Clinical Pharmacology & Therapeutics最新文献

{"title":"Use of FDA Expedited Programs and Development Timelines for New Molecular Entity Drug and New Biologic Approvals by Sponsor Experience.","authors":"Kanhai S Amin, Bhav Jain, Alissa Wong, Joseph S Ross","doi":"10.1002/cpt.70064","DOIUrl":"https://doi.org/10.1002/cpt.70064","url":null,"abstract":"<p><p>Industry reports indicate that small biopharmaceutical companies are increasingly launching their own new molecular entities, with first-time companies expected to represent the primary share of blockbuster product launches within the decade. However, company experience may affect the use of Food and Drug Administration (FDA) expedited programs, clinical development times, and FDA review times for new molecular entities and new biologics. Hence, we conducted a cross-sectional study examining all new molecular entity (NME) drug and new biologic approvals by the FDA from 2015 through 2022. Sponsors were categorized as first-time when the product represented their inaugural approval or followed their first approval by no more than 12 months. We extracted data on expedited program use (accelerated approval, breakthrough therapy, fast track, and priority review), first-cycle approval status, Prescription Drug User Fee Act (PDUFA) deadline achievement status, development and regulatory review timelines, and patent counts from public FDA data. From 2015 through 2022, 355 NMEs and new biologics were approved: 131 (36.9%) by first-time companies and 224 (63.1%) by experienced companies. The proportion of approvals attributed to first-time companies increased significantly over time (27.3% in 2015-2016 vs. 43.7% in 2021-2022; P = 0.04). Despite their lack of prior regulatory experience, there were no statistically significant differences in expedited program use, first-cycle approval rates, PDUFA deadline achievement rates, clinical development times, or patent counts between first-time and experienced companies. These findings suggest that first-time pharmaceutical companies appear to successfully navigate FDA regulatory processes as effectively as experienced firms.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GenoStaR: An R Package for Genotype to Star Allele Conversion for Major Cytochrome P450 Family of Genes.","authors":"Alex J Coulter, Megana Thamilselvan, James L Kennedy, Clement C Zai, Arun K Tiwari","doi":"10.1002/cpt.70059","DOIUrl":"https://doi.org/10.1002/cpt.70059","url":null,"abstract":"<p><p>Pharmacogenomics enables the personalization of drug therapy by linking genetic variations to differences in drug metabolism, efficacy, and risk of adverse reactions. Genetic polymorphisms within cytochrome P450 (CYP) genes significantly affect enzyme activity, influencing drug plasma levels, responses, and safety. Central to this process is accurate genotype-to-phenotype translation, especially for the CYP enzyme family, which metabolizes 70-80% of clinically used drugs. To address this, we have developed GenoStaR, an R package that converts genotypes into star alleles and predicts the associated metabolizer status for major cytochrome P450 genes-CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5. GenoStaR assigns star alleles using single-nucleotide polymorphisms, insertion-deletion variants, and structural variants. Given genotype data, GenoStaR uses comprehensive allele definition tables to determine diplotypes, activity scores, and predicted metabolizer status. The tool accounts for complex scenarios, including CYP2D6 copy number variations, using a tiered matching strategy and structural variant detection. We evaluated GenoStaR using two datasets. The first from the Centre for Addiction and Mental Health Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT) study (n = 8,287), which included genotyping data, along with star allele information from a commercial pharmacogenetic test. The second, the Toronto Schizophrenia sample (n = 188), with in-house genotype data and manually validated star alleles. GenoStaR achieved 100% concordance in diplotype calls across both datasets. GenoStaR offers a reliable, efficient, and accurate solution for converting genotypes into star alleles and predicting CYP-related metabolizer status. Its performance on a large validation dataset highlights its potential to enhance pharmacogenomic testing in clinical settings.