Re-PERFUSE: Phase 1b study of AZD3427, a novel relaxin receptor agonist, on renal perfusion in HFrEF patients.

Aims: Renal impairment frequently coexists with heart failure (HF) and is associated with increased risk of poor clinical outcomes. This highlights the urgent need for therapies targeting both cardiac and renal dysfunction. AZD3427, a long-acting recombinant fusion protein and relaxin analogue that selectively activates the relaxin family peptide receptor 1 (RXFP1), showed trends of increased stroke volume and estimated glomerular filtration rate (eGFR) in HF patients (NCT04630067).

A Phase 1b Randomized Clinical Trial of AZD5642 and Dapagliflozin in Patients with Heart Failure and Moderate Renal Impairment.

AZD5462 is the first oral selective relaxin/insulin-like family peptide receptor 1 agonist in clinical development. The aim of this mechanistic study is to investigate the renal effects of AZD5462 when administered on top of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in participants with heart failure and moderate renal impairment. AURORA is a phase 1b, placebo-controlled, double-blind, 2-centre study of AZD5462 on top of dapagliflozin as standard of care in 2 arms.

Efficacy and Safety of Zabedosertib, an Interleukin-1 Receptor-Associated Kinase 4 Inhibitor, in Patients with Moderate-to-Severe Atopic Dermatitis: A Phase II Randomized Study.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is expressed in various immune cells and regulates proinflammatory cytokine production. Its inhibition represents a novel, promising therapeutic option in the treatment of atopic dermatitis (AD). Zabedosertib (BAY1834845) is a potent, selective IRAK4 inhibitor that suppresses markers of local and systemic immune responses.

Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression.

Background: Previous cross-sectional transcriptomics studies on diabetic kidney disease (DKD) kidney tissue have shown correlations between gene expression and both disease status and kidney function at the time of biopsy; however, longitudinal data are scarce.

Methods: We utilized clinical follow-up data up to five years post-biopsy, linking the transcriptomes of diagnostic kidney biopsies to progression rates and outcomes in 19 patients with DKD. Patients were stratified into “rapid progressors” and “non-rapid progressors” based on clinical parameters (eGFR slope, CKD stage advancement, degree of albuminuria, composite outcome of kidney failure or 40% eGFR decline).

First-in-human study of an EGFRvIII x CD3 T cell bispecific antibody in the treatment of newly diagnosed glioblastoma.

Background: This first-in-human study evaluated EGFRvIII × CD3 TCB, a novel T cell bispecific antibody, in patients with newly diagnosed EGFRvIII-positive glioblastoma.

Methods: Patients with newly diagnosed glioblastoma received escalating doses of EGFRvIII × CD3 TCB following chemoradiation. The primary objectives were to evaluate safety/tolerability and define the maximum tolerated dose (MTD); secondary objectives included pharmacokinetics (PK), immunogenicity, pharmacodynamics, and clinical activity.

Population Exposure-Response Efficacy Analysis of Elranatamab (PF-06863135) in Patients with Multiple Myeloma.

Background: Elranatamab is a heterodimeric humanized full-length bispecific antibody composed of one B-cell maturation antigen (BCMA) binding arm and one cluster of differentiation 3 (CD3) binding arm. Results from the MagnetisMM-3 study indicated deep and durable responses in patients with relapsed or refractory multiple myeloma (RRMM).

Objective: The current analysis was conducted to characterize the relationship between free (i.

Deciphering differential biomarkers for anti-interleukin-6 receptor and anti-tumour necrosis factor-α treatment response in rheumatoid arthritis by multiomics analysis.

Objective: To identify blood-based predictive and pharmacodynamic biomarkers at different timepoints in patients with active rheumatoid arthritis (RA) treated with anti-interleukin-6 receptor (anti-IL-6R) and anti-tumour necrosis factor-α (anti-TNF-α).

Methods: This study used blood samples from the MONARCH trial (NCT02332590), a randomised, double-blind, phase III trial that compared the safety and efficacy of sarilumab (anti-IL-6R) and adalimumab (anti-TNF-α) monotherapy in patients with RA who were intolerant/inadequate responders to methotrexate. The study evaluated predictive biomarkers to anti-IL-6R and anti-TNF-α treatments at baseline and week 2 and pharmacodynamic biomarkers at week 2 and week 24 using Olink proteomics analysis (n=804 serum samples from 268 patients).

Dystrophin/mini-dystrophin expression analysis by immunoaffinity liquid chromatography-tandem mass spectrometry after gene therapy for DMD.

