Cts-Clinical and Translational Science最新文献

{"title":"A phase I randomized study to evaluate safety, pharmacokinetics, and pharmacodynamics of SIR2446M, a selective RIPK1 inhibitor, in healthy participants","authors":"Ana Liza Andresan Sun,&nbsp;John David Gillies,&nbsp;Yang Shen,&nbsp;Huajun Deng,&nbsp;Fenchao Xue,&nbsp;Yongfen Ma,&nbsp;Linan Song","doi":"10.1111/cts.13857","DOIUrl":"10.1111/cts.13857","url":null,"abstract":"<p>Activation of receptor-interacting protein kinase 1 (RIPK1), a broadly expressed serine/threonine protein kinase, by pro-inflammatory cytokines and pathogens can result in apoptosis, necroptosis, or inflammation. RIPK1 inhibition has been shown to reduce inflammation and cell damage in preclinical studies and may have therapeutic potential for degenerative and inflammatory diseases. SIR2446 is a potent and selective novel small molecule RIPK1 kinase inhibitor. This phase I, randomized, double-blind, placebo-controlled study in Australia (ACTRN12621001621808) evaluated the safety (primary objective), pharmacokinetics, and pharmacodynamics of single (3–600 mg) and multiple (5–400 mg for 10 days) ascending oral doses of SIR2446M (SIR2446 magnesium salt form) in healthy adults from Nov 24, 2021, until May 01, 2023. All treatment-emergent adverse events (TEAEs) were mild/moderate. The most reported TEAEs were vascular access site pain, headache, and rash morbilliform. SIR2446M plasma half-lives ranged from 11 to 19 h and there were no major deviations from dose proportionality for maximum concentration and area under the curve across doses. Renal excretion of unchanged SIR2446 was minimal. No marked accumulation was observed (mean accumulation ratio, 1.2–1.6) after multiple daily doses. A high-fat meal mildly reduced the exposure but was not considered clinically significant. SIR2446M had a rapid and sustained inhibitory effect on the activity of RIPK1, with an overall 90% target engagement at repeated doses ranging from 30 to 400 mg in peripheral blood mononuclear cells ex vivo stimulated to undergo necroptosis. The favorable safety, pharmacokinetic, and pharmacodynamic profile of SIR2446M in healthy participants supports its further clinical development in patients with degenerative and inflammatory diseases.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13857","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related off-label drug prescribing in pediatric patients in South Korea and consistency of labeling compared to the United States, Europe, and Japan","authors":"Bojung Park,&nbsp;Hyesung Lee,&nbsp;Hyeyoung Choi,&nbsp;Jaehyun Lee","doi":"10.1111/cts.13869","DOIUrl":"10.1111/cts.13869","url":null,"abstract":"<p>Insufficient labeling information regarding the appropriate age for prescribing drugs to the pediatric population is challenging. This study aimed to analyze the off-label prescription of age-related drugs for pediatric patients using claims data from South Korea and to assess the consistency of the approved age in South Korea, the United States, Europe, and Japan. In 2020, 1004 unique drugs were prescribed to the pediatric population in South Korea. We found that 641 drugs (63.8%, <i>p</i> &lt; 0.0001) were related to off-label prescriptions for age-related use at least once, and the total number of off-label prescriptions was 2,236,669 (62.2%, <i>p</i> &lt; 0.0001). Chlorpheniramine (28%) was the most frequently prescribed drug for pediatric patients with an age-related off-label, followed by budesonide (9%) and epinephrine (9%). The degree of agreement in the approved age range for 641 off-label drugs across countries was assessed using the overall kappa coefficient. We observed slight agreement in labeling across all countries (κ: 0.16, 95% confidence interval [CI]: 0.14–0.18). The highest degree of agreement was observed between the United States and Europe (0.41, 0.37–0.45) due to pediatric-population-specific legislation. South Korea showed the lowest degree of agreement with the United States and Europe (0.10, 0.06–0.14). The United States, Europe, and Japan showed fair agreement (0.23, 0.21–0.26). However, the degree of agreement between South Korea, the United States, and Japan (0.09, 0.06–0.11) and South Korea, Europe, and Japan (0.08, 0.05–0.10) was low. This study highlights the need for South Korean regulatory agencies to consider introducing pediatric legislation to prescribe evidence-based drugs for safe and effective use.