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Misuse of the Term Biorhythms Undermines Chronobiological Research.","authors":"Yvan Touitou","doi":"10.1002/cpt.70057","DOIUrl":"https://doi.org/10.1002/cpt.70057","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Novel Genetic Determinants of Thiopurine Response Via TWAS.","authors":"Carlotta Bidoli, Wenjian Yang, Seth E Karol, Marianna Lucafò, Gabriele Stocco, Jun J Yang","doi":"10.1002/cpt.70053","DOIUrl":"https://doi.org/10.1002/cpt.70053","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Thiopurines such as 6-mercaptopurine (6MP) are essential in ALL maintenance therapy. However, dose-limiting toxicities can significantly disrupt treatment. While genetic variants in TPMT and NUDT15 are known to affect thiopurine response, many patients with normal function genotypes in these genes still experience adverse effects, suggesting that additional genes might be involved. We analyzed 663 pediatric ALL patients enrolled in the AALL03N1 trial to identify novel genetic determinants of 6MP sensitivity, focusing on individuals with normal function TPMT and NUDT15 genotypes. A transcriptome-wide association study (TWAS) was conducted to focus on expression quantitative trait loci (eQTLs). Findings were validated in two independent cohorts: St. Jude Total Therapy XV (n = 390) and XVI (n = 552). TWAS identified 31 genes associated with 6MP dose intensity (q-value < 0.90). Of these, the imputed GNAQ expression was positively correlated with 6MP dose intensity and passed multiple testing thresholds in the validation cohorts. The rs60561071 variant, the eQTL in the GNAQ TWAS model, was associated with reduced gene expression and lower 6MP dose intensity. This study identifies GNAQ as a novel gene associated with thiopurine tolerance in ALL patients lacking known risk alleles in TPMT and NUDT15. Moreover, this research highlighted the innovative use of TWAS, providing deeper insights into the molecular mechanisms that explain drug response variability.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to \"Misuse of the Term Biorhythms Undermines Chronological Research\".","authors":"William J Jusko","doi":"10.1002/cpt.70055","DOIUrl":"https://doi.org/10.1002/cpt.70055","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recruiting and Consenting Decentralized Clinical Trial Participants-Learnings from the Trials@Home RADIAL Proof-of-Concept Trial.","authors":"Bart Lagerwaard, Linda Rutgrink, Danny van Weelij, Katarzyna Lipinska, Tina Bornemann, Robert Davey, Jaime Fons-Martinez, Sabine Dupont, Diederick E Grobbee, Mira G P Zuidgeest","doi":"10.1002/cpt.70042","DOIUrl":"https://doi.org/10.1002/cpt.70042","url":null,"abstract":"<p><p>Clinical trials often face recruitment challenges. From the participant's perspective, barriers such as time commitment, travel to sites, and logistical burden, like arranging care duties or time off work, can deter enrolment. Decentralized clinical trials (DCTs) aim to address these by shifting activities closer to participants' homes and using online methods for recruitment and consent. This study explores recruitment strategies and remote eConsent implementation in a decentralized setting. The RADIAL trial, a three-arm, open-label, phase IV study in six European countries, enrolled participants with type 2 diabetes mellitus administering Insulin Glargine 300 U/ml. Recruitment strategies included online campaigns, search engine advertising, social media, and research database outreach. The remote consent process involved eConsent, telemedicine consultations, eIdentification, and eSignatures. Online recruitment campaigns generated a lot of impressions but led to very few pre-screener completions or enrolments. In contrast, outreach through research databases proved more effective, accounting for 7 of the 8 enrolled participants in the decentralized arm. Major pre-screening drop-off occurred at the initial consent step, with 69% exiting before data collection. Eleven participants successfully completed eConsent; 4 others required remote paper-based consent due to eIdentification issues. Implementing the multimedia-enhanced eConsent system was resource-intensive, complicated by country-specific layouts and differing regulatory requirements. Tailored recruitment strategies and simplified remote consent processes are needed to enhance the accessibility and efficiency of DCTs. Further research should optimize targeting and keyword use in online recruitment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to \"Revisiting Tirzepatide's Body Composition Model: Underestimated Fat-Free Mass Loss and Clinical Implications\".","authors":"Emmanuel Chigutsa, Lucy Her, Xiaosu Ma, Shweta Urva, Karen Schneck","doi":"10.1002/cpt.70056","DOIUrl":"https://doi.org/10.1002/cpt.70056","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Pharmacokinetics, and