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Drug-Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC-122) in Healthy Adult Subjects

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JOURNAL OF CLINICAL PHARMACOLOGY 2019年第12期59卷 1620-1631页

作者： Ogasawara, Ken MacGorman, Kimberly Liu, Liangang Chen, Jian Carayannopoulos, Leonidas N. Zhou, Simon Palmisano, Maria Li, Yan Celgene Corp Translat Dev & Clin Pharmacol 556 Morris Ave Summit NJ 07901 USA Celgene Corp Biostat & Stat Programming Berkeley Hts NJ USA Celgene Corp Nonclin Dev Summit NJ USA

Avadomide (CC-122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4-RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open-label, nonrandomized, 2-period, single-sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-inf)) and maximum observed plasma concentration (C-max), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC(0-inf) and C-max, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC(0-inf) and C-max, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.

关键词： avadomide CYP3A drug-drug interactions immunomodulatory drug

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Testing factor-covariate interaction in rank repeated-measures analysis of covariance models

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COMMUNICATIONS IN STATISTICS-THEORY AND METHODS 2018年第11期47卷 2760-2778页

作者： Fan, Chunpeng Zhang, Donghui Sanofi US Inc Dept Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA

This article derives the asymptotic properties of rank-based tests for the covariate effects in rank repeated-measures analysis of covariance (ANCOVA) models (Fan and Zhang 2017) employing generalized estimating equation (GEE) techniques. One interested application of the proposed tests is to check the validity of the assumption of homogeneous covariate effects in different levels of the factors. Performance of the proposed tests has been confirmed by simulation studies and illustrated using the famous seizure count data. While the article mainly focuses on interaction tests, the scope of the proposed tests includes testing any contrast of the covariate effect such as the null of no overall covariate effect.

关键词： ANCOVA ANOVA-type test GEE Generalized estimating equations Longitudinal data Wald-type test

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RETRACTION: Robust Model Selection and Estimation for Censored Survival Data with High Dimensional Genomic Covariates (Retraction of Vol 67, Pg 225, 2019)

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ACTA BIOTHEORETICA 2020年第2期68卷 295-295页

作者： Chen, Guorong Wang, Sijian Sun, Guannan Pan, Huanxue Beijing Forestry Univ Dept Finance Beijing Peoples R China Rutgers State Univ Dept Stat & Biostat New Brunswick NJ USA Sanofi China Dept Biostat & Programming Beijing Peoples R China

The authors have retracted this article [1] because they found a fundamental mistake in the methodology that is not correctable at this time. This mistake is found in the methodology and the derivation of the model with Tukey and Huber's losses. Because of the error, the findings in the article are not reliable. All authors agree to this retraction.

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Bayesian hypothesis testing with frequentist characteristics in clinical trials

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CONTEMPORARY CLINICAL TRIALS 2019年 87卷 105858-000页

作者： Quan, Hui Zhang, Bingzhi Lan, Yu Luo, Xiaodong Chen, Xun Sanofi Biostat & Programming 55 Corp Dr Bridgewater MA 08807 USA

Through the use of an informative prior, Bayesian methodologies could potentially borrow the strength of historical information and become more and more popular for their applications to clinical trials. Nonetheless, even with tremendous effort, the reconciliation of the formulation of the hypotheses and the calculation of type I error between a Bayesian analysis and traditional frequentist analysis is still not very clear. In this research, we apply an inferential prior, null prior and design prior to the Bayesian data analysis, type I error control and sample size calculation. As demonstrated theoretically, the type I error control denies any borrowing of favorable prior information. Thus, the use of the calibrated critical value obtained through simulation for the commensurate or power prior for a Bayesian analysis has the effect of eliminating the borrowing of historical information. The validity of a Bayesian analysis with the borrowing of historical data should rest on the a priori assumption of consistency of data from the historical and current studies. Just in case the consistency assumption is not totally true, dynamic borrowing through the commensurate or power prior can regulate the level of borrowing based on the degree of consistency in the data. An example along with simulations are used to illustrate the applications and compare the characteristics of the methods.

