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Purpose: Despite advances in immunotherapy, unresectable recurrent/metastatic head and neck cancer (HNC) carries a poor prognosis, and effective treatments are needed. As nectin-4 is widely expressed in HNC, enfortumab vedotin (EV), a nectin-4-directed antibody-drug conjugate, was explored in HNC in EV-202 (ClinicalTrials.gov identifier: NCT04225117)., Methods: This open-label, multicohort, phase II study evaluated intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. In the HNC cohort, eligible patients had recurrent/metastatic HNC and had received platinum-based therapy for locally advanced/metastatic disease and a PD-1/PD-L1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary end points were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); overall survival (OS); and safety., Results: The primary analysis included 46 patients; all received EV (median follow-up, 9.3 months). Most patients (52.2%) had ≥3 previous lines of systemic therapy in the metastatic setting. Confirmed ORR was 23.9%, DCR was 56.5%, and median DOR was not reached (median DOR was 9.4 months at a later data cutoff [median follow-up, 11.3 months]). Median PFS and OS were 3.9 and 6.0 months, respectively. Treatment-related adverse events (TRAEs) occurring in >20% of patients were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Sixteen patients (34.8%) experienced grade ≥3 TRAEs; anemia and decreased neutrophil count occurred in ≥1 patient (both n = 2; 4.3%)., Conclusion: EV demonstrated antitumor activity in heavily pretreated HNC. Safety was consistent with the known safety profile of EV; no new safety signals were identified. These data support further evaluation of EV for advanced HNC not amenable to definitive local therapy.

Introduction: Despite many prostate cancer (PC) treatment options in Japan, physicians' and patients' preferences in metastatic castration-sensitive PC (mCSPC) and castration-resistant PC (CRPC) are unclear., Methods: For this cross-sectional study, an online questionnaire survey based on the best-worst scaling (profile case) approach was designed. Physicians' and patients' questionnaires, comprising six attributes (efficacy, safety, target patients, dosage, administration, and medical expenditures), had 24 and 26 items for mCSPC and CRPC surveys, respectively. Four items were presented during each session; respondents selected the "most important" and "least important" among these. The objective was to elicit attributes important for treatment and their relative importance levels among physicians and patients and to explore similarities and differences in choices. Multinomial logit and hierarchical Bayesian models were applied, and preferences were presented as relative importance and utility values., Results: Responses of 177 physicians (urologists: 173; oncologists: 4) and 292 patients (mCSPC: 94; CRPC: 198) were analyzed. Most patients with CRPC (63.1%) had no metastases. Efficacy was the most important attribute overall. Physicians considered patient survival the most important among efficacy items (11.1%), whereas patients with mCSPC prioritized prevention of metastases spread (9.7%) and prostate-specific antigen (PSA) elevation (9.3%). In CRPC, both physicians and patients prioritized prevention of metastasis development or its spread (physicians: 9.6%; patients: 8.3%) and PSA elevation (physicians: 9.3%; patients: 7.9%). After efficacy, physicians prioritized items related to target patients (cardiovascular disorders; mCSPC: 4.8%; CRPC: 3.4%), whereas patients prioritized safety (mCSPC: falls or fractures [5.6%]; CRPC: liver dysfunction [4.7%]). Patients with mCSPC were also concerned about rising medical expenditures (5.4%)., Conclusion: Treatment efficacy was the most important attribute for both physicians and patients in Japan in mCSPC and CRPC settings, although their preferences differed in priority based on outcomes. These findings may be useful to improve shared decision-making for PC treatment in Japan., Competing Interests: Declarations. Conflict of Interest: Noriko Takahashi, Keiko Asakawa, Atsushi Saito, Takeshi Mitomi, and Takumi Lee are employees of Astellas Pharma, Inc. Takahiro Kimura received honoraria from Astellas, AstraZeneca, Bayer, Janssen, Sanofi, and Takeda. Mika Matsumura is an employee of INTAGE Healthcare, Inc., a company contracted by Astellas to conduct and analyze the surveys. Ethical Approval: The study was conducted in compliance with the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects for ensuring the rights of participants in noninterventional studies. Participants had the right to withdraw from the survey at any time. Informed consent was obtained from all study participants before phases 3 and 4 of the study. The study protocol and informed consent form were submitted to an internal ethics committee of Astellas Pharma, Inc., for review and approval as a minimal risk study (approval number: 000420–00). The study was conducted in accordance with the protocol, International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use guidelines, applicable regulations and guidelines governing clinical study conduct, and the ethical principles that have their origin in the Declaration of Helsinki., (© 2025. The Author(s).)

Introduction: B-cell lymphoma 6 (Bcl6) inhibits osteoclast differentiation in vitro; however, its role in orthodontic tooth movement (OTM) remains unclear. This study aimed to investigate the role of Bcl6 in OTM of rat molars., Materials and Methods: OTM was performed on the maxillary first molars of male rats using nickel-titanium coil springs (25 gf) for 14 days with or without local injection of FX1 (50 mg/kg), a Bcl6 inhibitor (n = 10 per group). Micro-computed tomography (CT) images were used to analyse OTM distance and bone morphometric parameters. Immunohistochemistry (IHC) determined Bcl6 expression and tartrate-resistant acid phosphatase staining (TRAP) staining assessed osteoclast differentiation. TRAP staining, and reverse transcription-quantitative polymerase chain reaction determined the effect of FX1 (1 μM) on in vitro rat osteoclast differentiation. The effect of FX1 on cell proliferation and Smad4 expression in periodontal ligament (PDL) cells was determined., Results: Administration of FX1 significantly increased OTM distance and decreased the bone/tissue volume compared with vehicle treatment. IHC staining showed that the vehicle-OTM group had higher expression of Bcl6 than the FX1-OTM group. The number of osteoclasts on the compression side was significantly higher in the FX1-OTM group than that in the vehicle-OTM group. FX1 enhanced osteoclast differentiation and expression of Nfatc1, Dc-stamp, and Ctsk mRNA in osteoclasts in vitro. FX1 significantly promotes PDL cell proliferation in vivo and in vitro., Limitations: We evaluated only 14 days of OTM., Conclusions: Bcl6 may play an important role in OTM via modulation of osteoclast differentiation and PDL cell proliferation., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: This planned interim analysis of a mandatory post-marketing surveillance study in Japan evaluated the safety and effectiveness of roxadustat, the first approved hypoxia-inducible factor prolyl hydroxylase inhibitor in the world, in real-world clinical use., Research Design and Methods: This prospective observational study has a planned 104-week observation period. We report data obtained through 16 December 2023, as a planned interim analysis. Adverse drug reactions (ADRs), mean hemoglobin level change from baseline to 12 weeks of roxadustat treatment, and subgroup analyses stratified by either baseline C-reactive protein or albumin levels were reported., Results: Overall, 2084 patients were treated with roxadustat (total patient-years of exposure: 1579.2). In the non-dialysis-dependent (NDD) group ( n  = 1075), ADRs and serious ADRs occurred in 209 (19.4%) and 109 (10.1%) patients, respectively. In patients receiving hemodialysis (HD; n  = 856), ADRs and serious ADRs occurred in 224 (26.2%) and 142 (16.6%) patients, respectively. In patients receiving peritoneal dialysis (PD; n  = 146), ADRs and serious ADRs occurred in 46 (31.5%) and 26 (17.8%) patients, respectively. Mean hemoglobin levels reached target levels at 12 weeks in most patients (NDD: 54.6%; HD: 56.3%; PD: 45.4%)., Conclusions: Roxadustat safety was demonstrated in real-world clinical settings. No new safety concerns were identified. Trial Registration: NCT04408820.

All biotherapeutics have the potential to induce an immunogenic response and generate anti-drug antibodies (ADAs), especially when administered as multiple doses over prolonged periods. However, a clinically meaningful effect of ADAs can be difficult to identify to communicate the impact of immunogenicity on drug exposure, safety and efficacy outcomes in product labels in a way that is useful for health care providers. The immunogenicity working Group, IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices in analyzing immunogenicity data generated during clinical development and its impact on pharmacokinetics, clinically relevant pharmacodynamic biomarkers, safety, and efficacy outcome measures. Information was collected for 93 drugs, spanning multiple drug classes and over the different phases of clinical development, including post-approval. The predominant drug classes reported included monoclonal antibodies or Fc-fusion proteins, endogenous protein replacement therapies, bispecific antibodies, and antibody-drug conjugates. The extent of quantitative evaluation varied and was influenced by several factors, including descriptive analyses, statistical approaches, and modeling. In addition to understanding current practices, this survey also highlights areas for future exploration in analyzing clinical relevance of ADAs which can facilitate the use for regulatory submissions and product labels., (© 2025 Genentech Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

NLRP3 inflammasome inhibitor is a highly attractive drug target for the treatment of various inflammatory diseases. Here, we report the discovery of pyridazine derivatives as a new class of scaffold for NLRP3 inflammasome inhibitors. We optimized HTS hit 2a to improve both in vitro IL-1β inhibitory activity and the mean photo effect (MPE) value in the in vitro 3T3 neutral red uptake (NRU) phototoxicity test. As a result, we identified compound 5e (ASP0965) with brain penetrability and showing efficacy in the brain on oral administration in the rat pharmacodynamics (PD) model and the mouse α-synuclein injection model. These findings suggest that compound 5e is a promising clinical candidate for α-synucleinopathy therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: This study evaluated the safety and tolerability of fezolinetant in women with vasomotor symptoms (VMS) due to menopause in a pooled analysis of data from three 52-week phase 3 studies (SKYLIGHT 1, 2, and 4)., Methods: SKYLIGHT 1 and 2 were double-blind, placebo-controlled studies where women (≥ 40 to ≤ 65 years), with moderate to severe VMS (minimum average ≥ 7 hot flashes/day) were randomized to once-daily placebo, fezolinetant 30 mg or 45 mg. After 12 weeks, those on placebo were re-randomized to fezolinetant 30 mg or 45 mg, while those on fezolinetant continued on their assigned dose for 40 weeks. SKYLIGHT 4 was a placebo-controlled, double-blind, 52-week safety study. Safety was assessed by frequency of treatment-emergent adverse events (TEAEs) and endometrial events. TEAEs of special interest included liver test elevations and endometrial hyperplasia or cancer or disordered proliferative endometrium., Results: Totals of 952 participants receiving placebo, 1100 receiving fezolinetant 45 mg, and 1103 receiving fezolinetant 30 mg took ≥ 1 dose of study medication. TEAEs occurred in 55.3%, 62.9%, and 65.4%, respectively; exposure-adjusted results were consistent with these results. Most frequent TEAEs in fezolinetant-treated participants included upper respiratory tract infection (7.7-8.3%), headache (6.8-8.2%), coronavirus disease 2019 (5.8-6.1%), back pain (3.1-3.7%), arthralgia (2.9-3.2%), diarrhea (2.3-3.2%), urinary tract infection (2.9-3.4%), and insomnia (2.0-3.0%). The incidence of drug-related serious TEAEs and associated treatment withdrawals was low. Elevations in liver transaminases occurred in 1.5-2.3% of fezolinetant-treated participants, were typically asymptomatic and transient, resolved on treatment or discontinuation, with no evidence of severe drug-induced liver injury (Hy's law). Endometrial safety results were well within US Food and Drug Administration criteria. Analysis of benign and non-benign neoplasm controlled for exposure demonstrated no increased risk versus placebo., Conclusion: Pooled data confirm the safety and tolerability of fezolinetant over 52 weeks., Trial Registration: ClinicalTrials.gov identifiers, NCT04003155, NCT04003142, and NCT04003389. Graphical abstract available for this article., Competing Interests: Declarations. Conflict of Interest: RK has received consulting/advisory board fees from Astellas, Pfizer, and Mayne, participated in the data monitoring committee for Astellas (ended), received speaker fees from Pfizer and Astellas, and acted as Medical Advisor for Carrot Fertility. AC acted as former President of the European Menopause and Andropause Society and consulted for Astellas, Theramex, and Viatris. REN received grants from Fidia, consulting fees from Astellas, Besins, Bayer, Exeltis, Fidia, Freya, HRA, Theramex, and Vichy Laboratories, honoraria for lectures from Abbott, Bayer, Exeltis, Novo Nordisk, Organon, Shionogi, Theramex, and Viatris, was a researcher for Fidia, Merck, and Shionogi, and is President Elect of the International Menopause Society. MLE, SM, XW, and FDO are employees of Astellas. Ethical Approval: SKYLIGHT 1, 2, and 4 were conducted in accordance with Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines. An independent ethics committee or institutional review board reviewed ethical, scientific, and medical appropriateness of the study at each site before data collection. Written informed consent was obtained from all participants before any study-related procedures., (© 2024. The Author(s).)

