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Applications of contemporary tools to measure plasma protein binding of targeted protein degraders

Drug Metabolism and Disposition 2025年第5期53卷

作者： Niosi, Mark Zhang, Sam Burchett, Woodrow Heck, Carley J.S. Goetz, Gilles H. Federico, James J. Gernhardt, Steven Jordan, Samantha Gilbert, Adam M. Calabrese, Matthew F. Obach, R. Scott Steyn, Stefanus J. Pharmacokinetics Dynamics and Metabolism Pfizer Worldwide Research and Development Groton CT United States Global Biometrics and Data Management Pfizer Worldwide Research and Development Groton CT United States Pharmacokinetics Dynamics and Metabolism Pfizer Worldwide Research and Development Cambridge Massachusetts United States Medicinal Chemistry Pfizer Worldwide Research and Development Groton CT United States Discovery Sciences Pfizer Worldwide Research and Development Groton CT United States

Assessing the fraction unbound in plasma (fu,p) for highly bound compounds (fu,p < 1%) is challenging, in part due to the compound-specific factors that can influence assay variability and performance. This study investigates human plasma protein binding obtained using the presaturation technique, and the results are compared with the standard equilibrium dialysis method and an orthogonal approach for an emerging class of compounds known as proteolysis targeting chimeras (PROTACs). Four exemplary PROTACs, cereblon-based ARV-110 and dTAG-13, and VHL-based ARV-771 and ERRα-degrader-3, were used to illustrate the challenges of obtaining accurate protein-binding results. The results reveal a protein-binding range from 0.03% to 3%. ARV-110 and dTAG-13 are highly bound to plasma proteins (fu,p ≤ 0.004). Under the standard equilibrium dialysis method, all compounds, except for ARV-771, had high variability or were unstable. Following presaturation and temperature adjustment (37 °C or 4 °C), fu,p values were obtained for ARV-771 (0.020, 95% confidence interval [CI]: 0.019–0.021), dTAG-13 (0.0028, 95% CI: 0.0024–0.0033), and ARV-110 (0.00042, 95% CI: 0.00033–0.00054). ERRα-degrader-3 remained unstable under all conditions. A comparative analysis of the binding values measured for ARV-110, dTAG-13, and ARV-771 by different techniques revealed good concordance (1.1-fold to 2.7-fold difference) between the methods evaluated. Utilizing a presaturation technique with low temperature is effective for measuring protein binding for challenging unstable degraders. Presaturation can reduce assay failures due to nonspecific binding to equipment by ensuring the system has reached equilibrium. This study provides valuable insights into the challenges encountered when measuring protein binding for lipophilic and highly bound PROTACs. Significance Statement: This paper details the evaluation of plasma protein binding for complex proteolysis targeting chimeras (PROTACs) molecules using cont

关键词： Equilibrium dialysis Nonspecific binding Plasma protein binding Presaturation PROTACs

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Study Duration Prediction for Clinical Trials with Time-to-Event Endpoints Using Mixture Distributions Accounting for Heterogeneous Population

arXiv

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arXiv 2023年

作者： Zhang, Hong Pu, Jie Deng, Shibing Roychoudhury, Satrajit Chu, Haitao Robinson, Douglas Global Biometrics and Data Management Pfizer Inc. New YorkNY United States Division of Biostatistics School of Public Health University of Minnesota MinneapolisMN United States

In the era of precision medicine, more and more clinical trials are now driven or guided by biomarkers, which are patient characteristics objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. With the overarching objective to optimize and personalize disease management, biomarker-guided clinical trials increase the efficiency by appropriately utilizing prognostic or predictive biomarkers in the design. However, the efficiency gain is often not quantitatively compared to the traditional all-comers design, in which a faster enrollment rate is expected (e.g. due to no restriction to biomarker positive patients) potentially leading to a shorter duration. To accurately predict biomarker-guided trial duration, we propose a general framework using mixture distributions accounting for heterogeneous population. Extensive simulations are performed to evaluate the impact of heterogeneous population and the dynamics of biomarker characteristics and disease on the study duration. Several influential parameters including median survival time, enrollment rate, biomarker prevalence and effect size are identitied. Re-assessments of two publicly available trials are conducted to empirically validate the prediction accuracy and to demonstrate the practical utility. The R package detest is developed to implement the proposed method and is publicly available on CRAN. © 2023, CC BY.

