuticals (China), Sanofi China, LEO Pharma (Shanghai) Co. Ltd. GSK (China) Investment Co. Ltd., Eli Lilly and Company (China), Xi’an Jansen Pharmaceutical Ltd., Bristol-Myers Squibb (China) Investment Co. Ltd., Beijing Wenfeng Tianji Pharma Ltd., Keymed Biosciences (Chengdu) Ltd., Akeso Biopharma Co. Ltd., and Kintor Pharmaceutical Ltd. Adam El Mongy Jørgensen is an employee of LEO Pharma A/S; Merle Kurvits and Jens Strodl Andersen are shareholders and employees of LEO Pharma A/S. The remaining authors declare no conflicts of interest.