Prostate Cancer Diagnosis and Treatment Enhancement through the Power of Big Data in Europe (PIONEER) is a European network of excellence for big data in prostate cancer. PIONEER brings together 34 private and public stakeholders from 9 countries in one multidisciplinary research consortium with the aim of positively transforming the field of prostate cancer clinical care by answering pressing questions related to prostate cancer screening, diagnosis and treatment. PIONEER has developed a unique state-of-the-art big data analytic platform by integrating existing data sources from patients with prostate cancer. PIONEER leveraged this platform to address prioritized research questions, filling knowledge gaps in the characterization, management and core outcomes of prostate cancer across the different disease stages. The network has benefited from sustained patient and stakeholder involvement and engagement, but many challenges remain when using real-world data for big data projects. To continue to advance prostate cancer care, data need to be available, suitable methodologies should be selected and mechanisms for knowledge sharing must be in place. Now acting as the prostate cancer arm of the European Association of Urology's new endeavour, UroEvidenceHub, PIONEER maintains its goal of maximizing the potential of big data to improve prostate cancer care., Competing Interests: Competing interests: S.E.-A., J.B. and J.Z. are employees of Bayer; T.H. is an employee of Philips; R.S. and K.P. are employees of Astellas Pharma; T.A. was an employee of Astellas Pharma during the PIONEER project prior to retirement; A.B. has been a consultant and adviser for Accord, Astellas Pharma, AstraZeneca, Bayer, J&J and Pfizer and a board member, officer and trustee for Glactone Pharma, has received lecture honoraria for Accord, Astellas, AstraZeneca, Bayer, Ipsen, J&J and Merck, has participated in trials run by Astellas, Bayer, Ferring, Janssen and Pfizer, and holds stock in Glactone Pharma, LIDDS Pharma and WntResearch. All companies make products used to treat prostate cancer. The other authors declare no competing interests., (© 2024. Springer Nature Limited.)

An immunogenicity risk assessment (IRA) is a relatively new expectation of health authorities that is increasingly incorporated into the drug development process across the pharmaceutical/biotech industry. The guiding principle for an IRA includes a comprehensive evaluation of product- and patient-related factors that may influence the immunogenic potential of a biotherapeutic drug and a potential action plan. The Immunogenicity Working Group from the IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices for conducting IRAs and relevant aspects of bioanalysis. Survey results were provided by 19 IQ member companies participating in the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). Nearly all the respondents reported experience with monoclonal antibodies (mAb), with 10 other drug modalities including bioengineered protein therapeutics such as fusion and multi-domain proteins, peptides, oligonucleotides as well as gene and cell therapies. The survey results demonstrate that most companies have a defined IRA process, and there was a common understanding that the IRA may need to be revised as more information becomes available or the drug development strategy changes. Some differences found across the respondents are related to the time frame for implementation of IRA document, the types of preclinical data and computational methods used to assess risk, and how the IRA informs clinical plans and documentation practices. These results highlight that while there have been widespread insights gained with performing IRA for mAbs, more experience is needed to perform IRAs for the novel modalities., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background/aaims: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F , NYX and TRPM1 . High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression., Methods: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F , NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated., Results: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F , NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F , NYX and TRPM1 , respectively., Conclusions: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Limited data exist regarding treatment patterns and symptom burden of patients with anemia of chronic kidney disease (CKD) in the Middle East, South Africa, and Türkiye., Methods: This real-world study explored clinical characteristics, symptom burden, and treatment patterns of patients with anemia of CKD living in the Middle East, South Africa, and Türkiye. Physician and patient perceptions of treatment were captured via cross-sectional surveys; patients' clinical characteristics were recorded by retrospective review of medical records., Results: Data were collected from 1788 patients and 217 physicians. A high proportion of patients had never received treatment for their anemia (n = 701, 39.2%); the most common treatment was erythropoietin-stimulating agents (ESAs) + intravenous iron (n = 457, 50.3%). High symptom burden was reported, with lack of energy being the most common symptom (n = 394, 75.6% treated and n = 133, 59.9% non-treated patients). Patients' self-reported symptom burden was higher than physician-reported burden; less agreement was seen for non-dialysis-dependent (NDD) patients (kappa = 0.193, standard deviation [SD]: 0.081) than dialysis-dependent (DD) patients (kappa = 0.442, SD: 0.103). Median hemoglobin thresholds that physicians reported using for initiating treatment (NDD: <10.5 [interquartile range, 9.5-12.0] g/dL; DD: <9.3 [9.0-10.0] g/dL) were higher than actual test levels at treatment initiation (NDD: 9.2 [8.7-10.0] g/dL; DD: 9.0 [8.1-10.0] g/dL)., Conclusion: Treatment inertia is apparent despite high symptom burden in the Middle East, South Africa, and Türkiye, and disagreement was seen in physician and patient perspectives on symptomology. Improved awareness of this disagreement may help facilitate physician-patient dialogue to improve patient experience., Competing Interests: MA has received payment or honoraria for lectures, presentations, or speaker’s bureaus from Amgen, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, MSD, Novo Nordisk, Recordati, and Sanofi, and travel support from AstraZeneca and Astellas Pharma. SMGA-G has received speaker’s honoraria from AbbVie, AstraZeneca, and Vifor Pharma. AGA has received honoraria from Astellas Pharma as a speaker and advisor. AFE-K has received payment or honoraria for lectures, presentations, or speaker’s bureaus from Astellas Pharma and Roche, and travel support from Roche. AM and LJC are employees of Adelphi Group, contracted by Astellas Pharma to conduct the study. BS and EPL are former employees of Astellas Pharma Singapore Pte. Ltd. MB is an employee of Astellas Pharma Europe Ltd. DBN is an employee of Astellas Pharma Singapore Pte. Ltd. This study was sponsored by Astellas Pharma Singapore Pte. Ltd., (© 2025 Arici et al.)

Aims: Insulin therapy is a cornerstone in type 2 diabetes mellitus (T2DM) management, but its use is associated with several barriers, including hypoglycaemia, fear of injections and high costs. We compared the risk of insulin initiation and other treatment intensification between patients with T2DM newly treated with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus those newly treated with a dipeptidyl peptidase-4 inhibitor (DPP4i)., Materials and Methods: This Japanese retrospective cohort study was conducted between 1 January 2015 and 31 March 2023 using the JMDC Claims Database. Patients with T2DM newly treated with an SGLT2i or a DPP4i were matched 1:1 using propensity score (n = 18 488 each). Incidence rates (IR) of insulin initiation, other antidiabetic drugs (OAD) and antihypertensive drugs added onto baseline treatment were calculated for each treatment group. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model., Results: The IR of insulin initiation was 0.95 and 2.12 per 1000 person-years in the SGLT2i and DPP4i groups, respectively, with significantly lower risk in the SGLT2i group than in the DPP4i group (HR 0.46, 95% CI: 0.28-0.74, p = 0.001). The risks of OAD (HR 0.66, 95% CI: 0.64-0.69, p < 0.001) and antihypertensive drugs (HR 0.90, 95% CI: 0.85-0.95, p < 0.001) added onto baseline treatment were lower in the SGLT2i group than in the DPP4i group., Conclusions: The risk of insulin initiation was lower in patients with T2DM newly treated with an SGLT2i than in those newly treated with a DPP4i. SGLT2i may reduce or delay the need for insulin therapy., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The burden of pneumococcal diseases remains high in Japan. Pn-MAPS24v is a novel MAPS-based vaccine containing complexes of 24 serotype-specific polysaccharides (PS), non-covalently coupled with fusion protein 1 (CP1). This study evaluated the safety and immunogenicity of different dose levels of Pn-MAPS24v, administered in Japanese adults either subcutaneously (SC) or intramuscularly (IM)., Methods: In this phase 1, dose-escalation, observer-blind trial conducted in Japan, 54 pneumococcal vaccine-naïve adults aged 20-49 years (stage 1), and 72 adults aged 65-85 years (stage 2) were sequentially enrolled. In stage 1, participants were randomized 1:1 (SC:IM) to receive a single Pn-MAPS24v dose at one of the dose levels (1 μg, 2 μg, or 5 μg per PS). In stage 2, participants were randomized 3:1 (Pn-MAPS24v:23-valent pneumococcal polysaccharide vaccine [PPSV23]) and 1:1 (SC:IM) to receive a single dose of either Pn-MAPS24v (one of three dose levels), or PPSV23. Solicited adverse events (AEs) were collected through 7 days post-vaccination, and treatment-emergent AEs (TEAEs) up to 1 month post-vaccination. Serotype-specific opsonophagocytic activity titers and immunoglobulin G (IgG) concentrations, as well as anti-CP1 IgG concentrations were measured before and 1 month post-vaccination., Results: No safety or reactogenicity concerns were identified in any age category across groups. No grade 3-4 TEAEs, serious AEs, or deaths were reported. Regardless of the age category, dose level, administration route, or study vaccine, the frequency of reported TEAEs was low and all vaccine-related TEAEs were mild. Pain, tenderness, and fatigue were the most frequently reported solicited AEs. One month post-vaccination, Pn-MAPS24v induced serotype-specific immune responses that were comparable or higher than those elicited by PPSV23. The immune responses were similar after SC and IM administration., Conclusion: Pn-MAPS24v showed an acceptable safety profile and was immunogenic after SC and IM administration, therefore supporting the further development of Pn-MAPS24v in Japan., Clinicaltrials: gov: NCT04265911., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors report that financial support was provided by Astellas Pharma Inc. (for the study) and by GSK (for cost associated with manuscript development). Dorota Borys is a GSK employee and holds financial equities in GSK. Gurunadh R Chichili is an employee of Astellas Pharma Global Development Inc. Jasdeep Nanra was employee of Affinivax, Inc. at the time the study was designed, initiated, and/or conducted and is currently employee of GSK. Masaki Ebara is an employee of Astellas Pharma Inc. Mioko Iwahana is an employee of Astellas Pharma Inc. Miwa Haranaka has nothing to declare. Richard Malley was employee of Affinivax, Inc. at the time the study was designed, initiated, and/or conducted. Richard Malley was Affinivax, Inc. board member at the time the study was designed, initiated, and/or conducted. Richard Malley has issued or pending patents on MAPS technology. Richard Malley declares potential future payments and royalties as equity holder of Affinivax, Inc. and named co-inventor of MAPS technology. Richard Malley is a former employee of GSK and now a consultant of GSK. Richard Malley received consulting fees from GSK as consultant in the area of vaccines and disclosed GSK support for attending meetings and/or travel, and participation to a GSK Advisory board. Ronald Smulders is an employee of Astellas Pharma Global Development Inc. Shite Sebastian was employee of Affinivax, Inc. at the time the study was designed, initiated, and/or conducted and is currently employee of GSK. Shite Sebastian has issued and pending patents on Multivalent Pneumococcal Vaccine. Takashi Nakano declares consulting fees from Astellas Pharma Inc. and support from Daiichi Sankyo, Mitsubishi Tanabe, Biken, Shionogi, Sanofi, Meiji Seika Pharma, and KM Biologics. Yuki Oizumi is an employee of Astellas Pharma Inc. Atsuki Hashimoto is an employee of Astellas Pharma Inc., (Copyright © 2024 GSK Plc, Avenue Fleming, Wavre-1300, Belgium. Published by Elsevier Ltd.. All rights reserved.)