关键词： Biomarkers

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Robust Emax Model Fitting: Addressing Nonignorable Missing Binary Outcome in Dose-Response Analysis

arXiv

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arXiv 2024年

作者： Zhang, Jiangshan Pradhan, Vivek Zhao, Yuxi Department of Statistics University of California DavisCA95616 United States Global Biometrics and Data Management Immunology and Inflammation Pfizer Inc. 1 Portland Street CambridgeMA02139 United States

The Binary Emax model is widely employed in dose-response analysis during drug development, where missing data often pose significant challenges. Addressing nonignorable missing binary responses—where the likelihood of missing data is related to unobserved outcomes—is particularly important, yet existing methods often lead to biased estimates. This issue is compounded when using the regulatory-recommended ‘imputing as treatment failure’ approach, known as non-responder imputation (NRI). Moreover, the problem of separation, where a predictor perfectly distinguishes between outcome classes, can further complicate likelihood maximization. In this paper, we introduce a penalized likelihood-based method that integrates a modified Expectation-Maximization (EM) algorithm in the spirit of Ibrahim and Lipsitz (Ibrahim and Lipsitz, 1996) to effectively manage both nonignorable missing data and separation issues. Our approach applies a noninformative Jeffreys’ prior to the likelihood, reducing bias in parameter estimation. Simulation studies demonstrate that our method outperforms existing methods, such as NRI, and the superiority is further supported by its application to data from a Phase II clinical trial. Additionally, we have developed an R package, ememax, to facilitate the implementation of the proposed method. © 2024, CC BY.

关键词： Expectation maximization algorithm

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Nonparametric inference under b-bits quantization

The Journal of Machine Learning Research

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The Journal of Machine Learning Research 2024年第1期25卷 967-1034页

作者： Kexuan Li Ruiqi Liu Ganggang Xu Zuofeng Shang Global Biometrics and Data Sciences Bristol Myers Squibb Princeton Pike NJ Department of Mathematics and Statistics Texas Tech University Lubbock TX Department of Management Science University of Miami Coral Gables FL Department of Mathematical Sciences New Jersey Institute of Technology Newark NJ

Statistical inference based on lossy or incomplete samples is often needed in research areas such as signal/image processing, medical image storage, remote sensing, signal transmission. In this paper, we propose a nonparametric testing procedure based on samples quantized to B bits through a computationally efficient algorithm. Under mild technical conditions, we establish the asymptotic properties of the proposed test statistic and investigate how the testing power changes as B increases. In particular, we show that if B exceeds a certain threshold, the proposed nonparametric testing procedure achieves the classical minimax rate of testing (Shang and Cheng, 2015) for spline models. We further extend our theoretical investigations to a nonparametric linearity test and an adaptive nonparametric test, expanding the applicability of the proposed methods. Extensive simulation studies together with a real-data analysis are used to demonstrate the validity and effectiveness of the proposed tests.

关键词： B-bits quantization minimax rates of testing nonparametric inference smoothing splines

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POS0169 OPEN-LABEL, LONG-TERM (10-YEAR) STUDY OF THE SAFETY OF ETANERCEPT IN CHILDREN AND YOUNG ADULTS WITH EXTENDED OLIGOARTICULAR, ENTHESITIS-RELATED, OR PSORIATIC JUVENILE IDIOPATHIC ARTHRITIS

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Annals of the Rheumatic Diseases 2022年 81卷 313-314页

作者： J. Vojinovic J. Dehoorne V. Panaviene G. Susic G. Horneff V. Stanevicha K. Kobusinska Z. Żuber B. Dobrzyniecka J. Akikusa T. Avcin A. Martini C. Borlenghi E. Arthur S.Y. Tatulych C. Zang B. Vlahos N. Ruperto Paediatric Rheumatology International Trials Organisation (PRINTO) Paediatric and Rheumatology Genoa Italy Pfizer I&I Medical Affairs Buenos Aires Argentina Pfizer Clinical Development and Operations Peapack United States of America Pfizer Clinical Development Groton United States of America Pfizer Global Biometrics and Data Management Collegeville United States of America Pfizer Global Product Development Collegeville United States of America

