AMG-319

Telemetry‐based methods are recommended as best practice for monitoring changes in cardiovascular (CV) function in conscious nonrodent species during the development of new chemical entities. Such methods allow for unrestrained data collection in animals over extended time periods with high sensitivity to detect small effects. The CV profile of new drugs is also assessed in repeat‐dose toxicology studies, routinely utilizing non‐invasive blood pressure, heart rate, and ECG measurement methods that require physical or chemical restraint. These methods are limited to a short “snapshot” data collection period and incur physiological stress and behavioral excitement from handling/restraint during data collection. The resultant sympathetic activation impacts heart rate, blood pressure, and ECG intervals, causing increased variability and reduced sensitivity. Nonclinical best practices have been defined for standalone CV telemetry studies to support an integrated QTc risk assessment (ICH E14/S7B Q&A 5.1 & 6.1) using non‐restraint telemetry methods; however, the pharmacological and statistical sensitivity of restraint‐based methods used in repeat‐dose toxicology studies is a gap. This paper retrospectively analyzed two case studies (AMG 319 and AMG 337) in which proprietary small molecules were evaluated by both non‐restraint‐based telemetry and restraint‐based methods. AMG 319 and AMG 337 caused QTc interval prolongation and hypotension, respectively, in telemetry studies, which were also observed clinically with these compounds. However, in toxicology studies in which restraint‐based ECG and blood pressure methods were used, CV effects were missed, blunted, or directionally wrong. These case studies highlight the need for the utilization of unrestrained telemetry methods over restraint‐based methods.

The ribophorin family, including RPN1, has been associated with tumor progression, but its specific role in pan‐cancer dynamics remains unclear. Using data from TCGA, GTEx, and Ualcan databases, we investigated the relationship of RPN1 with prognosis, genomic alterations, and epigenetic modifications across various cancers. Differential analysis revealed elevated RPN1 expression in multiple cancer types, indicating a potential prognostic value. Amplification was the predominant mutation type of RPN1 in pan‐cancer, with notable correlations with DNA methylation and copy number variation. Gene set variation analysis identified RPN1's involvement in cancer development, immunity, and metabolism. Additionally, RPN1 expression correlated with the tumor microenvironment, immune response factors, and response to anti‐tumor therapies. Functional validation in triple‐negative breast cancer, glioblastoma, and bladder cancer cell lines demonstrated the role of RPN1 in tumor cell proliferation and migration. Our findings highlight RPN1 as a potential biomarker for cancer diagnosis and treatment response in pan‐cancer therapy.