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13869","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using electronic health records for clinical pharmacology research: Challenges and considerations","authors":"Eissa Jafari,&nbsp;Marisa H. Blackman,&nbsp;Jason H. Karnes,&nbsp;Sara L. Van Driest,&nbsp;Dana C. Crawford,&nbsp;Leena Choi,&nbsp;Caitrin W. McDonough","doi":"10.1111/cts.13871","DOIUrl":"10.1111/cts.13871","url":null,"abstract":"<p>Electronic health records (EHRs) contain a vast array of phenotypic data on large numbers of individuals, often collected over decades. Due to the wealth of information, EHR data have emerged as a powerful resource to make first discoveries and identify disparities in our healthcare system. While the number of EHR-based studies has exploded in recent years, most of these studies are directed at associations with disease rather than pharmacotherapeutic outcomes, such as drug response or adverse drug reactions. This is largely due to challenges specific to deriving drug-related phenotypes from the EHR. There is great potential for EHR-based discovery in clinical pharmacology research, and there is a critical need to address specific challenges related to accurate and reproducible derivation of drug-related phenotypes from the EHR. This review provides a detailed evaluation of challenges and considerations for deriving drug-related data from EHRs. We provide an examination of EHR-based computable phenotypes and discuss cutting-edge approaches to map medication information for clinical pharmacology research, including medication-based computable phenotypes and natural language processing. We also discuss additional considerations such as data structure, heterogeneity and missing data, rare phenotypes, and diversity within the EHR. By further understanding the complexities associated with conducting clinical pharmacology research using EHR-based data, investigators will be better equipped to design thoughtful studies with more reproducible results. Progress in utilizing EHRs for clinical pharmacology research should lead to significant advances in our ability to understand differential drug response and predict adverse drug reactions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1-associated cognitive and motor impairment","authors":"Vicki J. Swier,&nbsp;Katherine A. White,&nbsp;Pedro L. Negrão de Assis,&nbsp;Tyler B. Johnson,&nbsp;Hannah G. Leppert,&nbsp;Mitchell J. Rechtzigel,&nbsp;David K. Meyerholz,&nbsp;Rebecca D. Dodd,&nbsp;Dawn E. Quelle,&nbsp;Rajesh Khanna,&nbsp;Christopher S. Rogers,&nbsp;Jill M. Weimer","doi":"10.1111/cts.13858","DOIUrl":"10.1111/cts.13858","url":null,"abstract":"<p>Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor-predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various <i>Nf1</i> mouse models, here we employ an <i>NF1</i>^{<i>+/ex42del</i>} miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from <i>NF1</i>^{<i>+/ex42del</i>} and wild-type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, <i>NF1</i>^{<i>+/ex42del</i>} miniswine demonstrated slower and shorter steps, indicative of a balance-preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of <i>NF1</i>^{<i>+/ex42del</i>} miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision medicine in Asia enhanced by next-generation sequencing: Implications for Thailand through a scoping review and interview study","authors":"Chumut Phanthunane,&nbsp;Sutatip Pongcharoen,&nbsp;Supasit Pannarunothai,&nbsp;Jureepon Roboon,&nbsp;Pudtan Phanthunane,&nbsp;Jiraluck Nontarak","doi":"10.1111/cts.13868","DOIUrl":"10.1111/cts.13868","url":null,"abstract":"<p>Next-generation sequencing (NGS) significantly enhances precision medicine (PM) by offering personalized approaches to diagnosis, treatment, and prevention of unmet medical needs. Little is known about the current situation of PM in Asia. Thus, we aimed to conduct an overview of the progress and gaps in PM in Asia and enrich it with in-depth insight into the possibilities of future PM in Thailand. This scoping review focused on Asian countries starting with non-cancer studies, including rare and undiagnosed diseases (RUDs), non-communicable diseases (NCDs), infectious diseases (IDs), and pharmacogenomics, with a focus on