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Introduction: Vaccines can prevent influenza (flu) infections and are cost-effective for society and healthcare. However, the cost-effectiveness of post-exposure prophylaxis as a follow-up strategy is unclear. This study aims to evaluate the cost utility of post-exposure prophylaxis and treatment strategies with neuraminidase inhibitors and a cap-dependent endonuclease inhibitor for flu infections from the perspective of healthcare costs in Japan., Methods: A base-case analysis was used to compare oseltamivir, zanamivir, and laninamivir for neuraminidase inhibitors and baloxavir marboxil for the endonuclease inhibitor. The costs of the first visit to a physician and pharmacy were excluded because of the policy on out-of-pocket expenses for post-exposure prophylaxis in Japan. Direct medical costs include the second physician visit, pharmacy and hospital admission expenses, and drug prices, based on the 2020 Japanese Medical Fee Index. The EuroQol-5Dimention-5Level was utilized to measure healthy participants' quality of life scores, with a time horizon of 14 days. Deterministic and probabilistic sensitivity analyses were conducted., Results: We have found baloxavir marboxil as the post-exposure prophylaxis agent and laninamivir as the treatment agent to be the most cost-effective strategy in Japan, followed by oseltamivir as the post-exposure prophylaxis agent and zanamivir as the treatment agent., Conclusions: Baloxavir marboxil and oseltamivir are cost-effective prophylactic agents for flu from the perspective of healthcare costs in Japan. This strategy to select baloxavir marboxil or oseltamivir would be helpful to manage a formulary for post-exposure prophylaxis in Japan., Competing Interests: Declarations. Conflict of Interest: The authors, Naoto Nakagawa, Runa Ono, Keita Odanaka, Hiroshi Ohara, Shigeki Kisara, and Kitae Ito, declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article. Ethical Approval: The study was approved by the ethics commission of the university where the authors hold faculty positions (no. 330). The authors submitted a letter describing the study’s purpose under the condition that identifiable information would never be made public. The students were also advised that they would experience no disadvantage for refusing to participate in the study at any time. Written letters of intent were obtained from the participants. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Since 2000, rapid antigen detection kits and anti-influenza drugs have been used for the early diagnosis and treatment of influenza in Japan, respectively.　The main drugs available in clinical practice are the neuraminidase inhibitors oseltamivir, zanamivir, laninamivir, and peramivir, as well as the cap-dependent endonuclease inhibitor baloxavir marboxil.　Antiviral therapy with neuraminidase inhibitors has been practiced for many years, especially in Japan; it can shorten the febrile period and reduce complications.　Despite having similar structures, the pharmacologic background of neuraminidase inhibitors differs significantly, as reflected in their varying clinical efficacy.　Due to its inhibitory mechanism, baloxavir marboxil can rapidly reduce the viral load than neuraminidase inhibitors.　However, the duration of symptoms was similar after the administration of baloxavir marboxil and oseltamivir, and variants with reduced drug susceptibility have been detected in 20%-30% of pediatric patients treated with baloxavir marboxil.　Clinical trials of several novel anti-influenza drugs are currently underway.　When these drugs are first marketed, the characteristics of the influenza virus and the pharmacologic background of the drugs must be clarified before their administration to patients in clinical practice.

Type 2 diabetes (T2D) is increasing relentlessly globally, affecting ever younger patients. Many T2D patients do not attain glycemic target levels, indicating a clear need for novel antihyperglycemic drugs. Ideally, these should not only control glycemia, but also halt or slow the progressive loss of beta cells. Two entirely novel classes of antihyperglycemic agents - glucokinase activators and imeglimin -  were recently approved in Asian markets and will be discussed in this review. These two novel drug classes will be a welcome addition and complement to existing treatments. Time will tell whether these new antihyperglycemic agents will add value to the current treatment paradigms against T2D and provide sustained antihyperglycemic effect, acceptable safety, usefulness in combination therapy, and effects on hard end-points such as cardiovascular disease.

Type 2 diabetes (T2D) presents a formidable challenge to healthcare, with rising prevalence and complex pathogenesis involving beta-cell dysfunction and insulin resistance. Imeglimin, the progenitor of the "glimins" class, emerges as a multifaceted agent capable of attenuating beta-cell apoptosis, reducing hepatic gluconeogenesis, and augmenting muscular glucose uptake. This positions it as a promising solution for T2D management, especially for patients inadequately controlled by current therapies. This narrative review delves into the potential of imeglimin to address the mitochondrial dysfunctions central to T2D pathology, offering insights into its distinct mechanism that leverages the modulation of mitochondrial bioenergetics to enhance insulin sensitivity and reduce oxidative stress. The Trials of Imeglimin for Efficacy and Safety (TIMES) program, consisting of multiple clinical trials, has substantiated the efficacy and safety of imeglimin, illustrating significant glycated hemoglobin (HbA1c) reductions and favorable safety profiles. This review synthesizes evidence from these trials, providing a comprehensive overview of imeglimin as a novel monotherapy and its compatibility in combination therapies, heralding a novel approach to T2D treatment that targets the disease's mitochondrial roots., (© Journal of The Association of Physicians of India 2025.)

Background: Drug-induced atrial fibrillation (AF) is recognized as an important causal association. Lamotrigine (LTG) is a widely prescribed neurological agent with Class IB antiarrhythmic properties at therapeutically relevant concentrations. The United States Food and Drug Administration has issued a warning for a higher risk of LTG proarrhythmic events in patients with structural heart disease (SHD) and/or myocardial ischemia. This study evaluated the incidence of AF with LTG use., Methods: A retrospective observational study was performed using a large healthcare claims database of adult participants analyzing 2 years AF incidence. The analytic cohort included adult participants with bipolar I disorder (BPD), partial seizures (PSZ), or generalized tonic-clonic seizures (GTSZ). Exposure to LTG was compared with commonly prescribed alternative agents as the control comparators (CTR). Participants were free from supraventricular or ventricular arrhythmias during the 6 months baseline period prior to the index LTG or CTR date. Kaplan-Meier estimator calculated 2 years cumulative AF incidence, with participants censored at last enrollment, treatment switching, or discontinuation. The AF association hazard ratios (HR) for LTG versus CTR were adjusted for baseline characteristics., Results: The analytic cohort with BPD, PSZ, and GTSZ consisted, respectively, of 150,470 LTG versus 204,704 CTR, 9565 LTG versus 21,595 CTR, and 5505 LTG versus 15,513 CTR patients. In a predominantly middle-aged female population at baseline, the prevalence of cardiovascular conditions was low. The 12 months cumulative incidence of AF for LTG versus CTR was 0.764% versus 0.642% among BPD, 0.833% versus 0.646% among PSZ, and 0.585% versus 0.338% among GTSZ, respectively. The adjusted 365-day HR [95% confidence interval CI] of AF for LTG versus CTR in the BPD, PSZ, and CTSZ groups was 1.257 [1.088-1.453], 1.651 [1.104-2.468], and 1.451 [0.770-2.734], respectively., Conclusions: In adult AF-naïve participants, LTG has a strong association with increased AF risk compared with commonly prescribed alternatives., (© 2024 Pharmacotherapy Publications, Inc.)

