Apremilast Prolongs the Time to First Biologic Therapy in Japanese Patients with Psoriasis

Treatments for psoriasis include topical agents, oral systemic agents, phototherapy, and biologic therapies. Treatment usually begins with topical corticosteroids or vitamin D3; if topical therapy is ineffective, phototherapy with ultraviolet A or B and systemic therapy with cyclosporine or oral etretinate (a vitamin A analog) are used. The Japanese guidance for the use of biologics for psoriasis specifies that biologics should be used in severe cases in which the patient does not sufficiently respond to existing systemic therapies [1].

Although biologics are highly efficacious, their use is currently limited to institutions approved by the Japanese Dermatological Association [1], where essential examinations and care for serious adverse reactions are available. This ensures that other hospital departments are qualified to treat adverse events associated with the use of biologics, should it be needed. Such institutions are generally limited to cities and are rare in remote towns. Dermatology clinics are also approved to use biologics, in close cooperation with these approved hospitals; however, the total number of such clinics is still limited. This limited access sometimes causes inconvenience for patients who want biologic therapy, especially those who live in small towns. In addition, biologic therapy imposes some inconveniences on patients, such as injection [2] or relatively high drug costs [3]. Therefore, safe and effective systemic therapeutic modalities that are widely available in Japan are needed for patients before they escalate to biologic therapy.

Apremilast is an oral phosphodiesterase-4 inhibitor approved in 2016 in Japan for the treatment of patients with psoriasis vulgaris and psoriatic arthritis who have an inadequate response to topical therapies. Apremilast inhibits phosphodiesterase 4 and increases intracellular cyclic adenosine monophosphate, a mediator of inflammation inhibition, thereby exerting its therapeutic effects. In ESTEEM 1 [4] and ESTEEM 2 [5], which were global phase 3 studies of apremilast in psoriasis that focused on patients with moderate to severe psoriasis who were candidates for phototherapy or systemic therapy, the ≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI-75) response rate was significantly higher for the apremilast group compared with the placebo group, and favorable tolerability was reported, with mostly mild or moderate adverse events. In addition, in the phase 2b FREEDOM study [6] of Japanese patients with moderate to severe psoriasis vulgaris, the PASI-75 response rate was also significantly higher compared with the placebo group, and apremilast showed acceptable safety and tolerability. However, real-world data of Japanese patients treated with apremilast are limited. Some single institutions in Japan have reported real-world data studies of apremilast [7‐10], but no large-scale studies have been reported. The primary objective of the present study, which used a nationwide database, was to calculate the time from the beginning of treatment to first biologic use in patients with psoriasis. Among patients who had an inadequate response to topical therapies, we analyzed the difference between two groups, namely those treated with apremilast and those not treated with apremilast. In addition, we evaluated the total medical costs for these treatment groups after they had initiated their first topical therapy, including treatment, testing, and hospitalization costs.

This study showed a significantly lower incidence rate of first biologic therapy use in psoriasis patients taking apremilast vs. comparable psoriasis patients not taking apremilast using a Japanese claims database. To our knowledge, this is the first large-scale, nationwide, real-world data study to look at apremilast treatment patterns and costs in Japan.

Biologics for psoriasis are highly efficacious; however, several biologic-associated burdens are suggested by the literature and clinical practice. For example, in a discrete choice experiment study conducted by Tada et al. in Japanese patients with psoriasis to investigate preferences for biologics that differ in administration frequency, price, efficacy, and safety, it was reported that patients preferred treatments with a lower injection frequency and a lower cost burden [12]. In addition, biologics can only be used at a limited number of medical institutions, which may entail transferring patients to approved hospitals for treatment. Thus, apremilast may have the potential to reduce the treatment burden associated with biologics by decreasing the use of or prolonging the time to first biologic therapy use. The favorable safety profile, oral mode of administration (injection is used for many biologics), and lower cost of apremilast may also contribute to patient treatment choice. Finally, differences in treatment choices and time to initiation of biologic therapy may be influenced by the patient’s therapeutic goals, disease severity, quality-of-life impacts, and success with previous treatments.