Intratumoral administration is a widely used method for oncolytic virotherapy, as it enables immediate access of virus particles to the target tumor and potentially lead to the suppression of untreated distant tumors via in situ vaccination. However, because the injection volume and concentration of the virus solution are physically limited, the dose level cannot be increased. Additionally, efficacy in distant tumors needs improvement to prolong patient survival. Here, we demonstrate the benefit of oxaliplatin, with detailed mechanisms revealed through transcriptome analysis, which may provide a solution for the crucial deficiencies of oncolytic virotherapy. In virus-injected tumors, oxaliplatin improved virus retention through suppression of type I interferons. In distant virus-naive tumors, oxaliplatin induced alterations in the intratumoral macrophage characteristics, leading to the chemotaxis and recruitment of activated T cells and subsequently inducing an inflammatory state in the non-injected tumors. Our findings can be a trigger to change the therapeutic paradigm of oncolytic virotherapy for patients with systemic metastases., Competing Interests: Declaration of interests K.T., Y.M., K.I., Y.S., N.A., and S.N. are employees of Astellas Pharma Inc., Japan. S.N. is an inventor on the patent regarding recombinant oncolytic vaccinia virus carrying IL-7 and IL-12 (U.S. Patent No. US 10,888,594 B2)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post-hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively impacted RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared to 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild type clones (as assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multi-clonal disease. These data demonstrate the potential of using FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML., (Copyright © 2025 American Society of Hematology.)

Background/Objectives : Inflammation may contribute to hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) and is often present in patients with chronic kidney disease (CKD). Roxadustat is approved in multiple countries for the treatment of anemia of CKD. This pooled analysis evaluated the efficacy and safety of roxadustat in patients with dialysis-dependent (DD) or non-dialysis-dependent (NDD) CKD by inflammation status. Methods : Data from five studies comparing roxadustat versus ESAs were pooled by patient populations in this analysis (NDD: DOLOMITES; DD: ROCKIES, SIERRAS, HIMALAYAS, PYRENEES). The mean change from baseline in hemoglobin levels to Weeks 28-52 and mean weekly dose of roxadustat or ESA at Week 24 were assessed by baseline inflammation levels (determined by high-sensitivity C-reactive protein [hsCRP] levels, divided into quintiles). Safety data were summarized descriptively. Results : In total, 613 patients with NDD CKD (roxadustat n = 320; ESA n = 293) and 4072 patients with DD CKD (roxadustat n = 2022; ESA n = 2050) were evaluated. Roxadustat increased hemoglobin levels in a manner similar to ESAs, independent of baseline inflammation status. In both the NDD and DD populations, roxadustat doses did not increase at Week 24 in patients with higher hsCRP levels at baseline. Patients with high baseline hsCRP levels required greater ESA doses at Week 24 compared with patients who had lower baseline hsCRP levels in both patient populations. The incidence rates of treatment-emergent adverse events were generally comparable with those of roxadustat and ESA across hsCRP quintiles in both the NDD and DD populations. Conclusions : Roxadustat addresses the multiple causes of anemia of CKD, regardless of inflammatory status, without requiring dose increases.

Hepatic impairment (HI) trials are traditionally part of the clinical pharmacology development to assess the need for dose adaptation in people with impaired metabolic capacity due to their diseased liver. This review aimed at looking into the data from dedicated HI studies, cluster these data into various categories and connect the effect by HI with reported pharmacokinetics (PK) properties in order to identify patterns that may allow waiver, extrapolations, or adapted HI study designs. Based on a ratio ≥ 2 or ≤ 0.5 in AUC or Cmax between hepatically impaired participants/healthy controls these were considered "positive" or "negative". In case of more than one HI severity stratum per compound included in the HI trial, the comparison of the AUC ratios for mild, moderate, or severe HI were used to investigate the increase across HI categories. For the in total 436 hits, relevant PK information could be retrieved for 273 compounds of which 199 were categorized negative, 69 positive ups and 5 positive downs. Fourteen out of 69 compounds demonstrated a steep increase in the AUC ratios from mild to severe HI. Compounds demonstrating a steep increase typically had a high plasma protein binding of > 95%, high volume of distribution, lower absolute bioavailability, minor elimination via the kidneys, were predominantly metabolized by CYP3A4 or CYP2D6 and the majority of these compounds were substrates of OATP1B1. While for compounds with steep increase studies in all severity strata may be warranted they may also offer the potential to estimate the appropriate doses in an HI trial. On the other hand, for compounds with slow or no increase across HI severity strata, reduced HI trials may be justified, e.g. only testing PK in moderate HI., (© 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Novel approaches to improve long-term outcomes in kidney transplant recipients are required. Here, we present the 5-year data from a multicenter, prospective, Phase 3b trial evaluating treatment outcomes with standard (STD) or low (LOW) dose prolonged-release tacrolimus (TAC) combined with ACEi/ARB or other antihypertensive therapy (OAHT) in Canadian kidney transplant recipients., Methods: Adult de novo kidney transplant recipients were randomized 2 × 2 to STD or LOW dose TAC and ACEi/ARB or OAHT. Patients had received a first or second transplant from a living or deceased donor and had ≥ 1 human leukocyte antigen mismatch with their donor., Results: There were 281 patients from 13 sites across Canada. Overall patient survival was 95.7% and was comparable between groups. Graft survival at study end was 89.7% in the LOW+OAHT group and 94.4%-97.1% in the other groups and BPAR, and Class II de novo donor-specific antibodies (dnDSA) were higher in the LOW+OAHT group than in the other groups. However, these differences were not statistically significant. Graft function, blood pressure (BP), and proteinuria were similar between the groups; however, between 2 and 5 years there was a 2-fold or greater increase in the use of ACEi/ARB in patients randomized initially to OAHT, mostly because of hypertension and proteinuria. There were no unexpected safety findings., Conclusion: Patients randomized to LOW TAC with renin-angiotensin system (RAS) blockade had similar outcomes at 5 years as patients treated with STD TAC with or without RAS blockade, whereas those randomized to LOW TAC without RAS blockade showed a non-significant trend towards more rejections and dnDSA TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00933231., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Backgroud Aims: Regenerative therapies employing cell therapy products (CTPs) have attracted considerable attention. Biodistribution (BD) evaluation of CTPs is mainly performed to clarify the cell survival time, engraftment, and distribution site. This evaluation is crucial for predicting the efficacy and safety profiles of clinical studies based on non-clinical BD study outcomes. However, no internationally unified method has been established for assessing cell BD after administration. Here, we aimed to standardize the BD assay method used for CTPs, conducting the following evaluations using the same protocol across multiple study facilities: (1) in vitro validation of quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR) analyses using the primate-specific Alu gene, and (2) in vivo BD studies after the intravenous administration of human mesenchymal stem cells (hMSCs) to immunodeficient mice, commonly used in non-clinical tumorigenicity studies., Methods: Quality control samples were prepared and analyzed by adding a fixed number of human-derived cells to several mouse tissues. The respective quantitative performances of the qPCR and ddPCR methods were compared for accuracy and precision. hMSCs were intravenously administered to immunodeficient mice, and tissues were collected at 1, 4, and 24 h after administration., Results: Both methods demonstrated an accuracy (relative error) generally within ±50% and a precision (coefficient of variation) generally less than 50%. While differences in calibration curve ranges were observed between qPCR and ddPCR, no significant differences in quantification were found among the assay facilities. The BD of hMSCs in mice was evaluated at seven facilities (qPCR at three facilities; ddPCR at four facilities), revealing similar tissue distribution profiles in all facilities, with the lungs showing the highest cell distribution among the tissues tested., Conclusions: Quantitative evaluation of qPCR and ddPCR using Alu sequences was conducted, demonstrating that the test method can be adapted for BD evaluation., Competing Interests: Declarations of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article except for YY, who is an employee of Bio-Rad Laboratories., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

What Is This Summary About?: This summary includes information from the ARCHES and ENZAMET follow-up studies . Both studies looked at enzalutamide treatment for people with metastatic hormone-sensitive prostate cancer (known as mHSPC). In ARCHES, researchers compared the medications enzalutamide + androgen deprivation therapy (known as ADT) with placebo  + ADT. In ENZAMET, researchers compared enzalutamide + ADT with standard treatment  + ADT. Some people in ENZAMET also took enzalutamide with docetaxel (a chemotherapy treatment). In both studies, researchers wanted to find out if enzalutamide helps people with mHSPC live longer., What Are the Key Takeaways?: In both studies, researchers found that people with mHSPC who took enzalutamide lived longer than people who did not. People who took enzalutamide also lived longer without their cancer getting worse. The results were mostly similar in groups of people dependingon when and where their cancer was found. Researchers did not find any new safety concerns., What Were the Main Conclusions?: People with mHSPC may benefit from long-term treatment with enzalutamide + ADT. They may also benefit from taking enzalutamide with other treatments, like docetaxel. It may be better for people with mHSPC to have enzalutamide treatment before their cancer gets worse, rather than waiting. These people and their doctors should carefully consider the benefits and risks of each treatment to make a joint decision for treating mHSPC. Clinical Trial Registration: NCT02677896 (ARCHES), NCT02446405 (ENZAMET) (ClinicalTrials.gov).