Aim: To evaluate the efficacy of the antiviral drug riamilovir (trade name - «Triazavirin ® ») for the prevention of SARS-CoV-2 infection (COVID-19) and other acute respiratory viral infections in young people from organized groups., Materials and Methods: The study involved 386 individuals aged 18-22 years: 199 received riamilovir at a daily dose of 250 mg for 15 days, while 187 did not receive prophylactic drugs. For 30 days, disease occurrence was monitored among volunteers. In case of illness, the duration, severity of clinical manifestations, complications, and pathogen elimination dynamics were assessed via PCR from nasopharyngeal and oropharyngeal swabs., Results: During riamilovir administration, a statistically significant reduction in cases of acute respiratory viral infections of non-coronavirus etiology was observed, with no COVID-19 cases reported, confirmed by the absence of SARS-CoV-2 RNA in this group. The shortest duration of acute respiratory viral infections was noted in patients taking the prophylactic drug., Conclusion: Riamilovir (trade name - «Triazavirin ® ») showed statistically significant prophylactic efficacy during its administration in an organized group. Its use decreased the frequency of detection of viral pathogens and resulted in milder acute respiratory disease, likely due to reduced viral load in individuals.

Purpose: MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA., Methods: Patients with chemotherapy refractory mCRC and MET amp detected by cfDNA were treated with savolitinib until unacceptable toxicity or disease progression. The primary endpoint was objective response rate. Secondary endpoints were clinical activity and safety., Results: Five patients were enrolled and treated. Best overall response was stable disease (SD) in two patients, progressive disease (PD) in two patients, and one patient unevaluable for response. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common TEAEs included fatigue (n = 3) and nausea (n = 3). There were no grade 4 or 5 TEAEs., Conclusion: Savolitinib was well tolerated; however, in this small group of biomarker-selected patients, we observed no evidence of anti-tumor activity., Trial Registration: Clinicaltrials.gov Identifier: NCT03592641. Registered on July 17, 2018., Competing Interests: Declarations. Ethics Approval: Approval was obtained from the NCI Adult Central Institutional Review Board – Early Phase Emphasis. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Consent to Participate: Informed consent was obtained from all individual participants included in the study. Competing Interests: JJ: Consultant or advisory role: AstraZeneca, Cardinal Health Research funding or contracted research: Roche/ Genentech, AztraZeneca JS: Consultant or advisory role: Abbvie, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BMS, Daiichi-Sankyo, Eli Lilly, GE Healthcare, GSK, Incyte, Ipsen, Johnson and Johnson, Jazz Pharmaceuticals, Leap, Merck, Natera, Pfizer, Roche/Genentech, Regeneron, Sanofi, Taiho, Takeda, Xilio Therapeutics Stock options- Triumvira Immunologics Research funding or contracted research: Abbvie, Amgen, Apollo Therapeutics, AStar D3, Bayer, Beigene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, GSK, Leap Therapeutics, Novartis, Pfizer, Quanta Therapeutics, Revolution Medicines, Roche/ Genentech HJL: Stock options – Fulgent, 3 T Bioscience, Breakbio; Advisory Board-BMS, Adagene, 3 T Bioscience, Merck, Merck KG, Abbvie, Bayer; Research funding or contracted research: UM1CA186717, P30CA014089. MC: Honoraria-Amgen, AstraZeneca, Astellas, Bayer, Basilea, Bristol-Myers Squibb, Eisai, Exelixis, I-Mab, Ipsen, Incyte, Genetech/Roche, Natera, Pfizer, Seattle Genetics, Taiho, Tempus, QED; Employment – Replimune., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Monocytes mainly contribute to the development and progression of vascular inflammatory conditions via the M1 polarization. The elevated levels of advanced glycation end products (AGEs) in diabetic environment lead to severe inflammation, and the release of pro-inflammatory mediators. This shifts the balance towards the pro-inflammatory state of monocytes., Objective: The current study was aimed to determine the antiglycation activity of 1,2,4-triazine derivatives, and study of their molecular basis in regulating the AGEs-mediated inflammatory responses in THP-1 monocytes., Methods: Primarily, the antiglycation activity of a series of 1,2,4-triazine derivatives was evaluated against MGO-AGEs in vitro. The toxicity of antiglycation compounds was determined by a metabolic assay, using human hepatocyte (HepG2) and monocyte (THP-1) cell lines. DCFH-DA probe was used to evaluate the antioxidant potential of the compounds. Immunocytochemistry, Western blotting, and ELISA techniques were employed to determine the levels of pro-inflammatory markers (NF-κB, RAGE, COX-1, COX-2, and PGE 2 ) in THP-1 monocytes under in-vitro hyperglycemic conditions., Results: Results indicate that the triazine derivatives 22, and 23 were the most potent antiglycation agents among the entire series, while non-toxic to HepG2, and THP-1 cells. Both compounds inhibited the AGEs-induced upstream and downstream signaling of NADPH oxidase and inflammatory mediators p38 and NF-κβ, respectively, in THP-1 monocytes. They also inhibited the induction of COX-2 and its product PGE 2 by suppressing AGE-RAGE interactions. Moreover, compounds 22, and 23 reversed the AGEs-mediated suppression of COX-1 in THP-1 monocytes., Conclusion: In conclusion, 1,2,4-triazine derivatives 22, and 23 have the potential to suppress inflammatory responses under the diabetic environment through AGE-RAGE-NF-κβ/p38 nexus in THP-1 monocytes. These findings identify triazines 22, and 23 as compelling candidates for drug development, potentially beneficial for the diabetic patients with an elevated risk of vascular complications, such as atherosclerosis., 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 B.V. All rights reserved.)