Adeno-associated virus (AAV)-based gene replacement therapies in Duchenne muscular dystrophy (DMD) aim to restore dystrophin function via the introduction of micro- or mini-dystrophins. We report dystrophin and mini-dystrophin concentrations generated by immunoaffinity liquid chromatography-tandem mass spectrometry (IA-LC-MS/MS) in skeletal muscle biopsies from ambulatory participants with DMD in a phase 1b study of fordadistrogene movaparvovec, an AAV9-based gene replacement construct. The assay performed robustly for 26 months, as demonstrated by limited variability in calibration standards for peptides LLQV (dystrophin and mini-dystrophin) and LEMP (mini-dystrophin only), quality control samples consisting of spiked mini-dystrophin in DMD skeletal muscle lysate, as well as unspiked, pooled, non-dystrophic skeletal muscle lysate (normal pool).

Biotransformation research advances - 2024 year in review.

This is the ninth installment of this annual review. In line with previous years, the primary objective is to highlight articles deemed by us of significant interest in the broad field of biotransformation. Sixteen manuscripts have been collated and presented herein accompanied by a synopsis, commentary and relevant figures.

Bioactivation and reactivity research advances-2024 year in review.

Bioactivation continues to be an important aspect of compound evaluation during drug discovery and development, as understanding the metabolic pathways that can lead to the formation of reactive metabolites can facilitate the design of safer drugs. This year's review on bioactivation and reactivity features 17 articles that reflect the latest advances and findings in this research area. This collection of articles is organized into three general themes: (1) mechanisms of bioactivation and the impact of bioactivation on safety, (2) new assays for assessing reactive metabolite formation, and (3) computational approaches for predicting reactive metabolite formation.

ONO-4578 Plus Nivolumab in Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer.

ONO-4578, an EP4 antagonist, alone and combined with nivolumab, showed acceptable safety profiles and signs of antitumor activity in solid tumors. The expansion part examined the safety, preliminary efficacy, and biomarkers of ONO-4578 plus nivolumab in unresectable advanced or recurrent gastric or gastroesophageal junction (G/GEJ) cancer. Patients were enrolled into three groups: with previous immuno-oncology treatment (IO-treated; n = 30), without IO treatment (IO-naive; n = 30), and with UGT1A1 polymorphism (UGT1A1p; n = 6).

Exploratory Analysis of Practical Predictive Indices for the Efficacy of Mogamulizumab in Patients With Aggressive Adult T-Cell Leukemia-Lymphoma.

An exploratory analysis of past clinical trials was conducted to propose a predictive scoring system for the efficacy of mogamulizumab, an anti-CC chemokine receptor 4 (CCR4) antibody, based on easily measurable parameters. Factors affecting progression-free survival (PFS) were investigated using data from three clinical trials (NCT00920790, NCT01626664, and NCT01173887) and one clinical study (UMIN000013294) conducted in patients with relapsed/refractory (R/R) or untreated CCR4-positive aggressive adult T-cell leukemia-lymphoma (ATL) receiving mogamulizumab treatment. Twelve routinely measured clinical parameters and three calculated indices-lymphocyte-to-neutrophil count ratio, platelet-to-lymphocyte count ratio, and lymphocyte-to-monocyte count ratio (LMR)-were selected as variables.

Challenges and opportunities in assessing right ventricular structure and function: a Roadmap for standardization, clinical implementation and research.

Given its crucial role in determining patient symptoms and outcomes in various cardiopulmonary diseases, the thorough and accurate assessment of right ventricular function is essential for both diagnosis and ongoing patient monitoring. In the era of precision medicine, a more detailed characterization of patients with cardiopulmonary diseases is needed, especially with the emergence of novel pharmacological and device-based therapies, such as transcatheter tricuspid valve intervention, gene therapy in patients with cardiomyopathy and anti-obesity interventions for patients with heart failure. Precise and reproducible quantification of right ventricular morphology and function are crucial for risk stratification, the selection of different therapies for the appropriate patients and the evaluation of treatment outcomes.

Untangling "dissolved" drug species from various formulations of a poorly soluble drug: Sampling methods, mechanistic insights, and IVIVC.

Our study aimed to both provide comprehensive mechanistic enlightenment of the dissolution, supersaturation, and precipitation behavior of different formulations using various sampling approaches, as well as evaluate the predictive capabilities by in vitro in vivo correlation (IVIVC). In vitro two-stage dissolution tests, that simulate the transfer from gastric to intestinal phases, using four different formulations at two dose strengths of the poorly water-soluble and weakly basic drug emodepside were performed. During the two-stage dissolution tests, five different sampling approaches were employed simultaneously (in situ 2 derivative UV spectroscopy, benchtop centrifugation, filtration, nanofiltration, and microdialysis).