Aims: The combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors and anticancer therapies has been in the spotlight in recent years. However, the risks associated with these combination therapies are not fully elucidated. The primary objective of this study was to evaluate the relative risk of organ-specific immune-related adverse events (irAEs) and common adverse events (AEs) in patients treated with PD-1/PD-L1 inhibitor-based combination therapies compared to those treated with PD-1/PD-L1 inhibitor monotherapy for solid tumors., Materials and Methods: An electronic database search was performed using ClinicalTrials.gov, Medline, and American Society of Clinical Oncology (ASCO)/European Society for Medical Oncology (ESMO) annual meeting libraries. We included randomized controlled trials designed to assess the safety of combination therapies using PD-1/PD-L1 inhibitors and other anticancer drugs. All the selected clinical studies included solid tumors and provided information on the incidence of nonserious and serious AEs. The quality of evidence was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed using random-effect models to pool the results., Results: The primary analysis included 16 relevant clinical studies comprising 4232 patients, of whom 2071 and 2161 patients received PD-1/PD-L1 inhibitor--based combination therapy and PD-1/PD-L1 inhibitor monotherapy, respectively. Serious organ-specific irAEs were infrequent, even when PD-1/PD-L1 inhibitors were combined with other anticancer drugs. The incidence of serious colitis was significantly higher in the combination therapy group than in the monotherapy group. Among the common AEs associated with PD-1/PD-L1 inhibitors, the incidence of serious pyrexia/fever, nonserious pyrexia/fever, fatigue, nausea, decreased appetite, vomiting, diarrhea, dyspnea, and rash significantly increased in the combination therapy group. In the subgroup analysis based on the modes of action of concomitant anticancer drugs, the combination of PD-1/PD-L1 inhibitors and DNA synthesis inhibitors significantly increased the risk of serious colitis compared to PD-1/PD-L1 inhibitor monotherapy., Conclusion: Organ-specific irAEs occur infrequently when combinations of PD-1/PD-L1 inhibitors and other anticancer drugs are used. However, the risk of serious colitis and certain AEs is higher than that associated with PD-1/PD-L1 inhibitor monotherapy. Vigilant monitoring of AEs and implementation of appropriate clinical management strategies guided by the mode of action of the combination drugs are essential., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to assess the prevalence of postmenopausal vasomotor symptoms (VMS) and the impact of VMS and related treatment patterns among perimenopausal and postmenopausal Canadian women., Methods: A subgroup analysis of data from a cross-sectional online survey of women aged 40-65 years conducted November 4, 2021, through January 17, 2022, evaluated the prevalence of moderate/severe VMS among postmenopausal Canadian women. The analysis also assessed survey responses from perimenopausal and postmenopausal Canadian women with moderate/severe VMS who completed the Menopause-Specific Quality of Life questionnaire, Work Productivity and Activity Impairment questionnaire, and the Patient-Reported Outcomes Measurement Information System Sleep Disturbances-Short Form 8b and answered questions about treatment patterns and attitudes toward treatments., Results: Of 2,456 Canadian postmenopausal women, 360 (14.7%; primary analysis) reported moderate/severe VMS in the previous month. Perimenopausal and postmenopausal women with moderate/severe VMS (n = 400; secondary analysis) reported negative impact on overall quality of life (mean total Menopause-Specific Quality of Life questionnaire score: 4.3/8). VMS impaired overall work and daily activities by 30.2% and 35.7%, respectively. Overall mean (SD) Patient-Reported Outcomes Measurement Information System Sleep Disturbance-Short Form 8b score (scale 8-40) was 28.5 (6.9), confirming sleep disturbances in this population. The majority of women (88% of the total cohort) sought advice, but about half were never treated. Most women had positive or neutral attitudes toward menopause., Conclusions: In a survey conducted in Canada, moderate/severe VMS were reported by 14.7% of postmenopausal women and were associated with impairment in quality of life, work productivity, daily activities, and sleep in perimenopausal and postmenopausal women., Competing Interests: Financial disclosures/conflicts of interest: N.Y.: advisory board participant and/or speaker for BioSyent, Bayer, Astellas, Eisai, Organon, and Duchesnay and recipient of an unrestricted research grant from Bayer. L.T.: employee of Astellas Pharma. L.S.: employee of Astellas Pharma Inc. at the time of the study. C.R.: employee of IQVIA, which developed and conducted the survey and analyzed the data in collaboration with Astellas Pharma. C.B.: advisory board participant and/or speaker for Astellas Pharma, Bayer Canada, BioSyent, Lupin Pharma, and Pfizer Canada and recipient of research grants from Astellas., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Objective: This interim analysis of a phase 1/2, open-label, single-arm study assessed the safety, efficacy, and pharmacokinetics of gilteritinib plus chemotherapy in adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia., Methods: In sequential phase 1 and 2 studies, induction and consolidation therapy with gilteritinib 120 mg/day plus chemotherapy (induction: idarubicin/cytarabine once daily; consolidation: cytarabine twice daily) was followed by maintenance gilteritinib 120 mg/day monotherapy. Endpoints included maximum tolerated dose (MTD), recommended expansion dose (RED), and dose-limiting toxicity (phase 1), and complete remission (CR) rate following induction therapy (primary endpoint), overall survival (OS), safety, and pharmacokinetics (phase 2)., Results: In phase 1, MTD was not reached and RED was 120 mg/day. In phase 2, the CR rate was 50.0% after induction (90% confidence interval [CI] 40.4, 59.6); however, the lower confidence limit did not exceed the pre-defined 55% benchmark. Composite CR (CRc) rates were high following induction (86.6%, 95% CI [77.3, 93.1]), consolidation, and maintenance therapy (87.8%, 95% CI [78.7, 94.0], each). The probability of OS was 86.6% at 12 months. No new safety findings were reported., Conclusion: In this interim analysis, gilteritinib 120 mg/day in combination with chemotherapy was well tolerated, with similar CRc rates to previous studies., Competing Interests: Declarations. Conflict of interest: Sawa M reports payment/honoraria from Janssen Pharma and Sanofi. Miyamoto T reports payment/honoraria from Takeda Pharmaceutical Co., Otsuka Pharmaceutical Co., Ltd., MSD Co., Ltd, Astellas Pharmaceutical Co., Ltd., Janssen Co., Ltd., Abbvie Pharmaceutical Co., Ltd., and Kyowa Kirin Pharmaceutical Co. Kim H-J reports consulting fees from Astellas and honoraria from Astellas, and participated in advisory boards for Astellas. Cheong J-W reports payment/honoraria from Astellas, Bristol Myers Squibb, Merck, and GSK, and acted in a leadership/fiduciary role for The Korean Society of Hematology, AML/MDS Working Party, and The Korean Society of Blood and Marrow Transplantation. Naoe T reports payment/honoraria from Bristol Myers Squibb, Pfizer, Nippon Shinyaku, Astellas, Otsuka Pharma, and Japan Tissue Engineering. Akashi K reports grants from Asahi Kasei Pharma, Chugai Pharmaceutical, Kyowa Kirin and Sumitomo Pharma, and payment and/or honoraria from Asahi Kasei Pharma, Astellas, AstraZeneca, Abbvie, Kyowa Kirin, Chugai Pharmaceutical, Bristol Myers Squibb and Janssen Pharmaceuticals. Hill J reports stocks with Ligacept, LLC and is an employee of Astellas Pharma Inc. Kosako M, Ikegaya M, Terada W, Kadokura T, Gill SC, Heinloth A and Hasabou N are employees of Astellas Pharma Inc. Ikezoe T is editor of International Journal of Hematology. Hiramatsu Y, Morita S, and Miyawaki S have no disclosures to report., (© 2024. The Author(s).)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in patients with anaemia of chronic kidney disease may lead to increased ESA doses to achieve target haemoglobin levels; however, elevated doses may be associated with increased mortality. Furthermore, patients with hyporesponsiveness to ESAs have poorer clinical outcomes than those who respond well to ESAs. Incidence and clinical characteristics of patients with ESA hyporesponsiveness were explored in a real-world setting., Methods: This was a retrospective study of electronic medical records of adults with stage 5 chronic kidney disease receiving renal replacement therapy and ESA treatment, from 1 January 2015 to 31 December 2021. The primary objective was ESA hyporesponsiveness rate/1000 days, with a hyporesponsive event defined as ESA use at an elevated dose, according to National Institute for Health and Care Excellence (NICE) criteria. Other hyporesponsiveness definitions applied were erythropoietin resistance index-defined ESA hyporesponsiveness (ERI) Kidney Disease Improving Global Outcomes (KDIGO) and a clinical practicality algorithm., Results: In total, 85,259 patients were included in the analysis; 59.9% were male, median (interquartile range) ESA starting dose was 733.3 (400.0, 1200.0) IU/week and follow-up duration was 2.2 (1.0, 4.2) years. Incidence of ESA hyporesponsiveness varied when applying different definitions; NICE 0.05/1000 days (5.2% of patients), ERI 0.40/1000 days (40.7%), KDIGO 0.15/1000 days (15.4%), and clinical practicality algorithm 0.48/1000 days (47.9%). ESA doses remained higher in hyporesponsive versus responsive patients, yet haemoglobin levels were similar between groups., Conclusion: The results from this study, which applied multiple hyporesponsiveness definitions to a large, geographically diverse population of patients with anaemia of CKD, showed variation in ESA hyporesponsiveness incidence rates depending on definitions used and higher ESA doses in hyporesponsive versus responsive patients. These results underscore the need for individualised clinical assessment and thorough evaluation when considering ESA dose adjustments to reach haemoglobin targets. Graphical abstract available for this article., Trial Registration: NCT05530291., Competing Interests: Declarations. Conflict of Interest: Hans-Jürgen Aren, Luca Neri, Astrid Feuersenger, Mario Garbelli and Otto Arkossy are employees of Fresenius Medical Care, contracted by Astellas Pharma Global Development Inc. to conduct the study. Hans-Jürgen Aren reports Fresenius Medical Care stock shares. Christopher Atzinger and Alina Jiletcovici are employees of Astellas Pharma Global Development Inc. Alina Jiletcovici reports Eli Lilly stock shares. Robert Snijder is an employee of Astellas Pharma Europe B.V. Kirsten Leyland, Najib Khalife and Mahmood Ali are employees of Astellas Pharma Europe Ltd. Ethical Approval: All data were pseudonymised and all patients provided written informed consent for access and secondary use of their pseudonymised clinical data for research purposes. According to the National Institutes of Health definition of human subject research, this study falls under the exempt human subjects research category [27]., (© 2024. The Author(s).)

Objective: To estimate the prevalence of diagnosed vasomotor symptoms (VMS) due to menopause among US women aged 40-64 years and assess sociodemographic differences in VMS prevalence and risk of discontinuing VMS-related treatment. Materials and Methods: This retrospective study evaluated merged data from IQVIA's PharMetrics Plus medical claims and consumer attributes databases for 2017-2020. VMS diagnosis was identified using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes. Continuous enrollment was required ≥6 months before and 12 months after diagnosis date. Treatment discontinuation was measured for VMS-related treatments initiated at diagnosis or during the 12 months after diagnosis. Treatment duration was measured from diagnosis to the first day of a ≥90-day treatment gap. A Cox proportional hazards model was used to determine factors associated with risk of treatment discontinuation. Results: Among 7,386,206 eligible women, the 4-year prevalence of diagnosed VMS in 2017-2020 was 79.1 per 1,000 and was highest among non-Hispanic White women (82.5 per 1,000), followed by Hispanic (77.3), Black (71.6), and Asian women (64.5). Rates were higher among women living in urban areas and those with higher education and income. Among women newly diagnosed with VMS ( n = 226,262), median treatment duration was 297 days. Black, Asian, and Hispanic women had higher risks of discontinuing treatment than non-Hispanic White women. Lower income was also associated with higher risk of discontinuation than higher income. Conclusion: Lower prevalence of diagnosed VMS and higher risk of treatment discontinuation were observed among racial/ethnic minorities and women with less education and income, suggesting possible underdiagnosis and unmet needs.