NGS. Subsequent in-depth interviews with experts in Thailand were performed, and a thematic analysis served as the main qualitative methodology. Out of 2898 searched articles, 387 studies were included after the review. Although most of the studies focused on cancer, 89 (23.0%) studies were related to RUDs (17.1%), NCDs (2.8%), IDs (1.8%), and pharmacogenomics (1.3%). Apart from medicine and related sciences, the studies were mostly composed of PM (61.8%), followed by genetics medicine and bioinformatics. Interestingly, 28% of articles were conducted exclusively within the fields of medicine and related sciences, emphasizing interdisciplinary integration. The experts emphasized the need for sustainability-driven political will, nurturing collaboration, reinforcing computational infrastructure, and expanding the bioinformatic workforce. In Asia, developments of NGS have made remarkable progress in PM. Thailand has extended PM beyond cancer and focused on clinical implementation. We summarized the PM challenges, including equity and efficiency targeting, guided research funding, sufficient sample size, integrated collaboration, computational infrastructure, and sufficient trained human resources.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11197108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenomic studies of fertility outcomes in pediatric cancer survivors – A systematic review","authors":"Tayla Stenta,&nbsp;Michael Assis,&nbsp;Katie Ayers,&nbsp;Elena J. Tucker,&nbsp;Andreas Halman,&nbsp;Debra Gook,&nbsp;Andrew H. Sinclair,&nbsp;David A. Elliott,&nbsp;Yasmin Jayasinghe,&nbsp;Rachel Conyers","doi":"10.1111/cts.13827","DOIUrl":"10.1111/cts.13827","url":null,"abstract":"<p>For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11199333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune responsiveness in stable kidney transplantation patients: Complete inhibition of T-cell proliferation but residual T-cell activity during maintenance immunosuppressive treatment","authors":"Aliede E. in ’t Veld,&nbsp;Boukje C. Eveleens Maarse,&nbsp;Maria J. Juachon,&nbsp;Soufian Meziyerh,&nbsp;Aiko P. J. de Vries,&nbsp;Aline L. van Rijn,&nbsp;Mariet C. W. Feltkamp,&nbsp;Dirk Jan A. R. Moes,&nbsp;Jacobus Burggraaf,&nbsp;Matthijs Moerland","doi":"10.1111/cts.13860","DOIUrl":"10.1111/cts.13860","url":null,"abstract":"<p>The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low-dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations. We selected a panel of T-cell-based immune assays, which were used for immunomonitoring of 14 stable kidney transplantation patients. Whole blood was incubated with a T-cell stimulus, after which T-cell proliferation, T-cell activation marker expression and cytokine production were measured to study residual immune activity in vitro (before drug intake; drug added to the incubation) and ex vivo (after drug intake). T-cell proliferation was completely suppressed in all patients over the full day, while IL-2, IFN-γ, CD71, and CD154 showed fluctuations over the day with a strong inhibition (75%–25%) at 2 h post-dose. The level of inhibition was variable between patients and could not be related to pharmacokinetic parameters or the presence of regulatory or senescence immune cells. Moreover, the level of inhibition did not correlate with the in vitro tacrolimus drug effect as studied by incubating pre-dose blood samples with additional tacrolimus. Overall, IL-2, IFN-γ, CD71, and CD154 seem to be good markers to monitor residual immune activity of transplantation patients. To evaluate the correlation between these pharmacodynamic biomarkers and clinical outcome, prospective observational studies are needed.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11197031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moving the needle for oncology dose optimization: A call for action","authors":"Karthik Venkatakrishnan,&nbsp;Priya Jayachandran,&nbsp;Shirley K. Seo,&nbsp;Piet H. van der Graaf,&nbsp;John A. Wagner,&nbsp;Neeraj Gupta","doi":"10.1111/cts.13859","DOIUrl":"10.1111/cts.13859","url":null,"abstract":"<p>Project Optimus is a major FDA initiative aimed at ensuring dose optimization in oncology drug development, moving away from the maximum tolerated dose paradigm and prospectively characterizing dose–response for efficacy and safety for patient-focused maximization of benefit vs. risk.