Background CLIPPER2 was an 8-year, open-label extension of the phase 3b, multicenter, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in the treatment of patients (pts) with juvenile idiopathic arthritis (JIA) categorized as extended oligoarticular arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Objectives The objective of this analysis was to describe the safety of ETN in this population after 10 years of follow up. Methods Pts (n=127) with eoJIA (2-17 years), ERA, or PsA (each 12-17 years) who received ≥1 ETN dose (0.8 mg/kg once weekly [max, 50 mg]) in CLIPPER were eligible to enter CLIPPER2. The primary outcome measure was the occurrence of malignancy. Long-term safety was assessed as the total incidence of events from CLIPPER baseline (BL) to month (mth) 120, frequency of events per 100 patient-years (EP100PY), and frequency of events in each study year. Results A total of 109/127 (86%) pts entered CLIPPER2; 99 (78%) continued in the active treatment period. At mth 120, 84 (66%) pts had completed the study; 27 (21%) while actively taking ETN; 7 (6%) had withdrawn from treatment due to low/inactive disease; 5 (4%) had re-started ETN following an earlier withdrawal from treatment; and 45 (35%) had stopped ETN (but remained under observation); 25 (20%) pts permanently discontinued from the CLIPPER2 study. In CLIPPER/CLIPPER2, 1 case of malignancy (Hodgkin's disease) was reported (1 pt with eoJIA in Year 3). There was 1 case of uveitis (1 pt with eoJIA in Year 8) and 3 of Crohn's disease (2 pts with ERA, Year 1/Year 6; 1 pt with eoJIA, Year 5). There were 2 cases of opportunistic infections (both herpes zoster), and no deaths. Overall, there were 559 (81.82 EP100PY) treatment-emergent adverse events (TEAEs) excluding infections and injection-site reactions (ISRs). The overall rate of TE serious infections was low (N=14; 2.05 EP100PY) ( Table 1 ), with the most common TE serious infection being gastroenteritis

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Covariate Adjustment in Randomized Experiments Motivated by Higher-Order Influence Functions

arXiv

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arXiv 2024年

作者： Zhao, Sihui Wang, Xinbo Liu, Lin Zhang, Xin School of Mathematical Sciences CMA-Shanghai Institute of Natural Sciences MOE-LSC Shanghai Jiao Tong University China Department of Bioinformatics and Biostatistics School of Life Sciences Shanghai Jiao Tong University China SJTU-Yale Joint Center for Biostatistics and Data Science Shanghai Jiao Tong University China Global Biometrics & Data Management Pfizer Inc

Higher-Order Influence Functions (HOIF), developed in a series of papers over the past twenty years, is a fundamental theoretical device for constructing rate-optimal causal-effect estimators from observational studies. However, the value of HOIF for analyzing well-conducted randomized controlled trials (RCTs) has not been explicitly explored. In the recent U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines on the practice of covariate adjustment in analyzing RCTs, in addition to the simple, unadjusted difference-in-mean estimator, it was also recommended to report the estimator adjusting for baseline covariates via a simple parametric working model, such as a linear model. In this paper, we show that a HOIF-motivated estimator for the treatment-specific mean has significantly improved statistical properties compared to popular adjusted estimators in practice when the number of baseline covariates p is relatively large compared to the sample size n. We also characterize the conditions under which the HOIF-motivated estimator improves upon the unadjusted one. Furthermore, we demonstrate that a novel debiased adjusted estimator proposed recently by Lu et al. is, in fact, another HOIF-motivated estimator in disguise. Numerical and empirical studies are conducted to corroborate our theoretical findings. Copyright © 2024, The Authors. All rights reserved.

关键词： Controlled drug delivery

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Clinical characteristics and treatment patterns of patients with venous thromboembolism (VTE) transitioning from hospital to post-discharge settings

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Hospital Practice 2020年第4期48卷 196-205页

作者： Burton, Tanya Hlavacek, Patrick Guo, Jennifer D Rosenblatt, Lisa Mardekian, Jack Ferri, Mauricio Russ, Cristina Kline, Jeffrey A Health Economics and Outcomes Research Life Sciences Optum MA Boston United States Health Economics and Outcomes Research Pfizer Inc . NY NY United States Health Economics and Outcomes Research Bristol-Myers Squibb Lawrence Township United States US Medical Affairs Bristol-Myers Squibb Lawrence Township United States Statistics Global Biometrics & Data Management Pfizer Inc NY NY United States US Medical Affairs Pfizer Inc . NY NY United States Department of Emergency Medicine Indiana University School of Medicine IN Indianapolis United States