Aims/introduction: This study aimed to investigate the risk factors for diabetic retinopathy (DR) and diabetic kidney disease (DKD) in Japanese patients with diabetes mellitus (DM). Identifying these factors could provide insights into the shared and distinct mechanisms contributing to these complications in the diabetic population., Materials and Methods: We conducted a retrospective analysis using the J-DREAMS (Japan Diabetes compREhensive database project based on an Advanced electronic Medical record System) database, which is directly linked to electronic medical records. The study included Japanese people aged 18 years and older with diabetes, who were registered at a referral center between December 1, 2015, and March 31, 2021, and had simultaneous measurements of serum creatinine and hemoglobin A1c (HbA1c). The presence or absence of DR and DKD was determined for 8,794 and 8,770 patients, respectively. Multivariable logistic regression analyses were used to identify risk factors, considering patient characteristics, comorbid conditions, and laboratory data as explanatory variables., Results: Common risk factors for both DR and DKD included hypertension, anemia, diabetic neuropathy, cerebrovascular disease, chronic heart failure, low serum albumin levels, and elevated HbA1c. The contributions of age, duration of DM, and body mass index (BMI) differed between the DR and DKD groups., Conclusions: In addition to poor glycemic control and hypertension, anemia, low serum albumin, cerebrovascular disease, and heart failure were identified as independent common risk factors for DR and DKD, suggesting the existence of cardio-renal anemia syndrome in patients with DM., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objectives: Patient preferences have the potential to influence the development of new treatments for locally advanced/metastatic urothelial carcinoma (la/mUC), and therefore we explored how patients with la/mUC value different attributes of first-line treatments., Methods: An online preference survey and multidimensional thresholding (MDT) exercise were developed following a targeted literature review and qualitative interviews with physicians, patients with la/mUC, and their caregivers. Treatment attributes included two benefits (overall response rate [ORR], pain related to bladder cancer [scored 0-100; 100 being the worst pain possible]) and four treatment-related risks (peripheral neuropathy, severe side effects, mild to moderate nausea, mild to moderate skin reactions). A Dirichlet regression was used to estimate average preference weights. Marginal utility and the reduction in ORR that patients would accept in exchange for a 10-point decrease or a 10% decrease in other attributes were calculated., Results: A total of 100 patients were recruited and self-completed the survey and MDT. Mean patient age was 64.9 years (standard deviation, 7.6), 54% were female, and 38% identified as white. All included treatment attributes had a statistically significant impact on preferences. Changes in ORR had the largest impact, followed by cancer-related pain and treatment-related risks. Patients were willing to accept an 8.4% decrease in ORR to reduce their pain level by 10 points or a 7.8% decrease in ORR to reduce the risk of peripheral neuropathy by 10%. For a 10% decrease in severe side effects, mild to moderate nausea, or skin reaction, patients would accept decreases in ORR of 5.5%, 3.7%, or 3.4%, respectively., Conclusions: Of the attributes tested, changes in ORR were most important to patients. Patients made tradeoffs between treatment attributes indicating that a lower ORR may be acceptable for an improvement in other attributes such as reduced cancer-related pain or the risk of treatment-related adverse events., Competing Interests: Declarations. Funding: This study was funded by Seagen Inc, which was acquired by Pfizer in December 2023, and by Astellas Pharma Inc. Conflicts of Interest: Mallory Farrar and Zsolt Hepp are former employees of, and held stock in Seagen Inc, which was acquired by Pfizer in December 2023. Lisa Mucha is an employee of Astellas Pharma Inc. Christine Michaels-Igbokwe, Sebastian Heidenreich, Katelyn Cutts, Nicholas Krucien, and Natasha Ramachandran are employees of Evidera, which received funding from Seagen Inc. and Astellas Inc. in connection with this study. Sebastian Heidenreich is an editorial board member of The Patient, and was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Sebastian Heidenreich is also a minority stockholder of Thermo Fisher Scientific as part of his employment with Evidera. John L. Gore and David J. Benjamin have previously received consulting fees from Seagen Inc. Andrea B. Apolo and Nicholas I. Simon have no conflicts of interest to disclose. Authors of this manuscript include former employees of Seagen Inc, which was acquired by Pfizer in December 2023, and Astellas Pharma Inc. Availability of Data and Material: The data supporting the findings of this study are available within the article and its supplementary materials. Ethics Approval: The study protocol was approved by the Salus institutional review board (study number: 22147-01B). The study investigators were not employed by the study sponsors (Seagen Inc, which was acquired by Pfizer in December 2023, and Astellas Pharma Inc.), and any patient data were deidentified prior to being provided to study sponsors. Consent to Participate: Patients indicated their interest in participating and gave informed consent. Consent for Publication: Not applicable Code Availability: All software applications used are commercially available. Author Contributions: Concept and design: Andrea B. Apolo, Christine Michaels-Igbokwe, Nicholas I. Simon, David J. Benjamin, Mallory Farrar, Zsolt Hepp, Lisa Mucha, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran, and John L. Gore; acquisition of data: Christine Michaels-Igbokwe, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, and Natasha Ramachandran; analysis and interpretation of data: Andrea B. Apolo, Christine Michaels-Igbokwe, Nicholas I. Simon, David J. Benjamin, Mallory Farrar, Zsolt Hepp, Lisa Mucha, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran, and John L. Gore; drafting of the manuscript: Andrea B. Apolo, Christine Michaels-Igbokwe, Nicholas I. Simon, David J. Benjamin, Mallory Farrar, Zsolt Hepp, Lisa Mucha, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran, and John L. Gore; critical revision of the paper for important intellectual content: Andrea B. Apolo, Christine Michaels-Igbokwe, Nicholas I. Simon, David J. Benjamin, Mallory Farrar, Zsolt Hepp, Lisa Mucha, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran, and John L. Gore; obtaining funding: Mallory Farrar, Zsolt Hepp, and Lisa Mucha; administrative, technical, or logistic support: Christine Michaels-Igbokwe, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran; and supervision: Andrea B. Apolo, Christine Michaels-Igbokwe, Nicholas I. Simon, David J. Benjamin, Mallory Farrar, Zsolt Hepp, Lisa Mucha, Sebastian Heidenreich, Katelyn Cutts, Nicolas Krucien, Natasha Ramachandran, and John L. Gore. All authors were involved in the design and conduct of the study, analysis and interpretation of the data, and preparation and review of the manuscript. All authors read and approved the final version of the manuscript., (© 2024. The Author(s).)

Phage therapy has attracted attention again owing to the increasing number of drug-resistant bacteria. Although the efficacy of phage therapy has been reported, numerous studies have indicated that the generation of phage-specific antibodies resulting from phage administration might have an impact on clinical outcomes. Phage-specific antibodies promote phage uptake by macrophages and contribute to their rapid clearance from the body. In addition, phage-specific neutralizing antibodies bind to the phages and diminish their antibacterial activity. Thus, phage-specific antibody production and its role in phage therapy have been analyzed both in vitro and in vivo. Strategies for prolonging the blood circulation time of phages have also been investigated. However, despite these efforts, the results of clinical trials are still inconsistent, and a consensus on whether phage-specific antibodies influence clinical outcomes has not yet been reached. In this review, we summarize the phage-specific antibody production during phage therapy. In addition, we introduce recently performed clinical trials and discuss whether phage-specific antibodies affect clinical outcomes and what we can do to further improve phage therapy regimens., (© 2024 The Author(s).)

Background: Given the changing treatment landscape for locally advanced or metastatic urothelial carcinoma (la/mUC), this study aimed to describe real-world treatments, overall survival (OS), health care resource utilization (HCRU), and costs among US patients with la/mUC receiving first-line therapy., Methods: This retrospective study was conducted using 100% Medicare claims data (2015-2020). Patients with la/mUC were selected; initiation of first-line therapy was the index date. Treatments and OS were assessed during follow-up (index date to the earliest of end of data availability, health plan coverage, or death). All-cause HCRU and costs (2021 USD) were assessed during the first-line treatment period (index date to the earliest of first-line discontinuation, switch to second-line therapy, end of follow-up, or death). Outpatient pharmacy costs were not included. All-cause OS from start of first-line therapy was estimated using the Kaplan-Meier approach. The HCRU, cost, and OS analyses were stratified by 3 index treatment groups-platinum-based chemotherapy, non-platinum-based chemotherapy, and programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor monotherapy-and adjusted for baseline characteristics., Results: Of 9,939 patients included, 77.1% were men and mean age was 76 years. In total, 5,050 (50.8%) received platinum-based chemotherapy, 1,361 (13.7%) received non-platinum-based chemotherapy, and 3,242 (32.6%) received PD-1/L1 inhibitor monotherapy for first-line la/mUC. Median OS was 12.9, 12.9 (P = 0.960), and 9.0 months (P < 0.001) with platinum-based chemotherapy (reference), non-platinum-based chemotherapy, and PD-1/L1 inhibitor monotherapy, respectively. Most (> 99%) patients had ≥ 1 outpatient visit during the treatment period; mean number of visits per patient was 13.1 with platinum-based chemotherapy, 10.5 with non-platinum-based chemotherapy, and 18.3 with PD-1/L1 inhibitor monotherapy. In general, HCRU was significantly lower for patients receiving PD-1/L1 inhibitor monotherapy versus platinum-based chemotherapy. However, costs were significantly higher with PD-1/L1 inhibitor monotherapy versus platinum-based chemotherapy. Mean total monthly cost per patient was $10,285 for platinum-based chemotherapy, $8,982 for non-platinum-based chemotherapy, and $18,147 for PD-1/L1 inhibitor monotherapy., Conclusions: From 2015 to 2020, patients with la/mUC had substantial HCRU and costs and short survival, regardless of first-line treatment. More effective therapies were needed to prolong survival and reduce the economic burden of la/mUC., Competing Interests: Declaration of competing interest Ronald C. Chen reports paid consulting from Myovant, AbbVie, Astellas Pharma, Inc., Janssen, and Bayer, and reports support for attending Telix clinical trials investigator meeting. Rupali Fuldeore reports being an employee of Astellas Pharma, Inc. Alexandra Greatsinger reports being an employee of Analysis Group, Inc., which has received funding from Astellas Pharma Global Development, Inc. for this research. Zsolt Hepp reports being an employee of Pfizer Inc. and owns stocks and stock options of Pfizer Inc. Qing Liu reports being an employee of Analysis Group, Inc., which has received funding from Astellas Pharma Global Development, Inc. for this research. Phoebe Wright reports being an employee of Pfizer Inc. Bin Xie reports being an employee of Astellas Pharma, Inc. Hongbo Yang reports being an employee of Analysis Group, Inc., which has received funding from Astellas Pharma Global Development, Inc. for this research. Christopher Young reports being an employee of Astellas Pharma, Inc. Adina Zhang reports being an employee of Analysis Group, Inc., which has received funding from Astellas Pharma Global Development, Inc. for this research. Lisa Mucha reports being an employee of Astellas Pharma, Inc., and having a long-term incentive plan as an employee of Astellas Pharma, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Invasive aspergillosis (IA) and mucormycosis (IM) cause significant morbidity and mortality in immunocompromised and/or hospitalized patients. Isavuconazonium sulfate, a prodrug of the antifungal triazole isavuconazole, has been approved for treatment of IA and IM in adults; and was recently approved in children. This study describes the outcomes, safety, and pharmacokinetics of isavuconazole for the treatment of proven, probable, or possible IA or IM in children. In this phase 2, open-label, non-comparative study, patients aged 1 to <18 years with at least possible invasive mold disease were enrolled across 10 centers in the US, Spain, and Belgium from 2019 to 2022. Patients received 10 mg/kg isavuconazonium sulfate daily (maximum 372 mg; equivalent to 5.4 mg/kg or 200 mg isavuconazole) for up to 84 (IA) or 180 days (IM). Outcomes included rates of all-cause case fatality, overall response, treatment-emergent adverse events (TEAEs), and pharmacokinetics. Of 31 patients enrolled, 61.3% were 1-<12 years old; 58.1% had underlying hematologic malignancies. The successful overall response rate at the end of treatment was 54.8%. Day 42 all-cause case fatality was 6.5%; 93.5% experienced TEAEs, and two patients discontinued treatment due to drug-related TEAEs. Dosing at 10 mg/kg (maximum dose: 372 mg) met the pre-defined exposure threshold of above the 25th percentile for the area under the concentration-time curve (≥60 mg·h/L). Simulated doses of 15 mg/kg improved drug exposures in patients aged 1-<3 years. Isavuconazole was well tolerated in children, with exposure consistent with adult studies. Successful response was documented in 54.8% of patients.CLINICAL TRIALSThis study is registered at ClinicalTrials.gov as NCT03816176., Competing Interests: The authors declare a conflict of interest (see Acknowledgments).