Introduction: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC., Methods: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination., Conclusion: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy., Competing Interests: Disclosure C.M.B. receives institutional research funding from Novartis, AstraZeneca, Mirati, Verastem, and Puma. J.W.R. received institutional research funding from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Revolution Medicines, Arrivent and Spectrum; consulting fees from Blueprint, Boehringer Ingelheim, EMD Serono, and Novartis; participation on an Advisory Board for Bayer, Beigene, Biodesix, Regeneron, Turning Point, Bristol Myers Squibb, Daiichi Sankyo, Roche/Genentech, Janssen, Jazz Pharmaceuticals, Mervus, Seattle Genetics, Summit and Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Background: Savolitinib has been approved in China for advanced or metastatic non-small-cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations in previously treated patients and those unable to receive platinum-based chemotherapy. We report results from a treatment-naive cohort of a phase 3b study that was designed to evaluate the efficacy and safety of savolitinib in locally advanced or metastatic METex14-mutated NSCLC., Methods: This single-arm, multicohort, multicentre, open-label, phase 3b study was done at 48 hospitals in China in adult (≥18 years) patients with locally advanced or metastatic METex14-mutated NSCLC who had not received previous systemic antitumour therapy. Patients with a bodyweight of 50 kg or more and those with a bodyweight of less than 50 kg received savolitinib once daily at 600 mg or 400 mg, respectively, in 21-day cycles. The primary endpoint was objective response rate assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumours, version 1.1. The full analysis set comprised all patients who received at least one dose of study medication, which was used to assess the efficacy endpoints and baseline and safety data. This study is registered with ClinicalTrials.gov (NCT04923945) and is closed to accrual., Findings: Between Aug 31, 2021, and Oct 20, 2023, 125 treatment-naive patients were assessed for eligibility, of whom 87 were enrolled and received savolitinib. The median age of patients was 70·0 years (IQR 65·2-75·8) and 51 (59%) of 87 patients were male and 36 (41%) were female. In the full analysis set, the IRC-assessed objective response rate was 62% (95% CI 51-72) and the investigator-assessed objective response rate was 60% (49-70), showing a high concordance rate (84%). Treatment-related adverse events were reported in 85 (98%) of 87 patients, with peripheral oedema (54 [62%]) being the most common. Two of these treatment-related adverse events led to death (cardiac failure n=1, unknown reasons n=1)., Interpretation: Savolitinib showed manageable toxicity and promising efficacy in treatment-naive patients with advanced or metastatic METex14-mutated NSCLC., Funding: HUTCHMED and AstraZeneca., Competing Interests: Declaration of interests MS and WS are employees of HUTCHMED. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Source Citation: Zhao Y, Gao Y, Guyatt G, et al. Antivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysis. Lancet. 2024;404:764-772. 39181596., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Objectives: We perform a cost-effectiveness analysis (CEA) and budget impact analysis (BIA) of baloxavir marboxil compared to current care in the Netherlands for patients at risk of influenza-related complications, including patients with comorbidities and the elderly., Methods: In the CEA, a decision tree model was developed to assess the cost-effectiveness of baloxavir marboxil for a cohort of 52-year-olds from a societal perspective. A lifetime horizon was taken by incorporating the quality-adjusted life expectancy. The BIA included different epidemiological scenarios, estimating different plausible epidemiological scenarios for seasonal influenza considering the whole Dutch population with an increased risk of influenza complications., Results: The base-case ICER was estimated to be €8,300 per QALY. At the willingness-to-pay threshold of €20,000 per QALY, the probability of being cost effective was 58%. The base-case expected budget impact was €5.7 million on average per year, ranging from €1.5 million to €10.5 million based on the severity of the influenza epidemic and vaccine effectiveness., Conclusion: In the Netherlands, baloxavir is a cost-effective treatment option for seasonal influenza, with a base-case ICER of €8,300 per QALY for the population aged 60 years and over and patients at high risk of influenza-related complications. For a large part, this ICER is driven by the reduction of the illness duration of influenza and productivity gains in the working population., (© 2024. The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mesenchymal-epithelial transition (MET) signaling pathway plays a role in the pathogenesis of selected patients with papillary renal cell carcinoma (PRCC). In the phase II PAPMET trial (ClinicalTrials.gov identifier: NCT02761057), cabozantinib significantly prolonged progression-free survival and improved objective response rate compared with sunitinib in patients with advanced PRCC. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized phase II, open-label trial, 147 patients with advanced PRCC who have received up to one previous therapy (excluding vascular endothelial growth factor-directed agents) were assigned to sunitinib, cabozantinib, crizotinib, or savolitinib. Ultimately, savolitinib and crizotinib arms were closed because of futility. With a median follow-up of 17.5 months, the median OS was 21.5 months (95% CI, 12.0 to 28.1) with cabozantinib and 17.3 months (95% CI, 12.8 to 21.8) with sunitinib (hazard ratio, 0.83; 95% CI, 0.51 to 1.36; P = .46). The OS landmark estimates for cabozantinib and sunitinib were 50% versus 39% at 24 months and 32% versus 28% at 36 months. In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease.

Background: Influenza virus is a widespread pathogen that poses significant health risks to humans. Oseltamivir and Baloxavir Marboxil are commonly utilized medications for both treating and preventing influenza infections. Despite their widespread use, there remains a need to thoroughly investigate their safety profiles and potential adverse reactions., Objective: This study aims to comprehensively analyze the adverse events associated with oseltamivir and baloxavir marboxil in real-world clinical settings, with the goal of assessing their safety and potential risks in the management of influenza virus infections., Methods: We conducted a retrospective analysis utilizing data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, spanning from the first quarter of 2004 to the third quarter of 2023. The analysis encompassed examination of drug utilization patterns, types of adverse events reported, patient demographics, and other pertinent factors., Results: From the first quarter of 2004 to the third quarter of 2023, FAERS collected over 17,035,521 adverse event reports (AE reports). Among these reports, there were 38,384 reports associated with oseltamivir, and 3,364 reports associated with baloxavir marboxil. Oseltamivir and Baloxavir Marboxil were primarily used for the treatment of influenza virus infections, accounting for 62.43% and 67.49% of their total usage, respectively. The main adverse reactions reported for oseltamivir were vomiting (case reports = 1402) followed by confusional state (case reports = 353), while for baloxavir marboxil, adverse reactions mainly centered around off-label use (case reports = 378) and intentional product use issues (case reports = 278). In terms of systemic adverse reactions, oseltamivir primarily affected psychiatric disorders (n = 45), whereas baloxavir marboxil mainly impacted the gastrointestinal system (n = 7). Additionally, regarding adverse reactions in pregnant women, the occurrence of normal newborns was a significant signal for oseltamivir, suggesting a certain level of safety during maternal use. Conversely, reports of adverse reactions such as respiratory arrest were documented for baloxavir marboxil, while no such reports were associated with oseltamivir., Conclusion: This study provides a comprehensive analysis of the adverse reactions observed with the clinical use of oseltamivir and baloxavir marboxil, revealing the safety and risks associated with these two drugs in the treatment and prevention of influenza virus infections. Firstly, although both drugs are used for influenza treatment, they exhibit different types of adverse reactions. Oseltamivir predominantly affects the psychiatric system, while baloxavir marboxil primarily impacts the gastrointestinal system. Additionally, oseltamivir demonstrates a certain level of safety for use in pregnant women, while reports of adverse reactions such as respiratory arrest are associated with baloxavir marboxil. Despite the clinical significance of this study, limitations exist due to the voluntary nature of data reporting, which may lead to reporting biases and incomplete information. Future research could employ more rigorous prospective study designs, integrating clinical trials and epidemiological studies, to more accurately assess the safety risks of oseltamivir and baloxavir marboxil., Competing Interests: no, (Copyright: © 2024 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Influenza A virus infection, commonly known as the flu, has persisted in the community for centuries. Although we have yearly vaccinations to prevent seasonal flu, there remains a dire need for antiviral drugs to treat active infections. The constantly evolving genome of the influenza A virus limits the number of effective antiviral therapeutic options. Over time, antiviral drugs become inefficient due to the development of resistance, as seen with adamantanes, which are now largely ineffective against most circulating strains of the virus. Neuraminidase inhibitors have long been the drug of choice, but due to selection pressure, strains are becoming resistant to this class of drugs. Baloxavir marboxil, a drug with a novel mode of action, can be used against strains resistant to other classes of drugs but is still not available in many countries. Deep research into nanoparticles has shown they are effective as antiviral drugs, opening a new avenue of research to use them as antiviral agents with novel modes of action. As this deadly virus, which has killed millions of people in the past, continues to develop resistance, there is an urgent need for new therapeutic agents with novel modes of action to halt active infections in patients. This review article covers the available therapeutic antiviral drug options with different modes of action, their effectiveness, and resistance to various strains of influenza A virus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 [95% confidence interval (CI): -29.4, -10.7] h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.

