Nippon Shinyaku (Japan)

Tagraxofusp (TAG), a first-in-class CD123-targeted therapy, is a recombinant fusion protein of human interleukin-3 conjugated to a truncated diphtheria toxin payload. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive orphan hematologic cancer with a poor prognosis, and is derived from plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). This open-label phase I/II study evaluated the efficacy and safety of TAG in 11 Japanese BPDCN patients, of whom seven were treatment-naïve (TN) and four had relapsed/refractory (R/R) disease. In the phase I portion, seven patients (five TN, two R/R) were treated, and no dose-limiting toxicity was observed, with 12μg/kg/day tolerated. In the phase II portion, four patients (two TN, two R/R) were treated. Among the seven TN BPDCN patients, the rate of complete response (CR) + clinical CR (CRc: CR with minimal residual skin abnormality) was 57.1% (90% confidence interval [CI], 22.5-87.1), and the lower limit of the 90% CI (22.5%) exceeded the pre-specified threshold of 10%. Common adverse events included increased alanine aminotransferase (81.8%) and aspartate aminotransferase (72.7%), hypoalbuminemia, hypokalemia, and capillary leak syndrome (54.5%). The results indicate that TAG was effective and had a manageable safety profile in Japanese BPDCN patients.

The Rare Disease Consortium Japan (RDCJ) is a newly formalized cross-sector initiative launched to address the urgent and growing needs of individuals living with rare diseases in Japan, aiming to support a wide range of rare conditions, including—but not limited to—neuromuscular diseases. RDCJ hosted its inaugural symposium on July 18, 2023, at the Shonan Health Innovation Park. This symposium aimed to address the unique challenges of rare diseases through a collaborative approach involving industry, government, academia, patients, and the community. The event brought together these stakeholders to discuss the current state and future directions of rare disease research and treatment in Japan. The event featured a range of speakers and panel discussions on the state of drug development, patient journeys, and the future of patient-centered healthcare services. Highlights included a keynote on antisense oligonucleotide therapeutics and sessions on patient-centered healthcare, human-centered design in healthcare, and innovative approaches to rare disease treatment. This report provides a detailed overview of the symposium, the key takeaways from each session, and the future directions for RDCJ.

Literature on immunological pretreatment and mass spectrometry was searched in the Web of Science database. The collected data were utilized for bibliometric analysis and literature review to identify trends in this field. Immunological pretreatment initially began in chemical toxicology using gas chromatography mass spectrometry and research interests later shifted to biologics pharmacokinetics, biomarkers, anti-drug antibodies and diagnosis. The key advantage of using mass spectrometry was the ability to distinguish molecular subtypes. Future research interests are expected to focus on a broader range of analyte types (such as intact protein mass spectrometry) and methodological improvements, including better protein digestion and microfluidics, aiming for faster, less labor-intensive and more reliable analysis through multiplexing and automation.

The number of patients with visual impairment (VI) is increasing rapidly around the world, and its negative effects are becoming a problem. There is a strong relationship between VI and cardiovascular disease, and patients with cardiovascular disease have a higher prevalence of VI. The aim of this study was to examine the effects of VI on physical function, activities of daily living, and length of hospital stay in Phase I cardiac rehabilitation (CR) patients. This prospective multicenter cohort study included patients who underwent Phase 1 CR from October 2020 to March 2023 at four affiliated Regional Medical Care Support Hospitals in Japan. VI was assessed by a self-reported questionnaire. Linear mixed model analysis was performed to evaluate the association between VI and walking speed, short physical performance battery (SPPB), functional independence measure (FIM), and length of hospital stay, respectively. Of the 3608 patients with a hospital stay of at least 5 days and who underwent Phase 1 CR, 565 were included in this study. VI was reported by 23.9%. The VI group had slower walking speed (0.89 vs. 1.01 m/s, p < .001), lower SPPB (11.0 vs. 12.0 points, p < .001), and lower FIM (122.0 vs. 125.0 points, p < .001) than the non-VI group. There was no significant difference in length of hospital stay between the two groups. Multivariate linear regression analysis adjusted for confounding factors showed that VI was significantly associated with walking speed ( p = .030) and length of hospital stay ( p = .017), whereas VI was not associated with SPPB and FIM. This study revealed Phase 1 CR patients with VI decreased walking speed, which corresponds to sarcopenia. Furthermore, VI was independently associated with walking speed and length of hospital stay in Phase 1 CR patients.