Purpose: To evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP)., Design: Phase 1/2, open-label, dose-escalation study., Methods: Setting: Four centers in the United States. Patient or Study Population: Twenty-nine males with XLRP and confirmed pathogenic RPGR variants. Mean age was 31.6 years (range 15-55)., Intervention: Subretinal injection of AGTC-501 at doses ranging from 2.48 × 10 10 to 1.99 × 10 12 vg/eye administered in one eye per participant. Subretinal injection sites initially targeted the peripheral retina and then transitioned to the macula with successive cohorts., Main Outcome Measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory parameters, and immunological responses. Efficacy was evaluated by mesopic microperimetry mean sensitivity., Results: All 29 participants experienced ≥1 TEAE. Eleven (38%) experienced ≥1 grade 3 TEAE. Six (21%) experienced ≥1 ocular SAE related to AGTC-501, including retinal detachment (n=4), subcapsular cataract (n=1), and glaucoma (n=1). Two (6.9%) experienced non-ocular treatment-emergent SAEs. Immunological findings did not indicate safety concerns. Three of 4 participants at the highest dose exhibited concerning retinal pigment epithelial changes. Half the participants at the highest tolerated dose (6.8 × 10 11 vg/eye) maintained ≥7 dB improvement in ≥5 loci at 24 months., Conclusions: Subretinal AGTC-501 was generally well-tolerated. Despite all participants experiencing at least one TEAE, most of these events were mild in nature, exhibited complete resolution, and were associated with the subretinal injection procedure itself rather than the study agent. The highest dose exhibited an unfavorable risk-benefit profile due to the development of RPE changes. Although this group had the highest improvement in retinal sensitivity, our team has decided not to continue this dose in future clinical trials. Preliminary efficacy was observed at the maximum tolerated dose. Further studies are warranted to assess long-term safety and efficacy of AGTC-501 for XLRP treatment., Competing Interests: Declaration of competing interest No conflict, (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency., Methods: The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review., Results: Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy., Conclusion: We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities., Competing Interests: Conflict of Interest The funding and support listed here did not support development of this document unless included in the acknowledgments section. Susan A. Berry is a member of the Board of Directors of the National PKU Alliance. Barbara K. Burton has received consulting fees and honoraria for speaking engagements from BioMarin Pharmaceutical, consulting fees from PTC Therapeutics and Jnana Therapeutics and funding for conducting clinical trials in PAH deficiency from BioMarin, Jnana Therapeutics, Homology Medicines, and Synlogic. Kim L. McBride has received research funding from BioMarin Pharmaceutical, Homology Medicines, and Ultragenyx, received speaker fees from Ultragenyx, and serves on a data monitoring board for Sanofi. Jerry Vockley has received research funding from BioMarin Pharmaceutical, Jnana Therapeutics, Homology Medicines, and PTC Therapeutics for participation in clinical trials on PAH deficiency. All other authors report no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

In recent years, there has been an increasing demand for the detection of rare cells in drug discovery research, such as cells that have differentiated off-purpose or are required for immunogenicity evaluation. Since detection and quantification limits depend on the robustness of the experiment, inter-human differences in technique have a significant impact on the performance of the assay system. Here, we integrated flow cytometry into a cell experiment platform, Screening Station, to construct a robust assay system, examined each step of the flow cytometric pretreatment using Jurkat cells, and finally evaluated the overall assay performance. Cell detection rate when the experiment was performed manually was 48.8 % ± 5.7 % (CV=11.6 %) versus 73.7 %±2.0 % (CV=2.8 %) with the automated method. To further clarify the analytical performance of the automated method, 1-100 PD-1 expressing Jurkat cells were spiked with 1 × 10 5 Jurkat cells, and the lower limit of detection, linearity, and CV% were evaluated. Average detection rate was 69 %, decision count was 0.985, and lower limit of detection was 4 cells (0.004 %). We evaluated the CV% value of the number of detected cells per spiked cell and found our system to be highly robust, approximating a binomial distribution with a 69 % recovery rate. In conclusion, we have integrated the Novocyte flow cytometry system into an automated experimental platform, Screening Station, to create a fully automated flow cytometric assay system with high robustness. Our platform can fulfill the technology needs of drug discovery for rare cell detection, which have intensified in recent years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: This study aimed to investigate the prevalence of claudin 18.2 (CLDN18.2) positivity, with a particular focus on intratumoral heterogeneity, and its association with clinicopathological features in metastatic or unresectable gastric cancer (GC)., Patients and Methods: We investigated 400 patients who received systemic chemotherapy for unresectable, metastatic, or recurrent GC. Immunohistochemistry for CLDN18 (43-14A), human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), and fibroblast growth factor receptor 2, as well as HER2 silver in situ hybridization (ISH), Epstein-Barr virus (EBV) ISH, and microsatellite instability testing were carried out. CD3+, CD8+, CD4+, and Foxp3-positive immune cell densities were calculated using digital image analysis., Results: In GC cases with any CLDN18.2 expression, more than half of the cases (61.3%) showed different expression results between four different tissue microarray (TMA) cores. When comparing CLDN18.2 status between whole tissue sections and the combined results from the four TMA cores, discrepancies were observed in only 2 out of 85 GC cases (2.4%), with 1 false positive and 1 false negative. After considering intratumoral heterogeneity, a CLDN18.2 positivity rate of 31.3% was observed among the 400 GC patients. CLDN18.2 positivity was rare in GCs located in the antrum (or lower third) and in HER2-positive cases but was common in EBV-positive GCs (P < 0.05). No differences in overall survival (OS) were observed according to CLDN18.2 positivity (P = 0.116). Additionally, there was no association between OS and CLDN18.2 positivity in patients treated with fluoropyrimidine plus platinum, chemotherapy plus trastuzumab, paclitaxel with or without ramucirumab, and immuno-oncologic agents. CLDN18.2-positive/PD-L1-high GCs showed statistically significantly longer OS than others (P = 0.025) and higher CD8+ T-cell densities in both the tumor center and periphery (P < 0.001)., Conclusions: Characterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Previous studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era., Methods: We evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015-2018) and Veterans Health Administration (VHA; 2015-2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone., Results: We analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58-0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57-0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09-1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01-1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61-0.92), with no significant OS difference between races., Conclusions: Guideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes., (© 2024. The Author(s).)

Background: This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO)., Methods: This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test., Key Results: The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal., Conclusion & Inferences: The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: The γ-aminobutyric acid-B (GABA B ) receptor is a promising target for the development of new medications to treat alcohol use disorder (AUD). The GABA B agonist baclofen has been reported to reduce alcohol consumption but is associated with some undesirable side effects, including sedation. ASP8062 is a novel compound that acts as a positive allosteric modulator at the GABA B receptor and may be more tolerable than baclofen. This proof-of-concept human laboratory clinical trial evaluated the safety profile of ASP8062 and tested its effects on cue-elicited alcohol craving and alcohol use among treatment-seeking individuals with AUD., Methods: This double-blind, randomized, multisite trial tested the effect of ASP8062 (25 mg once daily), relative to placebo, on alcohol cue-elicited craving in a laboratory setting and alcohol consumption, craving, mood, sleep, cigarette smoking, and alcohol-related consequences in the natural environment over a 6-week treatment period. Participants were 60 individuals (26 females and 34 males) with moderate or severe AUD., Results: ASP8062, relative to placebo, was well tolerated, and there were no adverse events (AEs) that significantly differed between treatment groups. Most AEs were mild/moderate, and there were no serious AEs among individuals treated with ASP8062. However, ASP8062 did not attenuate alcohol cue-elicited craving compared with placebo. Moreover, exploratory analyses indicated that ASP8062, relative to placebo, did not significantly affect alcohol consumption, naturalistic alcohol craving, mood, sleep, cigarette smoking, or alcohol-related negative consequences during the 6-week treatment period., Conclusions: Although ASP8062 was well tolerated with no serious AEs, the novel compound did not significantly dampen alcohol cue-elicited craving or improve other AUD-related outcome measures. These data indicate positive allosteric modulation of the GABA B receptor at the dose evaluated here may not blunt alcohol cue-elicited craving, and preliminary drinking outcome data suggest it may not be an efficacious treatment strategy for AUD., (© 2024 Research Society on Alcohol. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: There are no large head-to-head phase 3 clinical trials comparing overall survival (OS) for abiraterone and enzalutamide. This study used Medicare claims data to compare OS in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) who initiated abiraterone or enzalutamide., Methods: This retrospective analysis of the Medicare database (2009-2020) included adult men with ≥1 claim for prostate cancer, metastatic diagnosis, and no prior chemotherapy or novel hormone therapy who initiated first-line (1L) abiraterone or enzalutamide in the index period (September 10, 2014 to May 31, 2017). Cox proportional-hazards models with inverse probability treatment-weighting (IPTW) were used to compare OS between abiraterone- and enzalutamide-treated patients, adjusting for baseline characteristics. Subgroup analyses by baseline characteristics were also conducted., Results: Overall, 5506 patients who received 1L abiraterone (n = 2911) or enzalutamide (n = 2595) were included. Median follow-up was comparable in both cohorts (abiraterone, 19.1 months; enzalutamide, 20.3 months). IPTW-adjusted median OS (95% CI) was 20.6 months (19.7‒21.4) for abiraterone and 22.5 months (21.2‒23.8) for enzalutamide, with an IPTW-adjusted hazard ratio (95% CI) of 1.10 (1.04-1.16). Median OS was significantly shorter for abiraterone versus enzalutamide in patients ≥75 years old; White patients; patients with baseline diabetes, cardiovascular disease, both diabetes and cardiovascular disease, and renal disease; and across all socioeconomic strata., Conclusions: In the Medicare chemotherapy-naïve mCRPC population, 1L abiraterone was associated with worse OS versus enzalutamide in the overall population and among subgroups with older age and comorbidities, supporting findings from previous real-world studies and demonstrating a disparity in outcomes., (© 2024. The Author(s).)