Opinion Statement: Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1., (© 2024. The Author(s).)

Background: Clinical data on patients infected with influenza B Victoria (BV) after the approval of baloxavir is lacking., Methods: This observational study of the Japanese 2023-2024 influenza season analyzed data from 25 outpatients with A(H1N1)pdm09, 36 with A(H3N2), and 65 with BV. Viral samples were collected before and after administering an antiviral (70 patients received baloxavir and 56 received a neuraminidase inhibitor), on days 1, 5, and 10. Isolated viruses after culturing were amplified using RT-PCR and sequenced to detect mutations of concern, including acidic protein (PA)-amino acid (AA) E23X/I38X for influenza A and M34X/I38X for BV. Fever and symptoms were tracked via self-reporting diaries., Results: No PA-AA-substituted virus was detected from 126 pre-treatment samples. In the baloxavir cohort, one (7.1%, 1/14) PA I38F-substituted A(H1N1)pdm09 and two (11.1%, 2/18) PA I38T-substituted A(H3N2) viruses were isolated on day 5 but not on day 10. No (0%, 0/37) PA-AA-substituted BV was detected on day 5 or after. The virus isolation rate on day 5 was higher among patients with BV than with influenza A in both baloxavir (35.1% vs. 14.3% for A(H1N1)pdm09 and 16.7% for A(H3N2)) and oseltamivir-treated patients (44.4% vs. 0% for A(H1N1)pdm09 and 33.3% for A(H3N2)). Patients with PA-AA-substituted influenza A after baloxavir administration did not have longer fever duration than those without virus isolation or with wild-type virus on day 5, for both A(H1N1)pdm09 and A(H3N2)., Conclusions: Baloxavir-resistant variants were not detected in influenza BV before treatment, as with A. The emergence of PA-AA-substituted influenza A after baloxavir administration was temporal and did not cause prolonged symptoms. No baloxavir-resistant BV variants were observed after baloxavir administration., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Nanotechnology has the potential to reduce drug dosage while increasing efficacy; thus, the current work intends to synthesize diclazuril nanoemulsion and assess its performance against experimental coccidiosis in broilers., Methods: Diclazuril nanoemulsion (DZN) was formulated and characterized by zeta seizer and zeta potential. The formulated DZN was evaluated in vivo against Eimeria tenella infected chicks. DZN and DZ were used in 2 programs; therapeutic and prophylactic. A total of 210 one-day-old broiler chicks were distributed equally into six groups. The controls were negative uninfected untreated and positive infected untreated (G1 & G2). Therapeutic groups (G3 & G4) treated by DZ and DZN after appearance of the clinical signs of coccidiosis and continued for 5 days. Prophylaxis groups (G5 & G6) received DZ and DZN at 3 days before challenge and continued for 5 days after infection. The treatments dosages were 10 mg/mL for DZ of commercial origin and 2.5 mg/mL for the prepared DZN. All groups (except negative control) orally infected then followed up for clinical signs of coccidiosis, mortality rate, oocysts count, performance, hematological and biochemical parameters in addition to histopathological lesions., Results: The therapeutic groups showed that both treated groups (DZ and DZN) revealed similar results including good body weight gain, a low lesion caecal score, a low daily and total oocyst shedding count, and a low mortality rate. Regarding the biochemical parameters, all parameters were affected during infection then restored after the 12th day post infection. However, in the prophylactic groups, showed mild clinical signs and the blood pictures and biochemical parameters were nearly like the control negative without infection., Conclusion: DZN at a quarter dose of standard DZ produced the same outcomes as DZ at 10 mg/mL. Furthermore, DZN does not impair the typical safety of diclazuril in treated chicks., (© 2024. The Author(s).)

Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib., Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed., Findings: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported., Interpretation: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests JW reports research grant support (to their institution) from Bristol Myers Squibb, Janssen Pharmaceutica, Novartis, and Pfizer; and consulting fees or honoraria for lectures and for attending meetings from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre Fabre, Roche, Seattle Genetics, Takeda, and Turning Point. MH declares personal honoraria for lectures and presentations from Boehringer Ingelheim, AstraZeneca, Takeda, Amgen, MSD, and Roche. J-YH reports research grants from Pfizer, Takeda, and ONO; consulting fees or honoraria for lectures and presentations from AstraZeneca, Jassen, Amgen, Oncobix, Daiichi Sankyo, Merck, Norvatis, Abion, Takeda, Pfizer, and Yuhan; participation in data safety monitoring board for AstraZeneca, Jassen; and a leadership role for National Cancer Drug Assessment Committee. NR declares research grants from Artidis, MSD, Amgen, and Roche; honoraria for lectures and presentations from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron; support for attending the meetings from Takeda, Regeneron, and Roche; and participation in a data safety monitoring and advisory board for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron. P-JS reports the research grants received (to their institution) from AstraZeneca, Bristol Myers Squibb, Genentech, and Gilead; and consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Pfizer, and Takeda. EFS reports consulting fees support to their institution from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi, Takeda, and Merck; honoraria for lectures and presentations for self from Boehringer Ingelheim and Daiichi Sankyo; and participation in a data safety monitoring and advisory board for Daiichi Sankyo and Taiho for institution. JV declares consulting fees received from Bristol Myers Squibb, Janssen, and PDCline; honoraria for lectures and presentations from AstraZeneca, Daiichi Sankyo, and Merck; and participation in a data safety monitoring and advisory board for AstraZeneca, Boehringer, and Transgene. MN reports honoraria received for lectures and presentations from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Lilly, AstraZeneca, MSD, AbbVie, Takeda Pfizer, Boehringer, Ingelheim, Novartis, Nippon, Kayaku, Merck, and Janssen; and support for attending meetings from Novartis. WA declares research grants received from Bristol Myers Squibb, AstraZeneca, Bioatla, Imugene, Astride, BridgeBio, AbbVie, and Novocure; and participation in data safety monitoring and advisory board for Lilly. EBG reports research grants received (to their institution) from ABL-Bio, Arrivent, AstraZeneca, Bristol Myers Squibb, Daiichi, Sanko, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Prelude, Regeneron, and Synthekine; consulting fees from AbbVie, Arcus, AstraZeneca, Arrivent, Atreca, BridgeBio, Bristol Myers Squibb, EMD Serono, Eli Lilly, Gilead, GlaxoSmithKline, Hookipa, LianBio, Merckl Merus, Novartis, Nuvalent, Personalis, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, Synthekine, Xilio, and Zymeworks; support for attending meetings from A2 and Novartis; patents issued (to their institution); and other financial support for independent medical education from Daiichi Sankyo and Ipsen. DSWT reports research grants support to their institution from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer, outside of the submitted work; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer, Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda; honoraria for lectures and presentations from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, BeiGene, Regeneron, and Zymeworks; and support for attending meetings from Bayer, Merck, Pfizer, Regeneron, and Zymeworks. TS declares honoraria for lectures from Amgen, AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, GlaxoSmithKline, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, and Towa Pharmaceutical. GMF declares the stocks and shareholder for Roche. AR, MC, SLM, CB, YY, LJ, LF, and AY are employees of Novartis. AB reports stocks and stock options from Novartis and Daiichi Sankyo. RSH declares research grants received to their institution for clinical trials from AbbVie, Agios, Corvus, Daichii Sankyo, Erasca, Lilly, Mirati, Mythic, Novartis, and Turning Point; and consulting fees for self from AbbVie, Astrazeneca, Biohaven, Claim Therapeutics, Daichii Sankyo, EMD Serono, Lilly, Merck, Novartis, Regeneron, and Sanofi. SVO, HJMG, and MJ declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder., Methods: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping., Results: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P  < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 and 1.7 ± 0.5 μg/ml per mg/kg) than those with the TT genotype (1.4 ± 1.1 μg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 μg/ml per mg/kg) than those with the CC genotype (1.3 ± 1.3 μg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P  < 0.001)., Conclusion: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Baloxavir marboxil is an oral, single-dose, cap-dependent endonuclease inhibitor that reduces the duration of influenza symptoms and rapidly stops viral shedding. We developed a susceptible, exposed, infected, recovered (SEIR) model to inform a cost-effectiveness model (CEM) of baloxavir versus oseltamivir or no antiviral treatment in the UK., Research Design and Methods: The SEIR model estimated the attack rates among otherwise healthy and high-risk individuals in seasonal and pandemic settings. The CEM assumed that a proportion of infected patients would receive antiviral treatment. Results were reported at the population level (per 10,000 at risk of infection)., Results: The SEIR model estimated greater reductions in infections with baloxavir. In a seasonal setting, baloxavir provided incremental cost-effectiveness ratios (ICERs) of £1884 per quality-adjusted life-year (QALY) gained versus oseltamivir and a dominant cost-effectiveness position versus no antiviral treatment in the total population; ICERs of £2574/QALY versus oseltamivir and £128/QALY versus no antiviral treatment were seen in the high-risk population. Baloxavir was also cost-effective versus oseltamivir or no antiviral treatment and reduced population-level health system occupancy concerns during a pandemic., Conclusion: Baloxavir treatment resulted in the fewest influenza cases and was cost-effective versus oseltamivir or no antiviral treatment from a UK National Health Service perspective.