Pharmacodynamics of Osivelotor for Sickle Cell Disease: First-in-Human Studies in Healthy Participants and Patients.","authors":"Eleanor A Lisbon, R Clark Brown, Andrew Redfern, Ken Duchin, Aline Barth, Erika S Roberts, Polo Gaputan, Kobina Dufu, Arthur Lo, Mira Patel Pochron, David R Archer, Wai Chin, Karena Kong, Carla B Washington, Adeyemi Adenola, Eric I Zimmerman","doi":"10.1002/cpt.70028","DOIUrl":"https://doi.org/10.1002/cpt.70028","url":null,"abstract":"<p><p>The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb-oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single-ascending doses (50-3,000 mg) or multiple-ascending doses (loading doses, then 15-100 mg once-daily maintenance doses through 14 days). A population PK-based adaptive design was used to inform loading- and maintenance-dose regimens from emerging data. Osivelotor was generally well tolerated, demonstrated dose-dependent PK exposure increase, and had a terminal elimination half-life of 19.9 to 30.7 days, with high partitioning into the red blood cell (RBC) compartment in healthy participants. In participants with SCD (N = 6), osivelotor treatment for up to 6 weeks was generally well tolerated; no participants discontinued due to treatment-emergent adverse events. Disease-dependent PK was observed in participants with SCD; notably, the terminal elimination half-life was shorter (~10 days) than in healthy participants. The percentage of Hb bound by osivelotor (%Hb occupancy) increased in a dose-dependent fashion, and improvements in Hb concentration and markers of hemolysis appeared related to osivelotor concentration. Furthermore, Hb-oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once-daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bringing Trial Activities to Participants-The Trials@Home RADIAL Proof-of-Concept Trial Investigating Decentralization of Trials.","authors":"Mira G P Zuidgeest, Megan Heath, Bart Lagerwaard, Danny R van Weelij, Linda Rutgrink, Sten Hanke, Tea Vedenkannas, Taru Kosonen, Stefania Collamati, Jaime Fons-Martínez, Duco Veen, Helga Gardarsdottir, Isla S Mackenzie, Sabine Dupont, Diederick E Grobbee","doi":"10.1002/cpt.70025","DOIUrl":"https://doi.org/10.1002/cpt.70025","url":null,"abstract":"<p><p>The interest in trials in which activities are being moved to the participants' direct environment, that is, decentralized, has increased in recent years, but limited research has been conducted into the feasibility and acceptability of such approaches. The Trials@Home RADIAL proof-of-concept (PoC) trial aims to assess the scientific and operational feasibility and quality of a fully decentralized and hybrid trial approach compared to a conventional, site-based approach. RADIAL is a three-arm parallel-group, open-label, multi-center low-intervention phase IV trial conducted in people living with Type 2 diabetes mellitus in six European countries (DE, DK, ES, IT, PL, UK). The RADIAL trial compares three arms with the same clinical intervention (Insulin Glargine 300 U/mL) but differing degrees of decentralization (the methodological intervention), including online recruitment, remote consenting, remote visits, home-shipment of Investigational Medicinal Product and study materials, home-based biological sample collection, app-reported events/ePROs, and home-devices for data collection. Key Performance Indicators regarding recruitment, retention, diversity, site satisfaction, participant satisfaction, cost, safety oversight, treatment adherence, and data quality are the main outcomes of the trial. This paper discusses the set-up of RADIAL, describing the design, endpoint selection, and decentralized elements evaluated, as well as discussing insight from RADIAL for future PoC trials. This is the introductory paper in a series of six papers in which we share the lessons learned during set-up, regulatory submission, and conduct of RADIAL. By sharing these insights, we aim to support clinical trial designers, technology developers, and other stakeholders to successfully implement decentralized elements into clinical trials. This trial was registered with identifier NCT05780151 in clinicaltrials.gov and under 2022-500,449-26-00 in the Clinical Trials Information System (CTIS) clinical trial database.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting Tirzepatide's Body Composition Model: Underestimated Fat-Free Mass Loss and Clinical Implications.","authors":"Chun-Chieh Chen, Shiuan-Chih Chen","doi":"10.1002/cpt.70058","DOIUrl":"https://doi.org/10.1002/cpt.70058","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}