【背景と目的】脳梗塞急性期再灌流療法は，発症から治療開始までが短いほど良好な予後が得られるが，その実施率と治療開始時間までの短縮がまだ十分とはいえない．院内体制整備が終了した後に脳卒中ホットライン（stroke hotline: S-Hot）を導入し，治療介入率の向上と治療開始までの時間短縮に対する効果を検証した．【方法】2021年6月から2022年12月までに再灌流療法を施行した患者をS-Hot群と非S-Hot群に分類し，後方視的に検討した．【結果】S-Hotの運用による再灌流療法は，それ以外よりも約2倍の実施率であった．救急隊の現場到着～来院の時間，来院～t-PA静注療法の時間，来院～機械的血栓回収療法開始の時間は短かったが，有意差があったのは現場到着～来院の時間のみであった．【結論】S-Hotの導入で発症～治療開始の時間短縮に有効であったが，院内の体制整備も不可欠である．

The spectrum of 31P-NMR is fundamentally simpler than that of 1H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative 31P-NMR (31P-qNMR) than using quantitative 1H-NMR (1H-qNMR), which has been already established as an absolute determination method. We have previously reported a 31P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using 31P-qNMR at multiple laboratories. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d4 were selected as the reference standards (RSs) for 31P-qNMR and 1H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CD3OH was selected as the solvent for 31P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CD3OD was the solvent of choice for the 1H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by 31P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by 1H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by 31P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional 1H-qNMR for the determination of organophosphorus compounds.

Increased sedentary behaviour (SB) is reportedly associated with mortality and morbidity in cardiovascular disease. However, its relation with physical function is not well understood in phase I cardiac rehabilitation (CR). This study aimed to investigate the rate of SB and the relation between SB and physical function among patients participating in phase I CR. This prospective multicentre cohort study enrolled patients participating in CR from October 2020 to July 2022. Patients with probable dementia and difficulty walking alone were excluded. We used sitting SB time as the index of SB and the Short Performance Physical Battery (SPPB) as the index of physical function at discharge. Patients were divided into the low SB group (< 480 min/day) or high SB group (≥ 480 min/day). We analysed and compared the two groups. The final analysis included 353 patients (mean age: 69.6 years, male: 75.6%), of whom 47.6% (168 of 353) were high SB patients. Total sitting SB time was higher in the high SB group versus the low SB group (733.6 ± 155.3 vs 246.4 ± 127.4 min/day, p < 0.001), and mean SPPB score was lower in the high SB group versus the low SB group (10.5 ± 2.4 vs 11.2 ± 1.6 points, p = 0.001). Multiple regression analysis identified SB as an explanatory variable for total SPPB score (p = 0.017). Patients with high SB had significantly lower SPPB scores than those with low SB. These findings underscore the importance of considering SB when improving physical function. Effective strategies to improve physical function can be developed that consider SB in phase I CR.

Polymorphous adenocarcinomas (PACs) are rare tumors arising from the salivary glands. Radical resection and postoperative radiotherapy are the mainstays of treatment. However, complete tumor resection is not always achievable when the tumor invades the skull base. Stereotactic radiosurgery (SRS) could be a less invasive alternative for treating skull base PACs. A 70-year-old male with a history of surgery for a right palatine PAC presented with right visual impairment, diplopia, and ptosis. Imaging studies revealed tumor recurrence invading the right cavernous sinus (CS). SRS using a gamma knife was performed for this recurrence, prescribing a marginal dose of 18 Gy at a 50% isodose line. Five months after SRS, his symptoms were relieved, and the tumor was well-controlled for 55 months without any adverse events. To the best of the authors' knowledge, this is the world's first case of recurrent skull base PAC invading the CS that was successfully treated with salvage SRS. Thus, SRS may be an applicable treatment option for skull base PACs.

Single-arm, open-label, phase 3 study to evaluate the efficacy and safety of ferric derisomaltose (FDI) for iron deficiency anemia (IDA) in Japanese women with postpartum hemorrhage (PPH). Postpartum women aged 20-39 years with serum ferritin <25.0ng/ml, hemoglobin (Hb) <10.0g/dl, and blood loss ≥500 ml within 24 h post-delivery were eligible to receive high-dose intravenous FDI. The primary endpoint was the maximum change in Hb concentration by Week 8. Key secondary endpoints included change in iron parameters and percentage of patients with a total Edinburgh Postnatal Depression Score (EPDS) ≥9. Safety assessments included treatment-emergent adverse events (TEAEs) and iron concentrations in maternal milk. All (n= 21 [100.0%]) patients received the predetermined total iron dose by Day 8. Hb concentrations increased rapidly and significantly (p< 0.001) following FDI. Serum ferritin levels also increased rapidly and were maintained near or above the upper limit of normal reference value (250 ng/ml). Following FDI, two (9.5%) patients had a total EPDS score of ≥9. TEAEs occurred in 23 of 42 (54.8%) patients and neonates overall, including 18 of 21 (85.7%) patients and 5 of 21 (23.8%) neonates. TEAEs were mild in all adult patients and four neonates, and moderate in one neonate. Iron concentrations in maternal milk remained within normal reference values. Appropriate patient selection and patient-adjusted dosage selection facilitated safe and effective administration of high-dose (≥1000 mg) FDI. Rapid and sustained improvements in Hb and iron stores occurred following FDI for IDA with PPH, with no new safety signals identified. JapicCTI-194888.