Background: Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy., Methods: A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L)., Results: For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration., Conclusions: Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Capmatinib is a selective MET inhibitor with demonstrated efficacy in a phase II study of non-small cell lung cancer (NSCLC) patients harboring METex14 mutations. However, the real-world outcomes of capmatinib are largely unknown. From June 2019, the French Early Access Program (EAP) provided capmatinib to METex14 NSCLC patients who were ineligible for or for whom first-line standard therapies had failed., Methods: IFCT-2104 CAPMATU was a multicenter study that included all METex14 NSCLC patients who received capmatinib as part of the EAP until August 2021. The primary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS) and objective response rate (ORR)., Results: A total of 146 patients were included. The median age was 74.9 years, 56.6 % were never-smokers, and 32.4 % had brain metastases. The median TTF, median PFS and median OS from capmatinib initiation were 5.1 months (95 % CI 4.2-6.0), 4.8 months (95 % CI 4.0-6.0) and 10.4 months (95 % CI 8.3-13.2), respectively. Evaluation of the best response to capmatinib was available for 134 patients and resulted in an ORR of 55.3 % (95 % CI 46.8 %-63.6 %). The median PFS was 7.7 months for treatment-naïve patients and 6.0 and 4.1 months for patients who had received one or 2 + prior lines of treatment, respectively. For patients with brain metastases, the median PFS was 3.0 months. Capmatinib had a known and manageable safety profile, with grade 3 to 4 adverse events, mostly peripheral edema (8.2 %), occurring in 17.8 % of patients., Conclusion: In this large real-world study of METex14 NSCLC patients, the efficacy of capmatinib was confirmed, with a manageable safety profile, even in patients with brain metastases and in those who received several lines of treatment. This study reinforces the key role of capmatinib for these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Ferreira: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, BMS. A. Swalduz: Financial Interests, Personal, Other, honoraria: AstraZeneca, Janssen, Roche, Amgen, BMS; Financial Interests, Personal, Advisory Role: AstraZeneca, Janssen, Roche, Amgen, BMS, Pfizer, Lilly. P. du Rusquec: Financial Interests, Personal, Other, Travel, Accommodations: Roche, Pfizer, Sandoz, Daiichi Sankyo, Merck, Novartis, Lilly, Amgen, Eisai, BMS, Takeda, AstraZeneca, Janssen, Sanofi. Advisory Role: Sanofi, Takeda. A.C. Toffart: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, BMS, Roche, Amgen, Takeda, Jannsen. J. Raimbourg: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS. V. Gounant: Financial Interests, Personal, Advisory Role: BMS, AstraZeneca, Takeda; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Sanofi, Pfizer. S. Couraud: Financial Interests, Personal, Other, honoraria: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Fabentech, Boehringer Ingelheim, Takeda; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, BMS, MSD, Roche, Sanofi, Chugai, Novartis, Pfizer, Sysmex, Cellgene, Takeda, Janssen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, Roche, Takeda. M. Wislez: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD, Amgen, BMS, Roche; Financial Interests, Institutional, Funding, research funding: AstraZeneca; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, MSD, Amgen, BMS, Roche. C. Descarpentries reports personal fees and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Novartis Pharma SAS, nonfinancial support from Roche SAS, nonfinancial support from Boehringer Ingelheim france, nonfinancial support from Pfizer, outside the submitted work; G. Herbreteau reports personal fees and nonfinancial support from Pierre Fabre Oncology. V. Westeel: Financial Interests, Personal, Other, Honoraria: AstraZeneca, BMS, Amgen, Roche; Financial Interests, Personal, Advisory Role: MSD, Takeda; Financial Interests, Personal, Speaker’s Bureau: BMS, AstraZeneca, Roche, MSD, Pfizer, Amgen; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, AstraZeneca, Sanofi. A. B. Cortot: Financial Interests, Personal, Other, Consulting fees: Roche Novartis; Financial Interests, Personal, Other, Honoraria: Novartis Pfizer Takeda Roche; Financial Interests, Personal, Advisory Board: Roche Novartis Pfizer Takeda. All other authors have declared no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pandemic influenza poses a recurring threat to public health. Antiviral drugs are vital in combating influenza pandemics. Baloxavir marboxil (BXM) is a novel agent that provides clinical and public health benefits in influenza treatment., Methods: We constructed a linked dynamic transmission-economic evaluation model combining a modified susceptible-exposed-infected-recovered (SEIR) model and a decision tree model to evaluate the cost-effectiveness of adding BXM to oseltamivir in China's influenza pandemic scenario. The cost-effectiveness was evaluated for the general population from the Chinese healthcare system perspective, although the users of BXM and oseltamivir were influenza-infected persons. The SEIR model simulated the transmission dynamics, dividing the population into four compartments: susceptible, exposed, infected, and recovered, while the decision tree model assessed disease severity and costs. We utilized data from clinical trials and observational studies in the literature to parameterize the models. Costs were based on 2021 CN¥ and not discounted due to a short time-frame of one year in the model. One-way, two-way, and probabilistic sensitivity analyses were also conducted., Results: The integrated model demonstrated that adding BXM to treatment choices reduced the cumulative incidence of infection from 49.49% to 43.26% and increased quality-adjusted life years (QALYs) by 0.00021 per person compared with oseltamivir alone in the base-case scenario. The intervention also amounted to a positive net monetary benefit of CN¥77.85 per person at the willingness to pay of CN¥80,976 per QALY. Sensitivity analysis confirmed the robustness of these findings, with consistent results across varied key parameters and assumptions., Conclusions: Adding BXM to treatment choices instead of only treating with oseltamivir for influenza pandemic control in China appears to be cost-effective compared with oseltamivir alone. The dual-agent strategy not only enhances population health outcomes and conserves resources, but also mitigates influenza transmission and alleviates healthcare burden., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Vorasidenib (VORANIGO ® ; Servier) is an orally administered, first-in-class, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes being developed for use in IDH-mutant diffuse glioma. Vorasidenib received its first approval on 6 August 2024, in the USA, for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery, including biopsy, sub-total resection, or gross total resection. Approval was based on results from the multinational phase III INDIGO trial, in which vorasidenib significantly improved progression-free survival and time to the next anticancer intervention relative to placebo. In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2 H ,4 H )-dione scaffold of our hits I4 and C1 , structure-activity relationship analysis led to the discovery of several more active derivatives (e.g., 19 , 34 , and 36 ) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