关键词： Inferential prior Design posterior Historical data borrowing Type I error rate Power Interim analysis

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Statistical modeling and prediction of clinical trial recruitment

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STATISTICS IN MEDICINE 2019年第6期38卷 945-955页

作者： Lan, Yu Tang, Gong Heitjan, Daniel F. Southern Methodist Univ Dept Stat Sci Dallas TX 75275 USA Sanofi Dept Biostat & Programming Bridgewater NJ USA Univ Pittsburgh Dept Biostat Pittsburgh PA 15261 USA NRG Oncol Philadelphia PA USA Univ Texas Southwestern Med Ctr Dallas Dept Clin Sci Dallas TX 75390 USA

Real-time prediction of clinical trial accrual can support logistical planning, ensuring that studies meet but do not exceed sample size targets. We describe a novel, simulation-based prediction method that is founded on a realistic model for the underlying processes of recruitment. The model reflects key features of enrollment such as the staggered initiation of new centers, heterogeneity in enrollment capacity, and declining accrual within centers. The model's first stage assumes that centers join the trial (ie, initiate accrual) according to an inhomogeneous Poisson process in discrete time. The second part assumes that each center's enrollment pattern reflects an early plateau followed by a slow decline, with a burst at the end of the trial following the announcement of an imminent closing date. By summing up achieved and projected enrollment, one can predict accrual as a function of time and, thereby, the time when the trial will achieve a planned enrollment target. We applied our method retrospectively to two real-world trials: NSABP B-38 and REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure). In both studies, the proposed method produced prediction intervals for time to completion that were more accurate than those from conventional predictions that assume a constant rate of enrollment, estimated either from the entire trial to date or over a recent time window. The advantage is substantial in the early stages of NSABP B-38. We conclude that a method based on a realistic accrual model offers improved accuracy in the prediction of enrollment landmarks, especially at the early stages of large trials that involve many centers.

关键词： Bayesian center initiation enrollment marginal likelihood

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Evaluating longitudinal markers under two-phase study designs

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biostatISTICS 2019年第3期20卷 485-498页

作者： Maziarz, Marlena Cai, Tianxi Qi, Li Lok, Anna S. Zheng, Yingye Univ Washington Dept Biostat 1705 NE Pacific St Seattle WA 98195 USA Harvard TH Chan Sch Publ Hlth Dept Biostat 677 Huntington Ave Boston MA 02115 USA Sanofi Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA Univ Michigan Dept Gastroenterol 1500 E Med Ctr Dr Ann Arbor MI 48109 USA Fred Hutchinson Canc Res Ctr Dept Biostat 1100 Fairview Ave N Seattle WA 98109 USA

Little attention has been given to the design of efficient studies to evaluate longitudinal biomarkers. Measuring longitudinal markers on an entire cohort is cost prohibitive and, especially for rare outcomes such as cancer, may be infeasible. Thus, methods for evaluation of longitudinal biomarkers using efficient and cost-effective study designs are needed. Case cohort (CCH) and nested case-control (NCC) studies allow investigators to evaluate biomarkers rigorously and at reduced cost, with only a small loss in precision. In this article, we develop estimators of several measures to evaluate the accuracy and discrimination of predicted risk under CCH and NCC study designs. We use double inverse probability weighting (DIPW) to account for censoring and sampling bias in estimation and inference procedures. We study the asymptotic properties of the proposed estimators. To facilitate inference using two-phase longitudinal data, we develop valid resampling-based variance estimation procedures under CCH and NCC. We evaluate the performance of our estimators under CCH and NCC using simulation studies and illustrate them on a NCC study within the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) clinical trial. Our estimators and inference procedures perform well under CCH and NCC, provided that the sample size at the time of prediction (effective sample size) is reasonable. These methods are widely applicable, efficient, and cost-effective and can be easily adapted to other study designs used to evaluate prediction rules in a longitudinal setting.

关键词： Biomarker evaluation Longitudinal and survival data Two-phase designs

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Venglustat combined with imiglucerase for neurological disease in adults with Gaucher disease type 3: the LEAP trial

