FIH

Pharmacologic inhibitors of cellular hydroxylase oxygen sensors are protective in multiple preclinical in vivo models of inflammation. However, the molecular mechanisms underlying this regulation are only partly understood, preventing clinical translation. We previously proposed a new mechanism for cellular oxygen sensing: oxygen-dependent, (likely) covalent protein oligomer (oxomer) formation. Here, we report that the oxygen sensor factor inhibiting HIF (FIH) forms an oxomer with the NF-κB inhibitor β (IκBβ)...

INTRODUCTION: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy...

Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH(SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BWh , a clearance exponent of 0...

Noncommunicable Chronic Diseases (NCD) are a socioeconomic burden and considered one of the major health challenges for coming decades. Mitochondrial dysfunction has been implicated mechanistically in their pathophysiology. Therefore, targeting mitochondria holds great promise to improve clinical outcomes in NCDs. SUL-138, an orally bioavailable small molecule efficacious from 0.5 mg/kg, improves mitochondrial function during disease in several preclinical animal models. As preparation for a First-in-Human (FIH) trial, SUL-138 was investigated in 30-day GLP repeated dose toxicity studies in rat and minipig, selected based on their comparability with human metabolism, to determine toxicokinetics, potential toxicity and its reversibility...

First-in-human (FIH) dose-escalation trials on oncology should prioritize safety and emphasize efficacy. We reviewed the FIH trials of 67 anti-tumor products approved by the Food and Drug Administration between 2018 and 2023 and found that the "3 + 3" design remains the predominant dose-escalation method (66.2%). The number of patients receiving sub-therapeutic doses is positively correlated with the maximum tolerated dose (MTD) or maximum dose (MD) to starting dose ratio (P = 0...

The objectives of this study were to support dose selection of a novel FXR agonist XZP-5610 in first-in-human (FIH) trials and to predict its liver concentrations in Chinese healthy adults. Key parameters for extrapolation were measured using in vitro and in vivo models. Allometric scaling methods were employed to predict human pharmacokinetics (PK) parameters and doses for FIH clinical trials. To simulate the PK profiles, a physiologically based pharmacokinetic (PBPK) model was developed using animal data and subsequently validated with clinical data...

Marine hypoxia poses a significant challenge in the contemporary marine environment. The horseshoe crab, an ancient benthic marine organism, is confronted with the potential threat of species extinction due to hypoxia, making it an ideal candidate for studying hypoxia tolerance mechanisms. In this experiment, juvenile Tachypleus tridentatus were subjected to a 21-day trial at DO:2 mg/L (hypoxia) and DO:6 mg/L conditions. The experimental timeline included a 14-day exposure phase followed by a 7-day recovery period...

BACKGROUND AND PURPOSE: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8)+ Treg cells in the tumour microenvironment through enhanced antibody-dependent cellular cytotoxicity (ADCC). EXPERIMENTAL APPROACH: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications...

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas...

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind...

The hypoxia-inducible factors are α,β-heterodimeric transcription factors that mediate the chronic response to hypoxia in humans and other animals. Protein hydroxylases belonging to two different structural subfamilies of the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase superfamily modify HIFα. HIFα prolyl-hydroxylation, as catalysed by the PHDs, regulates HIFα levels and, consequently, α,β-HIF levels. HIFα asparaginyl-hydroxylation, as catalysed by factor inhibiting HIF (FIH), regulates the transcriptional activity of α,β-HIF...

Cellular and tissue adaptations to oxygen deprivation (hypoxia) are necessary for both normal physiology and disease. Responses to hypoxia are initiated by the cellular oxygen sensors prolyl-4-hydroxylase domain (PHD) proteins 1-3 and factor inhibiting HIF (FIH). These enzymes regulate the transcription factor hypoxia-inducible factor (HIF) in a hypoxia-sensitive manner. FIH also regulates proteins outside the HIF pathway, including the deubiquitinase OTUB1. Numerous preclinical analyses have demonstrated that treatment with HIF hydroxylase inhibitors is beneficial and protective in many hypoxia-associated diseases...

OBJECTIVE: The creation of an arteriovenous fistula (AVF) is considered the most effective hemodialysis (HD) vascular access. For patients who are not suitable for AVF, arteriovenous grafts (AVGs) are the best access option for chronic HD. However, conventional AVGs are prone to intimal hyperplasia, stenosis, thrombosis, and infection. Xeltis has developed an AVG as a potential alternative to currently available AVGs based on the concept of endogenous tissue restoration. The results of the first 6-month follow-up are presented here...

AIM: This analysis was conducted to review the number, and describe the characteristics of first-in-human (FIH) Phase 1 clinical trials registered in India from 2008 to 2022. MATERIALS AND METHODS: The data were extracted from the Clinical Trials Registry - India database for all FIH Phase 1 clinical trials registered between 2008 and 2022. Early-phase trials that were not FIH trials (e.g., pharmacokinetic studies and drug-drug interaction studies) were excluded from the study...

BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692)...

In the drug development process, approximately 30% of failures are attributed to drug safety issues. In particular, the first-in-human (FIH) trial of a new drug represents one of the highest safety risks, and initial dose selection is crucial for ensuring safety in clinical trials. With traditional dose estimation methods, which extrapolate data from animals to humans, catastrophic events have occurred during Phase I clinical trials due to interspecies differences in compound sensitivity and unknown molecular mechanisms...

Activation of type I interferon (IFN-1) signaling is essential to protect host cells from viral infection. The full spectrum of IFN-I induction requires the activation of a number of cellular factors, including IκB kinase epsilon (IKKϵ). However, the regulation of IKKϵ activation in response to viral infection remains largely unknown. Here, we show that factor inhibiting hypoxia-inducible factor (HIF) (FIH), an asparaginyl hydroxylase, interacts with IKKϵ and catalyzes asparagine hydroxylation of IKKϵ at Asn-254, Asn-700, and Asn-701, resulting in the suppression of IKKϵ activation...

Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4-5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package...

INTRODUCTION: The differential diagnosis of focal biliary strictures comprises both malignant and benign conditions. We report a rare case of follicular cholangitis presenting with segmental stricture of the left hepatic duct. CASE DESCRIPTION: An asymptomatic 59-year-old male with no past medical history presented with dilation of the left intrahepatic bile ducts revealed as an incidental finding on an abdominal ultrasound. Blood examinations showed only a slightly elevated γ-glutamyl transferase (γGT) value, while carbohydrate antigen 19-9 (Ca 19-9) and serum immunoglobulin G4 (IgG4) were within normal range...

Tumorigenesis exemplifies the complex process of neoplasm origination, which is characterised by somatic genetic alterations and abnormal cellular growth. This multidimensional phenomenon transforms previously dormant cells into malignant equivalents, resulting in uncontrollable proliferation and clonal expansion. Various elements, including random mutations, harmful environmental substances, and genetic predispositions, influence tumorigenesis's aetiology. MicroRNAs (miRNAs) are now recognised as crucial determinants of gene expression and key players in several biological methods, including oncogenesis...