Comprehensive genomic profiling is highly recommended for treatment decision in nonsquamous, non-small cell lung cancer (NSCLC). However, rare genomic alterations are still being unveiled, with scarce data to guide therapy. Herein, we describe the treatment journey of a 56-year-old, never-smoker Caucasian woman with a metastatic NSCLC harboring a CD47-MET fusion, initially classified as a variant of unknown significance. She had undergone 3 lines of therapy over the course of 3 years, including chemotherapy, immunotherapy, and anti-angiogenic therapy. After reanalysis of her next-generation sequencing data in our service, the fusion was reclassified as likely oncogenic. The patient was started with fourth-line capmatinib, with a good tolerance so far and a complete metabolic response in the active sites of disease, currently ongoing for 18 months. In conclusion, we highlight the sensitivity of a novel MET fusion to capmatinib and emphasize the need for comprehensive panels in NSCLC and molecular tumor board discussions with specialized centers when rare findings arise., (© The Author(s) 2024. Published by Oxford University Press.)

Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS., Materials and Methods: Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry., Results: From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively., Conclusion: Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC)., Methods: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFR L858R/ex19del ; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFR L858R/ex19del ; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFR L858R/ex19del ; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients., Results: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %)., Conclusion: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable., Clinical Trial Registration: ClinicalTrials.gov NCT02335944., Competing Interests: Declaration of Competing Interest Enriqueta Felip: Consulting or Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Roche, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point Therapeutics, Daiichi Sankyo. Speakers' Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology. Travel, Accommodations, Expenses: AstraZeneca, Janssen, Roche. Other Relationship: Grifols. Uncompensated Relationships: Member of the Scientific Advisory Committee Hospital Universitari Parc Taulí , SEOM (Sociedad Española de Oncología Médica), President from 2021–2023, “ETOP IBCSG Partners” Member of the Scientific Committee. Giulio Metro: Consultants fee from Amgen, Pfizer, Takeda, and AstraZeneca. Ross A. Soo: Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, Yuhan. Research grant: AstraZeneca, Boehringer Ingelheim. Jürgen Wolf: Advisory boards and lecture fees: Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda; Research Support (to institution): BMS, Janssen Pharmaceutica, Novartis, Pfizer. Benjamin J. Solomon: Honoraria: AstraZeneca, Merck Sharp & Dohme (Inst), Roche/Genentech, Pfizer (Inst), Amgen (Inst). Consulting or Advisory Role: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Amgen, Lilly, BeiGene, Takeda, GlaxoSmithKline (Inst), Janssen (Inst), GlaxoSmithKline. Research Funding: Sanofi (Inst). Daniel SW Tan: Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer. Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer, C4 Therapeutics. Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst). Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche. Andrea Ardizzoni: Honoraria: AstraZeneca, BMS, Lilly, MSD Oncology, Abbvie, Roche. Consulting or Advisory Role: AstraZeneca, MSD Oncology, BMS, Lilly, Novartis, Takeda, Janssen Oncology, Roche, Sanofi. Dae Ho Lee: Honoraria: Abbvie; AstraZeneca/MedImmune; BC World Pharm; Boehringer Ingelheim; Bristol-Myers Squibb; ChongKeunDang Healthcare; Lilly; Menarini; MSD; Novartis; Ono Pharmaceutical; Pfizer; Roche/Genentech; Samyang; ST Cube; Takeda; Yuhan. Consulting or Advisory Role: ST Cube. Lecia V. Sequist: Consulting or Advisory Role: AstraZeneca; Genentech/Roche; Takeda. Research Funding: AstraZeneca (Inst); Boehringer Ingelheim (Inst); Delfi Diagnostics (Inst); Novartis (Inst). Fabrice Barlesi: Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst), Boehringer Ingelheim (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Takeda (Inst), Bayer (Inst), Amgen (Inst), Eisai Europe (Inst), Sanofi (Inst), Mirati Therapeutics (Inst). Research Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Roche/Genentech. Santiago Ponce-Aix: No conflicts of interest. Delvys Rodriguez Abreu: Consulting/advisory role from Roche, Bristol-Myers Squibb, AstraZeneca Spain, Novartis; Speaker fees from Roche, Bristol-Myers Squibb, and MSD; Travel expense from Roche, Bristol-Myers Squibb, MSD, and Novartis. Maria Rosario Garcia Campelo: Consulting or Advisory Role: Roche/Genentech, MSD Oncology, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, Janssen Oncology. Speakers' Bureau: Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, MSD Oncology, Sanofi/Aventis, Janssen Oncology, Amgen, Lilly. Travel, Accommodations, Expenses: Roche/Genentech, MSD Oncology, Pfizer. Mette Sprauten: No conflicts of interest. Leslie O’Sullivan Djentuh: Employee of Novartis. Nathalie Smith: Employee of Novartis. Aline Jary: Employee of Novartis. Riccardo Belli: Employee of Novartis. Sabine Glaser: Employee of Novartis and stockholder of Novartis, Alcon, Sandoz. Mike Zou: Employee of Daiichi Sankyo, Inc. Xiaoming Cui: Employee and stockholder - Novartis. Monica Giovannini: Employee of Novartis. James Chih-Hsin Yang: Honoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, Pfizer. Consulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim (Inst), Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, Incyte, Merck Serono (Inst), Janssen (Inst), GlaxoSmithKline (Inst), Amgen (Inst), Takeda (Inst), Daiichi Sankyo (Inst), AstraZeneca (Inst), Novartis (Inst), MSD Oncology (Inst). Travel, Accommodations, Expenses: Pfizer., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Immunocompromised patients may experience prolonged shedding of influenza virus potentially leading to severe infections. Alternatives to monotherapy with neuraminidase inhibitors should be evaluated to entirely suppress viral replication and prevent drug-resistant mutations., Methods: We investigated the clinical and virological evolution in a case of persistent influenza A and human coronavirus OC43 (HCoV-OC43) coinfection in a hematopoietic stem cell transplant recipient after different therapeutic strategies., Results: Successive oseltamivir and zanamivir monotherapies failed to control both infections, with positive results persisting for over 110 days each. This led to the emergence of highly resistant oseltamivir strains due to neuraminidase mutations (E119V and R292K) followed by a deletion (del245-248), while maintaining sensitivity to zanamivir. The intra-host viral diversity data showed that the treatments impacted viral diversity of influenza virus, but not of HCoV-OC43. Considering the patient's underlying condition and the impact of prolonged viral shedding on pulmonary function, eradicating the influenza virus was necessary. A 10-day regimen combining zanamivir and baloxavir-marboxil effectively controlled influenza virus replication and was associated with the clearance of HCoV-OC43, finally resulting in comprehensive respiratory recovery., Conclusion: These observations underscore the importance of further investigating combination treatments as the primary approach to achieve influenza eradication in immunocompromised patients., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The authors have demonstrated that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy., Methods: One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses., Results: No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate., Conclusions: The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy., Competing Interests: Conflicts of Interest and Sources of Funding: K. Mihara has received honoraria from GlaxoSmithKline and Otsuka. A. Nakamura has received honoraria from Dainippon Sumitomo Pharma, Otsuka, and Pfizer. T. Kondo has received honoraria from Eli Lilly, GlaxoSmithKline, and Otsuka. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aims/introduction: To investigate the effect of patient characteristics on imeglimin effectiveness in Japanese patients with type 2 diabetes mellitus., Materials and Methods: Data were pooled from two randomized, placebo-controlled, 24-week, double-blind studies of imeglimin monotherapy in Japanese adults with type 2 diabetes mellitus, with the proportion of responders (glycated hemoglobin [HbA1c] < 7.0%) and sustained responders (i.e., achieved and maintained response) in the imeglimin 1,000 mg twice daily group calculated at each visit. Patient factors significantly (P < 0.05) correlated with response were explored through multivariate logistic regression. Subgroup analyses compared the efficacy of imeglimin in patients with a HbA1c improvement less than or equal to -0.3% (early responders) versus greater than -0.3% (early non-responders) at week 4., Results: A total of 38.0% of imeglimin-treated patients and 7.2% of placebo-treated patients were responders (P < 0.001, number needed to treat = 4). The proportion of sustained responders at weeks 4, 8, 12, 16 and 20 was 10.6, 19.0, 24.0, 25.7 and 29.1%, respectively (>70% of responders at each visit). Improvements in HbA1c and fasting glucose were significantly greater in early responders versus early non-responders from week 4; between-group differences remained significant to week 24. Older age (odds ratio 1.09, 95% confidence interval 1.04-1.14; P < 0.001); treatment-naïve status vs previous treatment (odds ratio 3.70, 95% confidence interval 1.55-8.82; P = 0.003), and lower baseline HbA1c (odds ratio 0.06, 95% confidence interval 0.02-0.16; P < 0.001) predicted response., Conclusions: A significantly higher proportion of patients receiving imeglimin 1,000 mg twice daily monotherapy were responders versus placebo. Most (>70%) were sustained responders, suggesting that response is fairly predictable. Older age, treatment-naïve status and early treatment response significantly predicted imeglimin effectiveness., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly( D, L -lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy., 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.)