Background: Patients with advanced prostate cancer (PC) commonly experience fatigue related to the disease itself and its treatment, which affects their quality of life. There are limited real-world data available on patients' experiences of fatigue while receiving PC treatment and its management., Patients and Methods: This was a cross-sectional, noninterventional qualitative study involving individual concept-elicitation interviews with patients in the United States. Patients with advanced PC aged ≥18 years who had experienced fatigue and were on androgen-deprivation therapy in combination with second-generation androgen receptor pathway inhibitors were interviewed and their experiences quantified., Results: Of the 143 patients screened, 13 qualified and 11 completed the interview. Most patients used the term "fatigue" (n = 8) to describe their experiences of tiredness, exhaustion, lack of energy, and weakness. Most patients (n = 8) did not receive any form of educational support from their healthcare providers (HCPs), but some expressed an interest in receiving this support (pamphlets, n = 4; discussion with HCPs, n = 4; online resources, n = 3). Most patients (n = 9) self-discovered fatigue-management strategies over the course of their disease and treatment. Patients found that rigorous exercise (n = 5), regular naps (n = 2), increased rest (n = 3), and a healthy diet (n = 3) were the most effective approaches for managing their fatigue., Conclusion: Tools are needed to support HCPs with counseling patients with PC for effective management of disease- and treatment-related fatigue., Competing Interests: Disclosure Stephen Freedland is a consultant for Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Pfizer Inc., Janssen, Merck, Sanofi, Myovant, and Novartis, and has received compensation for consultation. He has also received speakers’ bureau fees from AstraZeneca, Astellas Pharma Inc., Pfizer Inc., and Sanofi. Marty Chakoian is an advisor for Pfizer Inc. and has received support for the present manuscript. He is also an advisor for the University of Washington Medical Center and has received consulting fees for this. Additionally, he has received travel support for attending congresses and is a member of the patient advocacy group, ZERO Prostate Cancer. Ted Wells and Alexandra Colon are employees of IQVIA, USA. Dina Elsouda is an employee of Astellas Pharma Inc. Agnes Hong is a former employee of Astellas Pharma Inc. and received support for this manuscript. She holds stocks in Veru Inc. and Revance Therapeutics Inc. Nader El-Chaar is an employee of Astellas Pharma Inc., has received support from Astellas Pharma Inc. for the present publication, and holds stocks in Tonix Pharmaceuticals Holding Corp., Recursion Pharmaceuticals, Inc., Soligenix, Inc., and Bionano Genomics, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oral insulin has therapeutic advantages, as it can mimic the endogenous insulin pathway and relieve patients from daily self-injections. Among the many investigated oral insulin delivery systems, lipid nanoparticle (LNP)-based drug delivery systems are considered promising platforms for improving oral insulin absorption due to their unique in vivo properties and high design flexibility. However, challenges such as toxicity and low oral bioavailability persist. Dioleoylglycerophosphate-diethylenediamine (DOP-DEDA) is a pH-responsive and charge-reversible lipid for cytosolic cargo delivery. In this study, an insulin-encapsulated DOP-DEDA-based LNP (Ins-LNP) system was developed to achieve highly biocompatible and efficient oral insulin delivery. The Ins-LNPs exhibited a positive charge at gastrointestinal pH levels of 1.2 and 6.8, suggesting enhanced stability in the acidic stomach environment and facilitating efficient absorption in the small intestine. In addition, they are noncationic at a physiological pH level of 7.4, indicating low toxicity. PEGylated Ins-LNPs had a particle size of 125.4 nm, a polydispersity index of 0.047, and an encapsulation efficiency of 57.2 %. PEGylated Ins-LNPs maintained their particle characteristics for more than 2 h in simulated gastrointestinal fluid containing digestive enzymes. They also retained 89 %, 51 %, and 44 % of insulin for 60 min in simulated gastrointestinal/physiological fluid at pH levels of 1.2, 6.8, and 7.4, respectively. Furthermore, in vivo studies using streptozocin-induced diabetic mice demonstrated a pronounced and sustained hypoglycemic effect following oral administration, characterized by a ∼40 % reduction in blood glucose levels for over 10 h, indicative of an optimal pharmacodynamic profile. This favorable pharmacodynamic profile may mitigate the risk of clinically relevant hypoglycemia, enhancing patient compliance and overall treatment outcomes. Consequently, this research presents a promising LNP system for oral insulin delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Objective: To report patient-reported quality-of-life (QOL) outcomes in the DAYLIGHT study., Study Design: DAYLIGHT was a phase 3b, randomized, double-blind, 24-week, placebo-controlled study. Participants were women aged ≥40 to ≤65 years with moderate to severe vasomotor symptoms (VMS) considered unsuitable for hormone therapy (HT) (contraindications, caution, stoppers, or averse) randomized 1:1 to placebo or fezolinetant 45 mg once daily., Main Outcome Measures: Primary endpoint: mean change in daily VMS frequency of moderate to severe episodes from baseline to week 24. Secondary: patient-reported sleep disturbance (PROMIS SD SF 8b). Exploratory: patient-reported sleep disturbance (Patient Global Impression of Severity/Change in Sleep Disturbance [PGI-S/PGI-C SD]), menopause and VMS-related QOL (Female Sexual Function Index [FSFI], Menopause-Specific Quality of Life [MENQOL], Patient Global Impression of Change in Vasomotor Symptoms [PGI-C VMS], Work Productivity and Activity Impairment questionnaire specific to VMS [WPAI-VMS]), and general QOL (European Quality of Life 5 Dimensions 5 Level Version [EQ-5D-5L], Patient Health Questionnaire for Anxiety and Depression [PHQ-4])., Results: Overall, 452 women received at least one dose of study drug (placebo n = 226; fezolinetant n = 226): HT contraindicated (50; 11 %), caution (165; 37 %), stoppers (69; 15 %), and averse (168; 37 %). DAYLIGHT results showed statistically significant reductions in VMS frequency/severity in the fezolinetant group versus placebo at week 24. Week 24 improvements were seen in the fezolinetant group versus placebo in: PROMIS SD SF 8b total score (least squares [LS] mean difference: -2.5; 95 % CI: -3.9, -1.1; p < 0.001), MENQOL total score (LS mean difference: -0.44; 95 % CI: -0.69, -0.18; p < 0.001), and WPAI-VMS (activity impairment [p < 0.001], overall work productivity loss [p = 0.036], and presenteeism [p = 0.002] domains). A higher proportion of participants in the fezolinetant group reported positive changes in sleep disturbance (PGI-C SD, p < 0.001), sleep disturbance severity (PGI-S SD, p = 0.042), and VMS (PGI-C VMS, p < 0.001) versus placebo., Conclusions: Patient-reported outcomes demonstrate that reductions in VMS frequency with fezolinetant treatment were associated with improvements in QOL., Competing Interests: Declaration of competing interest M.S.C.M. sits on advisory boards for and has received consulting fees and honorariums from Amgen, Aspen, Astellas, BioSyent, Bayer, CCRN, Duchesnay, Eisai, GSK, Idorsia, Merck, Mithra, Novo Nordisk, Organon, Pfizer, Sandoz, and Searchlight; receives support for attending meetings and/or travel from Astellas and The Menopause Society; has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the International Menopause Society and Terry Fox Research Institute. X. Wu, X. Wang, K. Miyazaki., A.M., and K. Martins are employees of Astellas Pharma. R.E.N. receives grants/contracts from Fidia; consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck, Novo Nordisk, Shionogi, Theramex, and Viatris; payment for expert testimony from Vichy Laboratories; and is president of the International Menopause Society. P.S. has received grants or contracts from the University of Bern and Swiss National Foundation; consulting fees from Astellas and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Astellas, Theramex, and Besins Healthcare; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for the European Menopause and Andropause Society, Deutsche Menopause Gesellschaft, and Swiss Society for Anti Aging Medicine and Prevention. K.S. has received payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from aidhere, Astellas Pharma, Bayer/Jenapharm, Besins Healthcare, Exeltis, Fidia, Gedeon Richter Pharma, Novo Nordisk, Organon, Theramex, Viatris, and Laborarztpraxis Rhein-Main; participates on a data safety monitoring board or advisory board for Astellas, Bayer, Exeltis, Besins Healthcare, and Viatris; is President of the German Menopause Society organises and lectures at conferences for the society; lectures and participates in conferences for the professional association of gynaecologists in Germany; is honorary member for the German Society of Obstetrics and Gynecology and lectures, is president at conferences, and participates on committees for the society., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Primary aromatic amines (PAAs) present significant challenges in the prediction of mutagenicity using current standard quantitative structure activity relationship (QSAR) systems, which are knowledge-based and statistics-based, because of their low positive prediction values (PPVs). Previous studies have suggested that PAAs are metabolized into genotoxic nitrenium ions. Moreover, ddE, a relative-energy based index derived from quantum chemistry calculations that measures the stability nitrenium ions, has been correlated with mutagenicity. This study aims to further examine the ability of the ddE-based approach in improving QSAR mutagenicity predictions for PAAs and to develop a refined method to decrease false positive predictions., Results: Information on 1,177 PAAs was collected, of which 420 were from public databases and 757 were from in-house databases across 16 laboratories. The total dataset included 465 Ames test-positive and 712 test-negative chemicals. For internal PAAs, detailed Ames test data were scrutinized and final decisions were made using common evaluation criteria. In this study, ddE calculations were performed using a convenient and consistent protocol. An optimal ddE cutoff value of -5 kcal/mol, combined with a molecular weight ≤ 500 and ortho substitution groups yielded well-balanced prediction scores: sensitivity of 72.0%, specificity of 75.9%, PPV of 65.6%, negative predictive value of 80.9% and a balanced accuracy of 74.0%. The PPV of the ddE-based approach was greatly reduced by the presence of two ortho substituent groups of ethyl or larger, as because almost all of them were negative in the Ames test regardless of their ddE values, probably due to steric hindrance affecting interactions between the PAA and metabolic enzymes. The great majority of the PAAs whose molecular weights were greater than 500 were also negative in Ames test, despite ddE predictions indicating positive mutagenicity., Conclusions: This study proposes a refined approach to enhance the accuracy of QSAR mutagenicity predictions for PAAs by minimizing false positives. This integrative approach incorporating molecular weight, ortho substitution patterns, and ddE values, substantially can provide a more reliable basis for evaluating the genotoxic potential of PAAs., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that there are no competing interests., (© 2024. The Author(s).)

Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (C max ) and area under the curve from time of dosing extrapolated to infinity (AUC inf ) to 182% and 939%, respectively, while ES259564 C max decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant C max and AUC inf decreased to 71.7% and 48.3%, respectively, while ES259564 C max increased to 130.2% and AUC inf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women., (© 2024 Astellas Pharma Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy., Design: Phase 3b randomised controlled trial., Setting: 16 countries., Participants: 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226)., Intervention: Fezolinetant 45 mg or placebo once daily for 24 weeks., Main Outcome Measures: The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety., Results: 370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference -1.93, 95% confidence interval (CI) -2.64 to -1.22; P<0.001) and severity of vasomotor symptoms (-0.39, -0.57 to -0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (-2.5, -3.9 to -1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%))., Conclusions: Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy., Trial Registration: ClinicalTrials.gov NCT05033886; EudraCT 2021-001685-38., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: support from Astellas Pharma. KS has received payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from aidhere, Astellas Pharma, Bayer/Jenapharm, Besins Healthcare, Exeltis, Fidia, Gedeon Richter Pharma, Novo Nordisk, Organon, Theramex, Viatris, and Laborarztpraxis Rhein-Main; participates on a data safety monitoring board or advisory board for Astellas, Bayer, Exeltis, Besins Healthcare, and Viatris; is President of the German Menopause Society organises and lectures at conferences for the society; lectures and participates in conferences for the professional association of gynaecologists in Germany; is honorary member for the German Society of Obstetrics and Gynecology and lectures, is president at conferences, and participates on committees for the society. XWang, XWu, and KM are employees of Astellas Pharma. CB has received research grants from Astellas, Incyte, and Mithra; consulting fees from Bayer Pharma, Astellas, and AbCellera; and honorariums for lectures from Pfizer, Lupin, and Orimed. ALH receives consulting fees from Astellas, Besins, and Exeltis; payments or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Besins, Gedeon Richter, and Bayer; support for attending meetings and/or travel from Astellas and Besins; participates on a data safety monitoring board or advisory board for Exeltis. AC has received payment or honorariums for educational events from Theramex and Astellas; support for attending meetings and travel from Astellas; participates on advisory boards for Astellas and Theramex. MSCM sits on advisory boards for and has received consulting fees and honorariums from Amgen, Aspen, Astellas, BioSyent, Bayer, CCRN, Duchesnay, Eisai, GSK, Idorsia, Merck, Mithra, Novo Nordisk, Organon, Pfizer, Sandoz, and Searchlight; receives support for attending meetings and/or travel from Astellas and The Menopause Society; has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the International Menopause Society and Terry Fox Research Institute. PS has received grants or contracts from the University of Bern and Swiss National Foundation; consulting fees from Astellas and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Astellas, Theramex, and Besins Healthcare; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for the European Menopause and Andropause Society, Deutsche Menopause Gesellschaft, and Swiss Society for Anti Aging Medicine and Prevention. LS was an employee of Astellas Pharma at the time of development. REN receives grants/contracts from Fidia; consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck, Novo Nordisk, Shionogi, Theramex, and Viatris; payment for expert testimony from Vichy Laboratories; and is president elect of the International Menopause Society., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The primary purpose of an oncology dose-finding trial for novel anticancer agents has been shifting from determining the maximum tolerated dose to identifying an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. In 2022, the FDA Oncology Center of Excellence initiated Project Optimus to reform the paradigm of dose optimization and dose selection in oncology drug development and issued a draft guidance. The guidance suggests that dose-finding trials include randomized dose-response cohorts of multiple doses and incorporate information on pharmacokinetics (PK) in addition to safety and efficacy data to select the OD. Furthermore, PK information could be a quick alternative to efficacy data to predict the minimum efficacious dose and decide the dose assignment. This article proposes a model-based trial design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients assigned to OD in various realistic settings., (© 2024 John Wiley & Sons Ltd.)

Introduction: 1L PBC has historically been recommended for patients with la/mUC. Maintenance avelumab is recommended for patients without disease progression following 1L PBC. Real-world data on the proportion of patients eligible for maintenance avelumab are limited, and outcomes among patients ineligible for maintenance avelumab are uncertain. This study assessed the proportion of patients with la/mUC initiating 1L PBC who were maintenance-avelumab eligible and real-world outcomes following 1L PBC by maintenance-avelumab eligibility., Methods: A retrospective, observational study was conducted using a longitudinal electronic health record-derived database comprising de-identified patient-level structured and unstructured data including adults with Ia/mUC who received ≥1 dose of 1L PBC (April 2020-January 2022). The proportion of patients eligible for maintenance avelumab (real-world stable disease, partial response, or complete response following 1L PBC) was estimated and median overall survival (mOS) assessed for maintenance avelumab-eligible and -ineligible patients., Results: Of 336 patients with Ia/mUC treated with 1L PBC (55.4% received cisplatin-based treatment 44.6% carboplatin-based treatment); 181 (54%) were maintenance-avelumab eligible; and 138 (41%) maintenance-avelumab ineligible (17 [5%] were nonevaluable). Of 181 maintenance-avelumab-eligible patients, 67 (37.0%; 19.9% of all 1L PBC-treated patients) received maintenance avelumab. mOS (95% CI) among all 1L PBC-treated patients was 15.0 (12.2-19.6) months and among maintenance-avelumab-ineligible patients was 8.0 (6.7-10.3) months; whereas among maintenance-avelumab-eligible patients (including 37% who received maintenance avelumab), mOS was 27.6 (23.4-not reached) months., Conclusions: In this study, approximately half of 1L PBC-treated patients were maintenance-avelumab eligible, and one-fifth received it. Real-world OS remains short for the overall 1L PBC-treated population. These results support the use of treatment-guideline preferred 1L treatment options that demonstrate survival benefit for all patients with la/mUC, and are available to patients irrespective of their eligibility for cisplatin, or response to PBC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Determine rates of progression of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) to complete retinal pigment epithelium and outer retinal atrophy (cRORA) and rates of progression of drusen to iRORA/cRORA in eyes with geographic atrophy (GA) treated with avacincaptad pegol (ACP)., Methods: Post hoc analysis of the GATHER1 prospective, randomized, double-masked Phase II/III study that evaluated ACP 2 mg vs. sham. Optical coherence tomography (OCT) data from GATHER1 were transferred to the Doheny Image Reading and Research Lab for masked analysis by readers experienced with Classification of Atrophy Meeting (CAM) grading features. Regions of OCT volume scans more than 500 µm from the border of GA lesions were evaluated at baseline and at months 6, 12, and 18. Participants with iRORA and/or drusen (≥ 40 µm height on OCT) at baseline were included in the analysis., Results: The proportion of eyes progressing from iRORA to cRORA in the ACP 2 mg group was 5.0%, 15.0%, and 20.0% at months 6, 12, and 18 respectively, as compared with 11.8%, 30.2%, and 41.8% of eyes in the sham group. The proportion of ACP 2 mg-treated eyes progressing from drusen to iRORA or cRORA was 3.8%, 7.6%, and 7.6% at months 6, 12, and 18 compared with 15.9%, 18.1%, and 27.2% of sham-treated eyes., Conclusions: Rates of progression from iRORA to cRORA and drusen to iRORA/cRORA were reduced in eyes treated with ACP 2 mg vs. sham, with increasing separation between groups over time, suggesting early intervention may slow disease progression., Trial Registration: ClinicalTrials.gov identifier: NCT02686658. Date of registration: February 16, 2016., Key Messages: What is known Geographic atrophy is an advanced form of age-related macular degeneration (AMD) that leads to irreversible vision loss, presenting a significant public health unmet need. The Classification of Atrophy Meeting (CAM) group recommended a new nomenclature for advanced AMD lesions, based on the affected anatomical layers on optical coherence tomography. Accordingly, the terms incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) and complete retinal pigment epithelium and outer retinal atrophy (cRORA) were introduced (Guymer et al., Ophthalmology 127:394-409, 2020; Sadda et al., Ophthalmology 125:537-548, 2018). What is new GATHER1 post hoc analysis shows that treatment with avacincaptad pegol (ACP) 2 mg decreases the proportion of eyes that progress from iRORA to cRORA, and from drusen to iRORA or cRORA, compared with sham, over 6, 12, and 18 months. These findings suggest a potential role for ACP in delaying the progression of existing pre-atrophic AMD lesions., Competing Interests: Declarations Ethics approval The GATHER1 trial was performed in accordance with the tenets of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines [13]. The appropriate ethics committee or institutional review board at each study center involved in the study (80 centers) approved the protocol [13]. Consent to participate Written informed consent was obtained from all participants [13]. Disclosure statement SriniVas R Sadda- although the author is the editor of the journal, there was no involvement with the peer review process for this article. Competing interests GC has received lecture fees from Nidek. AK, SS, SL, SBV, FC, YA, and MGN have no financial disclosures. SR Sadda has consulted/advised for: Apellis Pharmaceuticals, Inc.; Amgen Inc.; AbbVie/Allergan, Inc.; Samsung Bioepis; Biogen; Boehringer Ingelheim; Iveric Bio; Novartis; Roche/Genentech; Bayer Healthcare Pharmaceuticals; Regeneron Pharmaceuticals, Inc.; Pfizer Inc.; Astellas; Nanoscope Therapeutics; Janssen Pharmaceuticals, Inc.; CenterVue, Inc.; Optos, Inc.; and Heidelberg Engineering; has received lecture fees/speakers bureau fees from: Heidelberg Engineering; Roche/Genentech; Novartis; and Optos, Inc.; and has received research equipment from: CenterVue, Inc.; Optos, Inc.; Carl Zeiss Meditec; Topcon Medical Systems, Inc.; Heidelberg Engineering; and Nidek Inc. SR Sadda, the corresponding author, is an editor of the journal; however, there was no involvement with the peer review process for this article. DD and LZ are former employees of Astellas, and DA is an employee of Astellas., (© 2024. The Author(s).)

Background: eSource software that transfers patient electronic health record data into a clinical trial electronic case report form holds promise for increasing data quality while reducing data collection, monitoring and source document verification costs. Integrating eSource into multicenter clinical trial start-up procedures could facilitate the use of eSource technologies in clinical trials., Methods: We conducted a qualitative integrative analysis to identify eSource site start-up key steps, challenges that might occur in executing those steps, and potential solutions to those challenges. We then conducted a value analysis to determine the challenges and solutions with the greatest impacts for eSource implementation teams., Results: There were 16 workshop participants: 10 pharmaceutical sponsor, 3 academic site, and 1 eSource vendor representative. Participants identified 36 Site Start-Up Key Steps, 11 Site Start-Up Challenges, and 14 Site Start-Up Solutions for eSource-enabled studies. Participants also identified 77 potential impacts of the Challenges upon the Site Start-Up Key Steps and 70 ways in which the Solutions might impact Site Start-Up Challenges. The most important Challenges were: [1] not being able to identify a site eSource champion and [2] not agreeing on an eSource approach. The most important Solutions were: [1] eSource vendors accepting electronic data in the Health Level 7 Fast Healthcare Interoperability Resources (HL7® FHIR®) standard, [2] creating standard content for eSource-related legal documents, and [3] creating a common eSource site readiness checklist., Conclusions: Site start-up for eSource-enabled multi-center clinical trials is a complex socio-technical problem. This study's Start-Up Solutions provide initial steps for scalable eSource implementation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amy E. Cramer: Employment, Johnson & Johnson Innovative Medicine. Linda S. King: Employment, Astellas Pharma. Michael T. Buckley: Employment, Memorial Sloan Kettering Cancer Center. Peter Casteleyn: Employment, Johnson & Johnson Innovative Medicine. Cory Ennis: Employment: Duke University School of Medicine. Muayad Hamidi: Employment: UT Health San Antonio. Gonçalo M. C. Rodrigues: Employment, Janssen-Cilag. Denise C. Snyder: Employment, Duke University School of Medicine. Aruna Vattikola: Employment, Merck & Co., Inc. Eric L. Eisenstein: I have nothing to declare., (© 2024 The Authors.)