Although apremilast may decrease the burden of biologic therapy, the apremilast group had a higher number of outpatient visits per month than the non-apremilast group (1.54 vs 1.17, P < 0.001; Table 3). Although the number of outpatient visits was calculated during whole follow-up periods after the index date (including visits before apremilast or biologic prescription), high frequencies of outpatient visits may be a burden of apremilast treatment. On the other hand, in Japan, prescription amounts for new medications are limited by regulation to 2 weeks at a time until 1 year after their launch, which could have resulted in high frequencies of outpatient visits for some of the apremilast-treated patients in this study.

When this research was conducted, the latest date of available data was June 2019; the duration of the research period after the launch of apremilast was at most about 2 years (from March 2017 to June 2019). The results might have been different if the duration of the research period was longer. In the analysis of the monthly change in each HCRU cost item after the index date, the monthly cost of biologic therapies tended to increase greatly in the latter half of the follow-up period in the non-apremilast group, but was lower and relatively stable in the apremilast group throughout the entire follow-up period (Supplemental Fig. S1E). Therefore, this analysis using data from until about 2 years after apremilast launch may underestimate the costs of biologics; a greater reduction in medical costs for apremilast could potentially be observed if a longer analysis was performed. Among eligible patients, the incidence of biologic prescriptions and the time to first biologic therapy use were also analyzed for patients who were prescribed biologics during the follow-up period, but the CIs were wide and the point estimates unstable due to the small sample size. These points should be re-evaluated when more data are accumulated in the future.

Regarding the burden of medical costs, our study showed that the mean total medical cost per month after the start of treatment for psoriasis was significantly lower in patients taking apremilast than in those not taking apremilast. This finding is consistent with three US studies that used real-world data to compare healthcare costs for patients initiating treatment with apremilast or biologics [13‐15]. On the other hand, it should be noted that the costs in this study were calculated during whole follow-up periods after the index date; the costs included those before the initiation of apremilast. Although the costs for the period after apremilast initiation could not be analyzed due to the limitations of the study design, this should be further investigated by selecting appropriate comparison groups in future studies.

Prescription costs can be a barrier to biologic use, and the treatment cost of biologic therapies in Japan has been reported to be about 1.2 million yen to 4.4 million yen per year [16]. A study by Sruamsiri et al. [17] compared medical expenses for 12 months before and after the start of biologics using Japanese claims data, and reported that the start of biologics increased medical expenses by about 1.9 million yen per patient for the first year after biologic initiation, of which about 1.8 million yen was accounted for by outpatient expenses. In the current study, the cost item with the largest between-group difference was the average cost of biologic agents (the absolute difference between the apremilast and non-apremilast groups was 21,594 yen), and the major contributor to the high average total medical cost in the non-apremilast group was the high prices of biologics.

On the other hand, in our study, the average cost per month of topical agents, phototherapy, and oral drugs except for methotrexate (apremilast may have been a major contributor to this cost) was significantly higher in the apremilast group (Table 3). Due to the limitations of the study design, the cost includes the whole follow-up period (i.e., before, during, and after the apremilast prescription). In terms of topical agents, the use of apremilast in combination with topical therapy was effective in patients who were dissatisfied with stable maintenance topical therapy [18]. In addition, the effectiveness of the combination of apremilast and narrowband ultraviolet B has been reported in patients with moderate to severe psoriasis [19]. In accordance with the literature, the results of this study raise the possibility that apremilast may be preferentially used with topical therapy or phototherapy in clinical settings. A future real-world data study designed to evaluate the use of monotherapy and combination therapy with apremilast is needed.

In conclusion, this study found that patients treated with apremilast had a lower incidence of biologic use compared with non-apremilast users, suggesting that treatment with apremilast may ultimately reduce the clinical and cost burden on patients with psoriasis. Time to first biologic therapy use was also longer among patients treated with apremilast. Because biologic therapy is associated with various treatment burdens, reducing or delaying the need to use biologic therapy may be a benefit of apremilast to patients and society. Since this study was conducted using data obtained within a short period after the launch of apremilast in Japan, it is desirable to conduct further research when more data are accumulated.