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BRAIN 2023年第2期146卷 461-474页

作者： Schiffmann, Raphael Cox, Timothy M. Dedieu, Jean-Francois Gaemers, Sebastiaan J. M. Hennermann, Julia B. Ida, Hiroyuki Mengel, Eugen Minini, Pascal Mistry, Pramod Musholt, Petra B. Scott, David Sharma, Jyoti Peterschmitt, M. Judith Baylor Scott & White Res Inst Inst Metab Dis Dallas TX 75246 USA Univ Cambridge Dept Med Cambridge CB2 0QQ England Addenbrookes Hosp Cambridge CB2 0QQ England Sanofi Neurol Dev F-91385 Chilly Mazarin France Sanofi Global Pharmacovigilance 1105 BP Amsterdam Netherlands Univ Med Ctr Mainz Ctr Pediat & Adolescent Med Villa Metabol D-55131 Mainz Germany Jikei Univ Dept Pediat Sch Med Tokyo 1058461 Japan SphinCS Clin Sci LSD D-65239 Hochheim Germany Sanofi Biostat & Programming F-91385 Chilly Mazarin France Yale Sch Med Yale Lysosomal Dis Ctr New Haven CT 06510 USA Yale Sch Med Gaucher Dis Treatment Ctr New Haven CT 06510 USA Sanofi R&D Global Dev D-65926 Frankfurt Germany Clario Med & Sci Affairs Neurosci San Mateo CA 94404 USA Sanofi Pharmacokinet Dynam & Metab Bridgewater NJ 08807 USA Sanofi Neurol Clin Dev R&D Cambridge MA 02141 USA

Gaucher disease type 3 is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid beta-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy and substrate reduction therapy ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once-daily in combination with maintenance dose of imiglucerase enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC(0-24) on Day 1 was 851 (282) ng.h/ml;C-max of 58.1 (26.4) ng/ml was achieved at a median t(max) 2.00 h. After oncedaily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating similar to 2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean pla

关键词： Gaucher disease type 3 venglustat substrate reduction therapy glycosphingolipids CNS

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Borrowing external information to improve Bayesian confidence propagation neural network

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EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 2020年第9期76卷 1311-1319页

作者： Tada, Keisuke Maruo, Kazushi Isogawa, Naoki Yamaguchi, Yusuke Gosho, Masahiko Sanofi KK Biostat & Programming Shinjuku Ku Tokyo Opera City Tower3-20-2 Nishi Shinjuku Tokyo 1631488 Japan Univ Tsukuba Grad Sch Comprehens Human Sci Tennodai 1-1-1 Tsukuba Ibaraki 3058575 Japan Univ Tsukuba Fac Med Dept Biostat Tennodai 1-1-1 Tsukuba Ibaraki 3058575 Japan Pfizer R&D Japan Clin Stat Shibuya Ku Shinjuku Bunka Quint Bldg3-22-7 Yoyogi Tokyo 1518589 Japan Astellas Pharma Inc Data Sci Dev Chuo Ku 2-5-1 Nihonbashi Honcho Tokyo 1038411 Japan

Purpose A Bayesian confidence propagation neural network (BCPNN) is a signal detection method used by the World Health Organization Uppsala Monitoring Centre to analyze spontaneous reporting system databases. We modify the BCPNN to increase its sensitivity for detecting potential adverse drug reactions (ADRs). Method In a BCPNN, the information component (IC) is defined as an index of disproportionality between the observed and expected number of reported drugs and events. Our proposed method adjusts the IC value by borrowing information about events that have occurred in drugs defined as similar to the target drug. We compare the performance of our method with that of a traditional BCPNN through a simulation study. Results The false positive rate of the proposed method was lower than that of the traditional BCPNN method and close to the nominal value, 0.025, around the true difference in ICs between the target drug and similar drugs equal to 0. The sensitivity of the proposed method was much higher than that of the traditional BCPNN method in case in which the difference in ICs between the target drug and similar drugs ranges from 0 to 2. When applied to a database managed by Japanese regulatory authority, the proposed method could detect known ADRs earlier than the traditional method. Conclusions The proposed method is a novel criterion for early detection of signals if similar drugs have the same tendencies. The proposed BCPNN tends to have higher sensitivity when the true difference is greater than 0.