Objective: This study examined anticoagulant use during and after a hospital encounter for venous thromboembolism (VTE), a transition of care largely uncharacterized in the literature. Methods: Adults with a VTE diagnosis code during a hospital encounter (emergency department [ED], observation area [OBS], or inpatient hospital [IP]) from January 2012 to August 2017 were identified in an electronic health records database. The first such hospital encounter was defined as the index VTE encounter. Patients were linked to a claims database and required to be continuously enrolled for six months before the index admission date through six months after the index discharge date. Anticoagulants administered during the index VTE encounter and filled on or within 30 days of discharge were summarized descriptively overall, and by the type of index VTE encounter (IP, No IP) and anticoagulants administered during the index VTE encounter. Results: Among 2,968 eligible patients, mean (SD) age was 64 (16) years, 51% were female, 67% had an IP index VTE encounter, and 77% received anticoagulation therapy during the index VTE encounter. In total, 60% filled a prescription order for anticoagulant within 30 days post-discharge. Of those who received a direct oral anticoagulant (DOAC), warfarin, or parenteral anticoagulant only during the index VTE encounter, 74%, 69%, and 34%, respectively, filled a prescription for the same anticoagulant post-discharge. Patients treated with a DOAC or warfarin during an ED or OBS VTE encounter without a subsequent inpatient hospitalization were more likely to remain on the same anticoagulation therapy post-discharge than those with an inpatient hospitalization (81% vs 69% for DOAC and 75% vs 68% for warfarin). Conclusions: Many patients treated with anticoagulation therapy during a VTE hospital encounter did not fill a prescription for an anticoagulant within 30 days post-discharge, highlighting an opportunity for improved management of care transitio

关键词： apixaban direct oral anticoagulants oral anticoagulation transition of care Venous thromboembolism warfarin

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319P Real-world effectiveness of palbociclib (PAL) in combination with an aromatase inhibitor (AI) vs AI alone in HR+/HER2− bone-only metastatic breast cancer (MBC)

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ESMO Open 2025年 10卷 104891-104891页

作者： A.M. Brufsky R.M. Layman X. Liu B. Li L. McRoy A. Cohen M. Estevez P.H. Cottu G. Curigliano H.S. Rugo Division of Hematology/Oncology Department of Medicine UPMC Hillman Cancer Center University of Pittsburgh Medical Center Pittsburgh United States of America Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston United States of America US Oncology Medical Affairs Pfizer Inc. New York United States of America Global Biometrics & Data Management Pfizer Inc. New York United States of America Research Oncology Flatiron Health New York City United States of America Research Sciences Flatiron Health Inc. New York United States of America Department of Medical Oncology & Institute of Women Cancers Institut Curie Université Paris Cité Paris France Department of Oncology and Hemato-Oncology University of Milano European Institute of Oncology IRCCS Milan Italy Department of Medicine University of California San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco United States of America

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POS1293 TEN-YEAR EFFICACY data FROM THE CLIPPER STUDIES: OPEN-LABEL, LONG-TERM ETANERCEPT TREATMENT IN CHILDREN AND YOUNG ADULTS WITH EXTENDED OLIGOARTICULAR, ENTHESITIS-RELATED, OR PSORIATIC JUVENILE IDIOPATHIC ARTHRITIS

引用

Annals of the Rheumatic Diseases 2022年 81卷 983-984页

作者： J. Vojinovic J. Dehoorne V. Panaviene G. Susic G. Horneff V. Stanevicha K. Kobusinska Z. Żuber B. Dobrzyniecka J. Akikusa T. Avcin A. Martini C. Borlenghi E. Arthur S.Y. Tatulych C. Zang V. Tsekouras B. Vlahos N. Ruperto Paediatric Rheumatology International Trials Organisation (PRINTO) Paediatric and Rheumatology Genoa Italy Pfizer I&I Medical Affairs Buenos Aires Argentina Pfizer Clinical Development and Operations Peapack United States of America Pfizer Clinical Development Groton United States of America Pfizer Global Biometrics and Data Management Collegeville United States of America Pfizer I&I Medical Affairs Strovolos Cyprus Pfizer Global Product Development Collegeville United States of America

Background CLIPPER2 was an 8-year, open-label extension of the phase 3b, 2-year CLIPPER study of the safety and efficacy of etanercept (ETN) in patients (pts) with juvenile idiopathic arthritis (JIA), categorized as extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Objectives Evaluation of the efficacy of ETN and its effect on health outcomes over 10 years of follow-up were secondary objectives and are reported here. Methods Pts (n=127) with eoJIA (n=60; 2-17 years of age), ERA (n=38; 12-17), or PsA (n=29; 12-17) who received ≥1 ETN dose (0.8 mg/kg once weekly [max, 50 mg]) in CLIPPER were eligible to enter CLIPPER2. The study design has been reported previously. 1 Efficacy endpoints included proportions of pts achieving JIA American College of Rheumatology (ACR) 30/50/70/90/100 criteria, Juvenile Arthritis Disease Activity Score (JADAS) inactive disease and clinical remission criteria, and sustained clinical remission (ACR criteria) or JADAS ≤1 for 12 continuous months (mths). Exploratory efficacy endpoints included time to flare following ETN withdrawal (based on ≥30% worsening in ≥3/6 ACR Pedi components, with ≥30% improvement in <2/6 remaining components and ≥2 active joints), and time to re-treatment with ETN. Observed Cases were used (i.e., there was no imputation for missing data) for pts who were in the Active Treatment Period. Results A total of 109/127 (86%) CLIPPER participants entered CLIPPER2 (n=55 eoJIA, n=31 ERA, n=23 PsA), with 99 (78%) pts continuing in the Active Treatment Period. Overall, 84 (66%) pts completed 120 mths of follow-up; 27 (21%) while actively taking ETN. Thirty (24%) pts entered the Withdrawal Period from the Active Treatment Period (i.e., they discontinued ETN, either by meeting the Wallace definition for clinically inactive disease for at least 6 months on ETN, or by having had a good clinical response and being deemed to benefit from withdrawal in the investigator's judgment).

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POS0764 IMPACT OF TOFACITINIB TREATMENT ON HEIGHT IN JUVENILE IDIOPATHIC ARTHRITIS

引用

Annals of the Rheumatic Diseases 2023年 82卷 673-674页

作者： H. Brunner H. Wasserman M. Saul D. Robinson E. Nagy A. Diehl M. Mortezavi Cincinnati Children's Hospital Medical Center Division of Rheumatology Department of Pediatrics Cincinnati OH United States of America Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Division of Pediatrics Department of Endocrinology Cincinnati OH United States of America Pfizer Inc Biomarker Statistics Gilbert AZ United States of America Pfizer Inc Global Biometrics and Data Management Cambridge MA United States of America Pfizer Ltd Safety Surveillance and Risk Management Tadworth Surrey United Kingdom Pfizer Inc Inflammation and Immunology Collegeville PA United States of America Pfizer Inc Inflammation and Immunology New York NY United States of America

Background Diminished growth can be a consequence of juvenile idiopathic arthritis (JIA). [1] Growth hormone signals through a Janus kinase (JAK)2 tyrosine kinase-coupled receptor. [2] Tofacitinib, an oral JAK inhibitor approved for JIA, preferentially inhibits signalling by heterodimeric receptors associated with JAK1 and/or JAK3 and has less functional selectivity for JAK2. Objectives To evaluate the growth of patients (pts) with JIA treated with tofacitinib. Methods This post hoc analysis of the Phase 3 trial of tofacitinib in pts with JIA ( NCT02592434 ; a 44-week, 2-part, double-blind [DB], withdrawal study in 225 pts aged 2–<18 years) enrolled 212 pts (pts with systemic JIA were excluded). In part 1, pts received open-label tofacitinib 5 mg twice daily (BID; or weight-based oral solution) for 18 weeks/flare. In the DB phase, pts achieving JIA/American College of Rheumatology improvement ≥30% by Week 18 were randomised to receive tofacitinib or placebo until Week 44/flare. Pts could then receive tofacitinib in a long-term extension study. Height Z-scores were calculated for pts at baseline (BL), Weeks 18, 44, 68 and 92 using age- and sex-matched reference data from the World Health Organization. A repeated measures mixed-effects analysis of pts who received continuous tofacitinib assessed change in height Z-scores over time. The impact of JIA category, age, sex, race, ethnicity, biologic disease-modifying antirheumatic drug (bDMARD)/conventional synthetic DMARD (csDMARD) use, and C-reactive protein (CRP; normal/elevated) on BL height Z-score was also assessed. A separate analysis assessed the impact of treatment on change in height Z-scores during the DB phase. Growth velocity (cm/year) from BL to Week 44 was calculated. Results Ethnicity was the only characteristic associated with BL height Z-score (Table 1). For 83 pts who received continuous tofacitinib, mean (95% confidence intervals [CI]) BL height Z-score was -0.4 (-0.7, -0.1), and was stable up to Week 9

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