A multi-center, double-blind, randomized, placebo- and positive-controlled phase II clinical study of benvitimod for the treatment of atopic dermatitis.

To the Editor: Atopic dermatitis (AD) is a chronic, recurrent, and inflammatory skin disease that can be accompanied by asthma, allergic rhinitis, conjunctivitis, and other diseases.[1] Topical corticosteroids are mostly used in patients with AD. Considering the side effects of the long-term use of corticosteroids, additional topical treatments could be useful. Benvitimod cream (same active pharmaceutical ingredient as tapinarof) is a novel drug approved and marketed in China (tapinarof was approved for the treatment of psoriasis in the US in 2022) in 2019 for topical treatment of mild-to-moderate plaque psoriasis, and is an agonist of aryl hydrocarbon receptor and nuclear factor E2-related factor 2.[2,3] By regulating the skin barrier gene expression, benvitimod cream was proved to have the effect of treating AD in previous clinical studies.[4] This multi-center, randomized, double-blinded, placebo-, and positive-controlled phase II clinical trial was approved by the Ethics Committee of People's Hospital of Peking University (No. 2017PHA066-01) and was conducted in compliance with the principles of the Declaration of Helsinki, the standards of Good Clinical Practice (as defined by the International Conference on Harmonization), and Chinese regulatory requirements (Chinese Clinical Trial Registry: ChiCTR-IIR-17012153). The trial was conducted in five centers in China from October 2017 to April 2019. Before enrollment, written informed consent was obtained from each participant. The following were the inclusion criteria: (1) aged ≥18 years; (2) diagnosis of AD for >6 months together with an Investigator's Global Assessment score of ≥3 (IGA ≥ 3); and (3) a body surface area involvement in the range of 3% to 20%. Patients were randomly assigned in 1:1:1:1 ratio to receive placebo (vehicle of benvitimod), 0.1% tacrolimus, and 0.5% and 1.0% benvitimod cream twice a day for 6 weeks. No concomitant use of other AD treatment was allowed during this trial. (Details of the study design and statistical analysis are provided in Supplementary Appendix, https://links.lww.com/CM9/B352). The primary efficacy endpoint was the percentage of patients with an IGA score of 0 or 1 at week 6. The secondary efficacy endpoints included an average decline from the baseline and diachronic value of IGAs, body surface area, Eczema Area and Severity Index, and Pruritus Index at week 6. Safety was evaluated by monitoring adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events and by obtaining clinical laboratory measurements through 6 weeks. A total of 127 patients were screened and 115 were randomly assigned to the 1.0% benvitimod cream group (n = 29), 0.5% benvitimod cream group (n = 29), 0.1% tacrolimus cream group (n = 29), or placebo group (n = 28). The patient baseline demographic and clinical characteristics were generally similar among the four groups. An IGA score of 0 or 1 was achieved in 62.1% (18/29) of the 1.0% benvitimod group, 31.0% (9/29) of the 0.5% benvitimod group, 58.6% (17/29) of the 0.1% tacrolimus group and 39.3% (11/28) of the placebo group. There was no statistically significant difference between the 1.0% benvitimod group and the placebo group (P > 0.05). However, improvement in the mean change in IGA scores was achieved by a greater number of patients in the 1.0% benvitimod group and the 0.1% tacrolimus group compared with placebo (P < 0.05, respectively; details are provided in Supplementary Appendix, https://links.lww.com/CM9/B352). In this phase II trial, a total of 47 AEs was reported. No significant differences were observed between these groups with respect to AEs and ADRs [Table 1]. The adverse drug events were found in 14.3% (4/28) among the patients administered placebo, 13.8% (4/29) of the 0.1% tacrolimus group patients, 17.2% (5/29) of the 0.5% benvitimod group patients, and 17.2% (5/29) of the 1.0% benvitimod group patients [Table 1]. Among the most common AEs, pruritus was found in 7.1% (2/28) among the patients administered placebo, 3.4% (1/29) of the 0.1% tacrolimus group, 6.9% (2/29) of the 0.5% benvitimod group, and 0% of the 1.0% benvitimod group. Other common AEs included dermatitis, rash pruritus, medication site pigmentation, topical site pruritus, contact dermatitis, and some other systemic diseases (nasopharyngitis, folliculitis, and upper respiratory tract infection). In most cases, the symptoms were transient and mild. Serious AEs were found in two patients, and both cases were considered to be unrelated to the study drugs (one in the placebo group was pregnant and the one in the 0.5% benvitimod group had colonic polyps). No treatment-emergent systemic AEs were found. Table 1 - Adverse events during 6-week intervention period, n (%). Characteristics Placebo (n = 28) 0.1% tacrolimus (n = 29) 0.5% benvitimod (n = 29) 1.0% benvitimod (n = 29) AEs 12 (42.9) 9 (31.0) 15 (51.7) 11 (37.9) Adverse drug events 4 (14.3) 4 (13.8) 5 (17.2) 5 (17.2) SAEs 1 (3.6) 0 1 (3.4) 0 AEs by intensity Mild 5 (17.9) 7 (24.1) 13 (44.8) 8 (27.6) Moderate 6 (21.4) 1 (3.4) 2 (6.9) 3 (10.3) Severe 1 (3.6) 1 (3.4) 0 0 Skin and subcutaneous system Pruritus 2 (7.1) 1 (3.4) 2 (6.9) 0 Infectious diseases Nasopharyngitis 3 (10.7) 2 (6.9) 2 (6.9) 1 (3.4) Folliculitis 0 1 (3.4) 0 4 (13.8) Upper respiratory tract infection 0 0 1 (3.4) 2 (6.9) AEs: Adverse events; SAEs: Serious adverse event. This study revealed that after 6 weeks of treatment, the 1.0% benvitimod group had the highest rate of skin lesion clearance. The main reason why there was no statistically significant difference between the 1.0% benvitimod and placebo groups is that the number of patients enrolled in each group is too small. More importantly, compared with the placebo group, the score of IGA decreased significantly in the 1.0% benvitimod group. Topical medication can be used to treat AD. In this trial, topical application of 1% benvitimod cream twice daily for 6 weeks demonstrated a favorable tolerability profile. Additionally, 1.0% benvitimod cream exhibited much lower rates of treatment-related AEs than the vehicle cream (0% vs. 7.1%), suggesting that it may improve the quality of life of patients by a good antipruritic effect. As with any treatment, the benefits need to be weighed against the AEs, and the efficacy profile of longer-term treatment with benvitimod should be examined. Acknowledgements We would like to thank all the study participants, investigators, and clinical site staff involved in this phase II study. Funding This study was supported by Beijing Wenfeng Tianji Pharma Ltd. Conflicts of interest None.