Traditionally, the D1228 E/G/H/N mutation has been thought to cause Type I MET-TKI resistance. We reported a 75-year-old female with non-small cell lung cancer harboring MET exon 14 skipping mutation, who developed acquired MET D1228H mutation induced by capmatinib treatment. Interestingly, the patient demonstrated marked response to second-line savolitinib treatment with the duration of response of 19 months and several additional metastatic lesions appeared. Pathological assessment of rebiopsy sample showed adenocarcinoma and targeted next-generation sequencing revealed the loss of MET D1228H mutation and presence of MET p.Y1230N mutation. In response, the treatment regimen was amended to include a daily administration of 60 mg of cabozantinib, which resulted in moderate size reduction of the tumours. The switch of resistance mutations indicated that different type Ib MET inhibitors may exhibit distinct mechanisms of resistance. We call for futher studies on resistance based on patient-derived pre-clinical models including patient-derived tumor-like cell clusters, patient-derived organoids, and patient-derived xenografts., (© 2024. The Author(s).)

Background: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care., Methods: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints., Results: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib., Conclusions: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AK reports study support from Novartis. MS reports an advisory role/speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, Siemens Healthineers, Takeda. MS has also received research support for his institution from Amgen, Dracen Pharmaceuticals, Janssen, Novartis; and travel support from AstraZeneca, Boehringer Ingelheim, Janssen, Pfizer. MW reports institutional support from Takeda; consulting fees from Daiichi Sankyo, GlaxoSmithKline, Amgen, AstraZeneca, Janssen, Novartis, Pfizer, Roche; personal honoraria from Takeda, Roche, Amgen, and AstraZeneca; travel grant support from Amgen, and Janssen. MW also participated on data safety monitoring board for Boehringer Ingelheim. HDH reports advisory role/ personal honoraria from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb; institutional financial support as local principal investigator from Amgen, AstraZeneca, AvenCell Europe GmbH, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Dracen, Merck, Novartis, Revolution Medicines; support as steering committee member and coordinating principal investigator from Amgen. JK reports advisory support on behalf of institution from Lilly Deutschland, Merck Sharp & Dohme, Amgen, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Roche Pharma AG, Merck Serono GmbH and Janssen-Cilag GmbH. TG reports study support from Novartis; and participation on data safety monitoring board for Bristol-Myers Squibb. SK received personal honoraria from Boehringer Ingelheim and GlaxoSmithKline; and also received grants from Deutsche Forschungsgesellschaft. SMB reports grants or contracts from Roche and Quality Initiative Pathology; and received consulting fees and personal honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Discovery Life Science, Janssen, Menarini, Merck, Novartis and Quality Initiative Pathology. AT received grants from AstraZeneca and Lilly; consulting fees from Amgen, AstraZeneca, Pierre Fabre, Sanofi, Daiichi, Merck Sharp & Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Takeda, Novartis; honoraria for lectures from Amgen, AstraZeneca, Pierre Fabre, Sanofi, Daiichi, Merck Sharp & Dohme, Roche, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Takeda, Novartis; support for attending meetings/travel from Sanofi, AstraZeneca and Pfizer; leadership role in AIO and ERS. AT also participated on the data safety monitoring board study ROSE study (AIO-YMO/TRK-0120 / ROSE). DKG received consulting fees from Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Janssen, Bristol-Myers Squibb, Sanofi and Roche; and received support for meeting and/or travel from Takeda and Boehringer Ingelheim. KO, MZ and UJ are employees of Novartis. JW received personal honoraria/consulting fees, support for meetings and/or travel from and participated on data safety monitoring board from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda, Turning Point; and received research support for institution from Bristol-Myers Squibb, Janssen Pharmaceutica, Novartis, Pfizer. JK, SG, CS, MCD, MJ, CW have no conflicts of interest to disclose outside of the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: ZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD)., Aim: The aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure-response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials., Methods: Analysis of pooled concentration-time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored., Results: A two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601's pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure-response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUC ss ) on the 29th day. ZSP1601 exposure levels (C max1 ) exhibited a significant exposure-response relationship with headaches (p < 0.001)., Conclusion: The PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601's pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations., Competing Interests: Conflict of interest Jufang Huang and Yue Hu declare no conflict of interest. Kun Wang, Yuting Yang, Fengyan Xu and Zhongyi Sun have received research funding and served in consultant role to Raynovent. Haijun Li and Xiaoxin Chen were the full time employee in Raynovent., (Copyright © 2024. Published by Elsevier B.V.)