Current practices on the measurement of electrocardiogram and hemodynamic parameters in non-rodent species in regulatory safety assessment studies.

Introduction: Cardiovascular (CV) parameters such as blood pressure (BP), electrocardiogram (ECG), and heart rate (HR) are recorded in non-rodent non-clinical safety studies to support drug development. However, measurement quality varies depending on the methodology used, including restraint-based or telemetry (implanted or jacketed) techniques. Measurement quality, in this context, refers to the sensitivity and reliability of CV measurements in affecting baseline values of measured CV parameters and in detecting pharmacological effects.

Phase I Study of the Anti-interleukin 33 Fragment Antigen-Binding Region RO7303359 in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Purpose: Interleukin (IL) 33 is a potent proinflammatory cytokine and a potential target in age-related macular degeneration (AMD) pathophysiology. This study evaluated RO7303359, an anti-IL-33 fragment antigen-binding region (Fab) targeting the IL-33/serum stimulation-2 (ST2) pathway, in patients with geographic atrophy (GA) secondary to AMD.

Design: Phase I, open-label, multicenter, single-dose, dose-escalation study.

A phase 1 study evaluating the safety, tolerability, and pharmacokinetics of the porcupine inhibitor, AZD5055.

Excessive Wnt signaling contributes to the development of fibrotic diseases and cancer. Here, we report the findings of a phase 1 study evaluating AZD5055, an orally administered porcupine inhibitor, which inhibits Wnt signaling. The primary objective was to evaluate the safety and tolerability of AZD5055 in healthy volunteers.

A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants.

Introduction: Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1.

Methods: This 2-part Phase I trial enrolled healthy participants aged 18-55 years.

Zabedosertib, a novel interleukin-1 receptor-associated kinase-4 inhibitor, shows a favorable pharmacokinetic and safety profile across multiple phase 1 studies.

Introduction: Zabedosertib, the interleukin-1 receptor-associated kinase-4 (IRAK4) inhibitor, is in clinical development as an oral therapeutic for immune-mediated inflammatory diseases and was thoroughly investigated in several phase 1 studies in healthy male volunteers.

Methods: Pharmacokinetics, safety, and tolerability of zabedosertib were characterized in two clinical phase 1 studies with single oral doses up to 480 mg and multiple oral doses up to 200 mg twice daily over 10 consecutive days. The absolute oral bioavailability was determined in a third study using the intravenous microtracer methodology.

Interlaboratory study to assess precision and reproducibility of the meningococcal antigen surface expression (MEASURE) assay to quantify factor H binding protein expression at the surface of meningococcal serogroup B strains.

Background: The serum bactericidal antibody using human complement (hSBA) assay, the accepted surrogate measure of meningococcal vaccine efficacy, is limited by human sera and complement requirements. Pfizer developed and validated the flow-cytometry-based Meningococcal Antigen Surface Expression (MEASURE) assay to quantify surface-expressed factor H binding protein (fHbp) levels on intact meningococci. Surface expression of fHbp is correlated with hSBA assay killing by MenB-fHbp (Trumenba)-induced antibody, meaning the MEASURE assay can be used to predict meningococcal serogroup B (MenB) strain susceptibility to antibodies elicited by MenB-fHbp.

Combined TNF-α and OX40L targeting as a new treatment option for hidradenitis suppurativa.

Background: Chronic inflammatory conditions are among the leading causes of disability and mortality. Although therapies have been significantly improved with the introduction of target-specific biologics, many chronic inflammatory conditions can be only moderately controlled by inhibition of individual cytokines.

Objective: We sought to compare individual versus simultaneous blockade of TNF-α and OX40L in controlling inflammation.

Results from an EFPIA, JPMA, PhRMA industry survey on reopening and revamping the ICH S7A guidance on safety and secondary pharmacology.

The ICH S7A guideline on safety pharmacology has remained unchanged since its inception in 2000, fulfilling its crucial role in safeguarding clinical trial participants and patients (ICH S7A). However, in the meanwhile there has been significant scientific and technological advancements in drug safety science, a paradigm shifts of the drug discovery and development process, and an continuously evolving regulatory landscape, that led to the recommendation to revisit, adapt and evolve the ICH S7A guideline (Valentin & Leishman, 2023, 2025). A revision of the guidance would imply opening an ICH process, the first step consists in the development of a 'concept paper'.