关键词： Pharmacovigilance Signal detection Information component Dynamic borrowing

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Additive efficacy of a bispecific anti-TNF/IL-6 nanobody compound in translational models of rheumatoid arthritis

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SCIENCE TRANSLATIONAL MEDICINE 2023年第681期15卷 eabq4419页

作者： Biesemann, Nadine Margerie, Daniel Asbrand, Christian Rehberg, Markus Savova, Virginia Agueusop, Inoncent Klemmer, Daniel Ding-Pfennigdorff, Danping Schwahn, Uwe Dudek, Markus Heyninck, Karen De Tavernier, Evelyn Cornelis, Sigrid Kohlmann, Markus Nestle, Frank O. Herrmann, Matthias Industriepark Hoechst Sanofi R&D Immunol & Inflammat Therapeut Area Type 1 17 Immunol Cluster D-65926 Frankfurt Germany Industriepark Hoechst Sanofi R&D Digital & Data Sci D-65926 Frankfurt Germany Sanofi R&D Precis Med & Computat Biol 350 Water St Cambridge MA 02141 USA Industriepark Hoechst Sanofi R&D Biostatisticsand Programming D-65926 Frankfurt Germany Industriepark Hoechst Sanofi R&D Biostat & Programming Nonclin Efficacy & Safety D-65926 Frankfurt Germany Industriepark Hoechst Sanofi R&D Translat Med Early Dev Biomarkers & Clin Bioanal D-65926 Frankfurt Germany NANOBODY Res Platform Sanofi R&D Technologiepk 21 B-9052 Zwijnaarde Belgium Industriepark Hoechst Sanofi R&D Early Clin Dev Therapeut Area Immunol & Inflammat D-65926 Frankfurt Germany Sanofi R&D 350 Water St Cambridge MA 02141 USA

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases affecting primarily the joints. Despite successful therapies including antibodies against tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor, only 20 to 30% of patients experience remission. We studied whether inhibiting both TNF and IL-6 would result in improved efficacy. Using backtranslation from single-cell RNA sequencing (scRNA-seq) data from individuals with RA, we hypothesized that TNF and IL-6 act synergistically on fibroblast-like synoviocytes (FLS) and T cells. Coculture of FLS from individuals with RA and T cells supported this hypothesis, revealing effects on both disease-driving pathways and biomarkers. Combining anti-TNF and anti-IL-6 antibodies in collagen-induced arthritis (CIA) mouse models resulted in sustained long-term remission, improved histology, and effects on bone remodeling pathways. These promising data initiated the development of an anti-TNF/IL-6 bispecific nanobody compound 1, with similar potencies against TNF and IL-6. We observed additive efficacy of compound 1 in a FLS/T cell coculture affecting arthritis and T helper 17 (TH17) pathways. This nanobody compound transcript signature inversely overlapped with described RA endotypes, indicating a potential efficacy in a broader patient population. In summary, we showed superiority of a bispecific anti-TNF/IL-6 nanobody compound or combination treatment over monospecific treatments in both in vitro and in vivo models. We anticipate improved efficacy in upcoming clinical studies.

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powerEQTL: an R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis

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BIOINFORMATICS 2021年第22期37卷 4269-4271页

作者： Dong, Xianjun Li, Xiaoqi Chang, Tzuu-Wang Scherzer, Clemens R. Weiss, Scott T. Qiu, Weiliang Harvard Med Sch Brigham & Womens Hosp Dept Neurol Genom & Bioinformat Hub Boston MA 02115 USA Harvard Med Sch Ctr Adv Parkinson Res & Precis Neurol Program Brigham & Womens Hosp Dept Neurol Boston MA 02115 USA Aligning Sci Parkinsons ASAP Collaborat Res Netwo Chevy Chase MD 20815 USA Harvard Med Sch Brigham & Womens Hosp Dept Pathol Mol Pathol Epidemiol Program Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Dept Med Channing Div Network Med Boston MA 02115 USA Sanofi Biostat & Programming Dept Nonclin Efficacy & Safety Framingham MA 01701 USA

A Summary: Genome-wide association studies (GWAS) have revealed thousands of genetic loci for common diseases. One of the main challenges in the post-GWAS era is to understand the causality of the genetic variants. Expression quantitative trait locus (eQTL) analysis is an effective way to address this question by examining the relationship between gene expression and genetic variation in a sufficiently powered cohort. However, it is frequently a challenge to determine the sample size at which a variant with a specific allele frequency will be detected to associate with gene expression with sufficient power. This is a particularly difficult task for single-cell RNAseq studies. Therefore, a user-friendly tool to estimate statistical power for eQTL analyses in both bulk tissue and single-cell data is needed. Here, we presented an R package called powerEQTL with flexible functions to estimate power, minimal sample size or detectable minor allele frequency for both bulk tissue and single-cell eQTL analysis. A user-friendly, program-free web application is also provided, allowing users to calculate and visualize the parameters interactively.

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