We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC (0-∞) and C max of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib., (© 2024, The American College of Clinical Pharmacology.)

Objective: To provide up-to-date clinical guidance on the efficacy of lamotrigine in bipolar disorder (BD)., Methods: Eligible studies were identified during a systematic literature search according to PRISMA-guidelines. We included randomized controlled trials (RCTs) and cohort studies that quantitatively assessed lamotrigine's efficacy in BD. We divided the included studies into three groups: 1. acute treatment of depression, 2. acute treatment of mania and hypomania, and 3. maintenance treatment. Analyses were stratified by control group (placebo vs active comparator) and treatment strategy (monotherapy vs add-on treatment)., Results: We included 20 RCTs (n = 1166 lamotrigine users) and 20 cohort studies (n = 11,141 lamotrigine users). Twenty-four of these studies were included in meta-analyses. During depressive episodes, greater decreases in depressive symptomatology were associated with initiation of lamotrigine as add-on treatment than with placebo (SMD -0.30 [95% CI = -0.51, -0.10], df = 3, p = 0.004). Decreases in depressive symptomatology did not differ significantly between lamotrigine and the active comparator (SMD -0.28 [95% CI = -1.06, 0.50], df = 3, p = 0.488). As a maintenance treatment, lamotrigine was associated with a significantly lower relapse/recurrence rate than placebo (risk ratio (RR) 0.84 [95% CI = 0.71, 0.99], df = 2, p = 0.037). Relapse/recurrence rates did not differ significantly between lamotrigine and lithium (RR 1.06 [95% CI = 0.89, 1.25], df = 2, p = 0.513). A qualitative assessment of high-quality register-based studies found that lamotrigine was associated with lower hospital admission rates than other commonly used treatment regimes., Conclusions: There is substantial evidence for the efficacy of lamotrigine in BD, specifically as add-on treatment during acute depressive episodes and as maintenance treatment for preventing relapse and recurrence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization., Competing Interests: Declaration of competing interest W.Z., K.L., M.W., L.L. and Z.H. filed a patent for baloxavir sodium in treatment of CCHF to China Intellectual Property Office. Remaining authors declare no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Through a Rapid Health Technology Assessment (RHTA), we evaluated the efficacy, safety and cost-effectiveness of baloxavir in the treatment of influenza, providing the necessary scientific information and evidence-based basis for healthcare professionals and health insurance decision-makers in making rational selections. Through systematic searches of Pubmed , Embase , Web of Science , The Cochrane Register of Clinical Trials database and the official website of Health Technology Assessment (HTA) agencies, we collected systematic reviews (SR)/Meta-analysis, cost-effectiveness evaluations and HTA reports of baloxavir for influenza, with a search time frame of date of database establishment to July 31, 2022. We then performed data extraction, literature screening and quality evaluation on the literature that met our selection criteria, after which the results of the studies were pooled and qualitatively described for analysis. 10 studies were included, including 6 SR/Meta-analysis, three economics studies, and 1 HTA report. In terms of efficacy, baloxavir had an advantage over oseltamivir for all three types of influenza patients (otherwise healthy patients, high-risk patients, and patients are not separated into groups with and without underlying health conditions) concerning change in virus titer from baseline at 24 and 48 h; about otherwise healthy patients and high-risk patients, baloxavir had an advantage over peramivir; pertaining to high-risk patients, baloxavir had an advantage over laninamivir; the above differences between groups were all statistically significant. In terms of safety, in otherwise healthy patients and patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of DRAEs and nausea compared with oseltamivir, as well as significantly reduced the incidence of DRAEs compared with laninamivir; in patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of AEs and diarrhoea compared with oseltamivir; the differences between the above groups were all statistically significant. Economically, in Japanese adult influenza patients and high-risk populations, the Quality-Adjusted Life Years (QALY) of baloxavir slightly triumphed over that of laninamivir (Δ = 0.000112 and 0.00209 QALY per 1 patient, respectively); moreover, the incremental cost-effectiveness ratio (ICER: 2,231,260 and 68,855 yen/QALY, respectively) was below the willingness-to-pay (WTP) threshold (5,000,000 yen/QALY); in Chinese adult influenza patients without underlying diseases and adult high-risk influenza patients, baloxavir had a higher QALY compared with oseltamivir (Δ = 0.000246 and 0.000186 respectively), however, their ICER (12,230 and 64,956 RMB/QALY) was above the local WTP threshold (10,000 RMB/QALY) and thus did not provide a cost-effectiveness advantage. Baloxavir had a favorable efficacy and safety profile compared to neuraminidase inhibitors (NAIs), and the currently available evidence suggested that it had an economic advantage only in Japan.

Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has lasted for three years. Coinfection with seasonal influenza may occur resulting in more severe diseases. The interaction between these two viruses for infection and the effect of antiviral treatment remains unclear., Methods: A SARS-CoV-2 and influenza H1N1 coinfection model on Calu-3 cell line was established, upon which the simultaneous and sequential coinfection was evaluated by comparing the viral load. The efficacy of molnupiravir and baloxavir against individual virus and coinfection were also studied., Results: The replication of SARS-CoV-2 was significantly interfered when the influenza virus was infected simultaneously or in advance (p < 0.05). On the contrary, the replication of the influenza virus was not affected by the SARS-CoV-2. Molnupiravir monotherapy had significant inhibitory effect on SARS-CoV-2 when the concentration reached to 6.25 μM but did not show any significant anti-influenza activity. Baloxavir was effective against influenza within the dosage range and showed significant effect of anti-SARS-CoV-2 at 16 μM. In the treatment of coinfection, molnupiravir had significant effect for SARS-CoV-2 from 6.25 μM to 100 μM and inhibited H1N1 at 100 μM (p < 0.05). The tested dosage range of baloxavir can inhibit H1N1 significantly (p < 0.05), while at the highest concentration of baloxavir did not further inhibit SARS-CoV-2, and the replication of SARS-CoV-2 significantly increased in lower concentrations. Combination treatment can effectively inhibit influenza H1N1 and SARS-CoV-2 replication during coinfection. Compared with molnupiravir or baloxavir monotherapy, combination therapy was more effective in less dosage to inhibit the replication of both viruses., Conclusions: In coinfection, the replication of SARS-CoV-2 would be interfered by influenza H1N1. Compared with molnupiravir or baloxavir monotherapy, treatment with a combination of molnupiravir and baloxavir should be considered for early treatment in patients with SARS-CoV-2 and influenza coinfection., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging., Competing Interests: Conflict of interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)