<span>^1-3</span> Mitigating toxicities and enhancing the overall benefit vs. risk of oncology therapies necessitates dose optimization with a commitment to evaluation of innovative dosing paradigms including individualized approaches, where appropriate. This requires the quantitative integration of pharmacological mechanisms of action, efficacy, and safety in the context of associated population variability. The problem of dose optimization in the context of the mechanism of action, cancer pathophysiology, and associated population variability sits neatly at the intersection of translational/ precision medicine and quantitative clinical pharmacology and is important to approach with a patient-focused mindset.</p><p>Forums convened on the topic of oncology dose optimization largely engage scientific leaders primarily working on oncology research and development, and cancer medicine. These include workshops organized by Friends of Cancer Research (FOCR),<span>⁴</span> American Society of Clinical Oncology (ASCO),<span>^{5, 6}</span> American Association for Cancer Research (AACR),<span>^{7, 8}</span> and the International Society of Pharmacometrics (ISoP)<span>⁹</span> in partnership with the US Food and Drugs Administration (FDA). Of note, some of these efforts have yielded seminal publications<span>^{1, 2, 10-13}</span> and White Papers<span>¹⁴</span> offering initial recommendations, including the availability of a Draft FDA guidance on the topic.<span>¹⁵</span> We posited that the American Society for Clinical Pharmacology and Therapeutics (ASCPT)—as a premier scientific and professional organization for clinical pharmacology and translational medicine—is optimally positioned to host a discussion of opportunities for our constituent disciplines (e.g., translational science, clinical pharmacology, pharmacometrics) to synergistically address this problem with a multi-disciplinary approach. To this end, a session was convened at the 2023 ASCPT Annual Meeting bringing together representative scientific leaders from the three scientific journals of the Society—<i>Clinical Pharmacology and Therapeutics (CPT)</i>, <i>Clinical and Translational Science (CTS)</i>, and <i>CPT: Pharmacometrics and Systems Pharmacology (PSP)</i>. These scientific leaders, as at-large representatives of the disciplines of clinical pharmacology and translational medicine were invited to bring forward their opinions and participate in a fireside chat to identify opportunities for moving the oncology dose optimization needle. This enabled the engagement of a broad group of experts without requiring primary scientific","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A first-in-human, single and multiple dose study of lunsekimig, a novel anti-TSLP/anti-IL-13 NANOBODY® compound, in healthy volunteers","authors":"Annemie Deiteren,&nbsp;Lieselot Bontinck,&nbsp;Griet Conickx,&nbsp;Marie Vigan,&nbsp;Nele Dervaux,&nbsp;Matthieu Gassiot,&nbsp;Selcuk Bas,&nbsp;Benjamin Suratt,&nbsp;Heribert Staudinger,&nbsp;Emmanuel Krupka","doi":"10.1111/cts.13864","DOIUrl":"10.1111/cts.13864","url":null,"abstract":"<p>Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, two key mediators of asthma pathophysiology. In this first-in-human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10–400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment-emergent adverse events were COVID-19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose-proportional increases in exposure and linear elimination. Mean <i>t</i>_1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL-13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study","authors":"Joaquina C. Baranda,&nbsp;Debbie Robbrecht,&nbsp;Ryan Sullivan,&nbsp;Bernard Doger,&nbsp;Armando Santoro,&nbsp;Minal Barve,&nbsp;Jean-Jacques Grob,&nbsp;Oliver Bechter,&nbsp;Maria Vieito,&nbsp;Maria Jose de Miguel,&nbsp;Dirk Schadendorf,&nbsp;Melissa Johnson,&nbsp;Clemence Pouzin,&nbsp;Cathy Cantalloube,&nbsp;Rui Wang,&nbsp;Jooyun Lee,&nbsp;Xiaofei Chen,&nbsp;Brigitte Demers,&nbsp;Amele Amrate,&nbsp;Giovanni Abbadessa,&nbsp;F. Stephen Hodi","doi":"10.1111/cts.13854","DOIUrl":"10.1111/cts.13854","url":null,"abstract":"<p>SAR439459 (SAR'459), a “second-generation” human anti-transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13854","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}