Increased risk of hypocalcemia with decreased kidney function in patients prescribed bisphosphonates based on real-world data from the MID-NET® in Japan: a new-user cohort study.

BACKGROUND: In the post-marketing stage, cases of hypocalcemia associated with bisphosphonate preparations (BPs) have been reported in patients with decreased kidney function, despite warning against use of BPs in such patients in the package insert (PI) of Japan. The purpose of this study was to investigate the safety of BPs in patients with decreased kidney function. METHODS: The cohort study was conducted in patients with osteoporosis and newly prescribed bisphosphonate utilizing real-world data from MID-NET® in Japan. The adjusted hazard ratios (aHRs) for hypocalcemia (a corrected serum Ca level < 8.00 mg/dL) relative to the normal group were calculated in each decreased kidney function group (mild, moderate or severe group). RESULTS: A total of 14,551 patients were included in the analysis, comprising 2,601 (17.88%) with normal (eGFR ≥ 90 mL/min/1.73m2), 7,613 (52.32%) with mild (60 ≤ eGFR < 90 mL/min/1.73m2), 3,919 (26.93%) with moderate (30 ≤ eGFR < 60 mL/min/1.73m2), and 418 (2.87%) with severe kidney function (eGFR < 30 mL/min/1.73m2). The aHRs (95% confidence interval) for hypocalcemia were 1.85 (0.75-4.57), 2.30 (0.86-6.21), and 22.74 (8.37-61.78) in the mild, moderate, and severe groups, respectively. The increased risk of hypocalcemia depending on kidney function was also observed even when calculating the aHR for each specific BP such as alendronate sodium hydrate, minodronic acid hydrate, and sodium risedronate hydrate. Furthermore, similar results were obtained in the sensitivity analysis by altering the outcome definition to a 20% or more reduction in corrected serum Ca level from the baseline, as well as when focusing on patients with more than one laboratory test result per 30 days during the follow-up period. CONCLUSIONS: These findings suggest that the risk of hypocalcemia during BP prescription is higher in patients with decreased kidney function, particularly those with severely decreased kidney function. The quantitative real-world evidence on the safety risk of BPs obtained in this study has led to the PI revision describing a relationship between hypocalcemia risk and decreased kidney function as a regulatory action in Japan and will contribute to promoting the proper use of BPs with appropriate risk management in clinical practice.

Risk of neutropenia in psoriasis patients prescribed anti-IL-23 antibody in comparison with anti-IL-17 antibody or adalimumab based on real-world data from the MID-NET® in Japan.

BACKGROUND: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. METHOD: We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/µL) or grade 3 (neutrophil count < 1,000/µL) neutropenia. RESULTS: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. CONCLUSION: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.

Recent Status of Phase I Clinical Trials for Brain Tumors: A Regulatory Science Study of Exploratory Efficacy Endpoints.

BACKGROUND: Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. METHODS: Using Clarivate's Cortellis™, 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). RESULTS: Selected studies included a median of 1.5 PEs (range, 1-6) and 5 SEs (range, 0-19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B (p = 0.0039). CONCLUSIONS: Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.