Treatment patterns and drug survival for generalized pustular psoriasis: A patient journey study using a Japanese claims database.

Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease. Although several medications are approved for treating GPP in Japan, there are limited data on real-world treatment patterns or drug survival (the number of prescribed days of treatment). This retrospective cohort study describes drug survival and treatment patterns of patients with newly diagnosed GPP (International Classification of Diseases, 10th Revision code L40.1), and ≥1 year of follow-up, using de-identified claims data (Medical Data Vision Co., Ltd.) from January 2016 to August 2021. Most (97.0%) of the 434 Japanese patients received first-line therapy of etretinate (26.4%), topical medications (14.7%), or cyclosporin (14.3%); 80.0% and 60.1% of patients received a second and third line of therapy (LOT), respectively. Use of etretinate (12.6%) and cyclosporin (5.9%) decreased in second-line therapies, whereas use of biologics (interleukin [IL]-17, 14.3%; IL-23 inhibitors, 7.6%) and topical medications (22.1%) increased or remained consistent. Approximately 50% of biologics were prescribed in combination with systemic medications or systemic corticosteroids. Median (range) time to next therapy (TTNT) was 2.8 (0.03-48.07) months for first-line therapy and 3.3 (0.03-52.97) months for all other LOTs. TTNT was longer for combination therapies (up to 16.5 months) compared with monotherapies (up to 7.5 months). Biologics exhibited longer drug survival with fewer treatment episodes compared with non-biologic systemic medications. Among frequently used therapies, the median (95% confidence interval) drug survival was 8.8 (5.8-11.8) months for etretinate, 4.3 (2.2-6.9) months for systemic corticosteroids, and 19.6 (16.1-26.7) months for secukinumab. Treatment patterns varied considerably, highlighting the need for treatment algorithms and effective, well-tolerated medications to support patients to help them remain on long-term therapy.

Regional differences in the prevalence of generalized pustular psoriasis in Japan.

Generalized pustular psoriasis (GPP), a rare form of psoriasis, is characterized by neutrophil-rich, sterile pustules. In Japan, GPP has intractable and rare disease designation, which allows patients to access support from national and local governments for medical expenses. Previously, similar numbers of patients in Tokyo and Hokkaido have been shown to have GPP designation, despite different population sizes. Here, we determine whether there are regional differences in the proportion of patients receiving GPP designation status in Japan and aim to identify causal factors. In this descriptive, retrospective cohort study, publicly available data were collected on the number of patients with intractable and rare disease designation for GPP in each prefecture and age classification (April 2018-March 2021). Three other designated intractable and rare disease cohorts were included: pemphigus, rare skin diseases, and all diseases. The primary outcome was the standardized morbidity ratio (SMR) of patients at prefecture level (observed numbers divided by expected). Regional differences were compared with the statistical expectation for the total population and age distribution of each prefecture. Regional differences were observed in all cohorts. Overall, 1910 patients had GPP as a designated intractable and rare disease in 2020. Regional differences in SMRs for GPP were observed with high SMRs (≥1.5) in Hokkaido, Tottori, Kagawa, and Miyazaki, and low SMRs (<0.6) in Gunma and Kanagawa. Regional differences in SMRs for GPP did not correlate with the number of medical doctors or dermatologists or internal migration. The number of medical doctors or dermatologists correlated with SMRs in the rare skin diseases and total cohorts. Regional differences in Japan exist in the number of patients with GPP who have an intractable and rare disease designation. Managing rare diseases is an important public health issue, and further research is required to elucidate the factors contributing to these differences.

Factors associated with generalized pustular psoriasis progression among patients with psoriasis vulgaris in Japan: Results from a claims database study.

Of those patients diagnosed with generalized pustular psoriasis (GPP) in Japan, approximately 30% have a prior psoriasis vulgaris (PsV) diagnosis. Therefore, understanding factors associated with a GPP diagnosis is essential for early diagnosis of GPP in patients with PsV. This retrospective cohort study was conducted to identify associated factors for GPP diagnosis in patients with PsV. Eligible patients with two confirmed diagnoses of PsV with/without a confirmed GPP diagnosis (International Classification of Disease 10th revision codes L40.0 and L40.1, respectively) were identified from the Japanese Medical Data Center database (JMDC) (July 1, 2005-January 31, 2019). Weighted logistic regression was used to identify associated factors (based on recorded comorbidities) between the PsV only and PsV with GPP cohorts. Odds ratios (ORs) of ≥1.5, associated with a high probability of a GPP diagnosis, were reported for factors with ≥5 patients/cohort. The time from event to GPP diagnosis was evaluated. The highest associated factor for GPP diagnosis was psoriatic arthritis (OR 20.2, 95% confidence interval [CI] 17.06-23.92, P < 0.0001), which also had the shortest time from event to GPP diagnosis (median 119 days). Other comorbidities associated with GPP diagnosis were other psoriasis, tonsillitis, and sinusitis. Treatments associated with GPP diagnosis included systemic corticosteroids (OR 2.19, 95% CI 1.98-2.43, P < 0.0001; median time from treatment initiation to GPP diagnosis 180 days). Other associated treatments (other immunosuppressants, interleukin [IL]-17 or IL-23 inhibitors, and phototherapy) had a delay of ≥1 year from treatment initiation to GPP diagnosis. Back pain, headache, and fever were also identified as associated with a GPP diagnosis. Patients with PsV requiring systemic therapies are more likely to receive a GPP diagnosis than those not requiring systemic treatment. These data will help identify patients with PsV at high risk of developing GPP and potentially support early GPP diagnosis.

The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells to tumors.

The Wnt/ß-catenin pathway, which is associated with disease progression, is activated in many cancers. Tankyrase (TNKS) has received attention as a target molecule for Wnt/ß-catenin pathway inhibition. We identified K-476, a novel TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and potently inhibited TNKS and led to stabilization of the Axin protein, resulting in Wnt/ß-catenin pathway suppression. Aberrant Wnt/ß-catenin pathway activation was recently reported as a possible mechanism of ineffectiveness in immune checkpoint inhibitor (ICI) treatment. Because the Wnt/ß-catenin pathway activation causes dendritic cell inactivation and suppresses chemokine production, resulting in a paucity of CD8+ T cells in tumor tissue, which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a monotherapy, it significantly enhanced the antitumor effect in combination with anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8+ T cells was increased by combination treatment. K-476 upregulated the chemokine expression (e.g., Ccl3 and Ccl4), which attracted CD8+ T cells. This was considered to contribute to the increased CD8+ T cells in the tumor microenvironment. Furthermore, while the potential gastrointestinal toxicity of TNKS inhibitors has been reported, it was not observed at effective doses. Thus, K-476 could be an attractive therapeutic option to enhance the efficacy of ICIs.

The Discovery and Characterization of K-756, a Novel Wnt/ß-Catenin Pathway Inhibitor Targeting Tankyrase.

The Wnt/ß-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/ß-catenin pathway. To discover the small molecule inhibitors of the Wnt/ß-catenin pathway, we conducted high-throughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/ß-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active ß-catenin, and inhibits the genes downstream of endogenous Wnt/ß-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/ß-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/ß-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. Mol Cancer Ther; 15(7); 1525-34. ©2016 AACR.