Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.

A statistical perspective on baseline adjustment in pharmacogenomic genome-wide association studies of quantitative change.

In pharmacogenetic (PGx) studies, drug response phenotypes are often measured in the form of change in a quantitative trait before and after treatment. There is some debate in recent literature regarding baseline adjustment, or inclusion of pre-treatment or baseline value as a covariate, in PGx genome-wide association studies (GWAS) analysis. Here, we provide a clear statistical perspective on this baseline adjustment issue by running extensive simulations based on nine statistical models to evaluate the influence of baseline adjustment on type I error and power.

An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson's Disease.

Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD).

Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD.

Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants.

Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types.

We evaluated the impact of class I and class II human leukocyte antigen (HLA) genotypes, heterozygosity, and diversity on the efficacy of pembrolizumab. Seventeen pembrolizumab clinical trials across eight tumor types and one basket trial in patients with advanced solid tumors were included (n > 3,500 analyzed). Germline DNA was genotyped using a custom genotyping array.

Current challenges and opportunities for pharmacogenomics: perspective of the Industry Pharmacogenomics Working Group (I-PWG).

Pharmaceutical companies have increasingly utilized genomic data for the selection of drug targets and the development of precision medicine approaches. Most major pharmaceutical companies routinely collect DNA from clinical trial participants and conduct pharmacogenomic (PGx) studies. However, the implementation of PGx studies during clinical development presents a number of challenges.

Global Landscape of Clostridioides Difficile Phylogeography, Antibiotic Susceptibility, and Toxin Polymorphisms by Post-Hoc Whole-Genome Sequencing from the MODIFY I/II Studies.

Introduction: Clostridioides (Clostridium) difficile infection, the leading cause of healthcare-associated diarrhea, represents a significant burden on global healthcare systems. Despite being a global issue, information on C. difficile from a global perspective is lacking.

Genetic Association Reveals Protection against Recurrence of Infection with Bezlotoxumab Treatment.

Bezlotoxumab is a human monoclonal antibody against toxin B, indicated to prevent recurrence of infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped.

Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing.

Background: Bezlotoxumab has been shown to prevent Clostridium difficile infection recurrence (rCDI) in high-risk patients.

Methods: We used whole genome sequencing to estimate the impact of bezlotoxumab on same-strain relapse or new-strain reinfection in MODIFY I/II trials. Reinfection with a new strain and relapse with the same strain were differentiated by the comparison of ribotype (RT) and pair-wise single-nucleotide whole genome sequencing (WGS) variations (PWSNV).

Impact of Genotype on Response to Anacetrapib.

Background: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of genotype on response to anacetrapib in the REVEAL trial.

The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/grazoprevir.

To evaluate the effect of genetic variants on grazoprevir pharmacokinetics and efficacy. A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC) were: rs4149056 (risk allele C), one copy, 1.

Pharmacogenetic Analysis of OATP1B1, UGT1A1, and BCRP Variants in Relation to the Pharmacokinetics of Letermovir in Previously Conducted Clinical Studies.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration-time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.

Effect of tildrakizumab (MK-3222), a high affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis.

Aims: Tildrakizumab, an interleukin (IL)-23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL-23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease-drug interactions, in psoriasis patients was unknown.

The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis.

Background & Aims: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis.

Methods: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study.

Mobilizing pharmacogenomic analyses during clinical trials in drug development.

The utilization of pharmacogenomics (PGx) in drug development is increasing as pharmaceutical companies and regulatory agencies work to understand variation in response to medications. The implementation of PGx in clinical trials requires a number of considerations that begin early at the point of program development for a compound. This article will discuss the issues involved in mobilizing a PGx study during the conduct of a clinical trial, including the development of a PGx hypothesis, the identification of genetic markers for analysis, PGx platform selection and assay development, as well as challenges that arise in relation to global laws and regulations related to genetic research and logistical/timeline concerns in the execution of a PGx analysis.

Quantifying factors for the success of stratified medicine.

Co-developing a drug with a diagnostic to create a stratified medicine - a therapy that is targeted to a specific patient population on the basis of a clinical characteristic such as a biomarker that predicts treatment response - presents challenges for product developers, regulators, payers and physicians. With the aim of developing a shared framework and tools for addressing these challenges, here we present an analysis using data from case studies in oncology and Alzheimer's disease, coupled with integrated computational modelling of clinical outcomes and developer economic value, to quantify the effects of decisions related to key issues such as the design of clinical trials. This illustrates how such analyses can aid the coordination of diagnostic and drug development, and the selection of optimal development and commercialization strategies.

Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group.

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine).

Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting.

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear.

Methodology/principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis.

DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival.

Hepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification.

The value of banked samples for oncology drug discovery and development.

To gain insights into human biology and pathobiology, ready access to banked human tissue samples that encompass a representative cross section of the population is required. For optimal use, the banked human tissue needs to be appropriately consented, collected, annotated, and stored. If any of these elements are missing, the studies using these samples are compromised.

EMT is the dominant program in human colon cancer.

Background: Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.

Methods: We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.

Generating and weighing evidence in drug development and regulatory decision making: 5th US FDA-DIA workshop on pharmacogenomics.

The 5th US FDA-Drug Industry Association (DIA) workshop in a series on pharmacogenomics entitled: 'Generating and Weighing Evidence in Drug Development and Regulatory Decision Making', contained four major topics (tracks): 'Learning from Labels and Label Changes: How to Build Pharmacogenomics into Drug Development Programs'; 'Enabling Pharmacogenomic Clinical Trials Through Sampling'; 'Designing Pharmacogenomics Studies to be Fit for Purpose'; and 'Co-Development of Drugs and Diagnostics'. The meeting was attended by approximately 200 professionals, primarily involved in drug development and healthcare delivery. Several critical elements drove the success of the meeting: it was recognized that the enriched conversation at this workshop between regulators and drug developers was driven with less inhibition than before and with a greater scientific focus on the issues.

Asp92Asn polymorphism in the myeloid IgA Fc receptor is associated with myocardial infarction in two disparate populations: CARE and WOSCOPS.

Objective: Statins reduce inflammation and risk of myocardial infarction (MI). Because the myeloid IgA Fc receptor encoded by FCAR mediates inflammation, we hypothesized that the FCAR Asp92Asn polymorphism is associated with risk of MI and that this risk would be modified by pravastatin.

Methods And Results: In the placebo arm of the Cholesterol and Recurrent Events (CARE) study, male carriers of the 92Asn allele had an adjusted hazard ratio for incident MI of 1.

Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts.

Introduction: Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction.

Methods: We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years.

Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke.

Background And Purpose: The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial.