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Population pharmacokinetic modeling of asciminib in support of exposure-response and ethnic sensitivity analyses in patients with chronic myeloid leukemia.
No full textThe original population pharmacokinetics (popPK) model for asciminib in patients with chronic myeloid leukemia in chronic phase (CML-CP) was refined to address drug development needs in support of drug submission, namely, attainment of target drug exposure in specific patient populations, populating individual daily exposures for exposure-response analyses of key efficacy and safety endpoints, confirmation of comparability in exposure between 40 mg b.i.d. and 80 mg q.d., and assessment of ethnic insensitivity.Participants from two organ dysfunction studies, patients with CML in blast and acute phases and acute lymphoblastic leukemia and patients from a phase III efficacy study in newly diagnosed Ph + CML-CP, and data from a dedicated phase II study in the Chinese patients previously treated with at least two prior tyrosine kinase inhibitors, and a phase IIIb study comparing two dose regimens of asciminib (40 mg b.i.d. and 80 mg q.d.) were included in the revised popPK model. Covariates evaluated were line of therapy, baseline renal and hepatic functions, Chinese or Japanese ethnicity.The apparent clearance and steady-state volume of distribution of asciminib were 6.84 L/h and 110 L, respectively, for a typical individual of 70 kg weight and 90 mL/min absolute glomerular filtration rate. Both the 40 mg b.i.d. and 80 mg q.d. resulted in a steady-state daily AUC of 12,600 ng.h/mL, and there was no difference between lines of therapy. Effects of renal or hepatic impairment on clearance were not clinically relevant. Chinese and Japanese exhibited similar PK as that of the global population.The 40 mg b.i.d. and 80 mg q.d. regimens are comparable in their daily exposure, supporting the use of the two dosing regimens in newly diagnosed and previously treated CML-CP patients. The PK of asciminib is insensitive to ethnic differences and no dose adjustment is required for severe renal and hepatic impaired patients
Comprehensive extractables and leachables sensitization analysis and practical application of a risk-based approach to sensitization assessment for parenteral drug products.
No full textThe Extractables and Leachables Safety Information Exchange (ELSIE) Consortium added to the sensitization potency analysis of Parris et al. (2023) by including the Product Quality Research Institute (PQRI) extractable and leachable dataset (Johnson et al., 2024; Product Quality Research Institute, 2021). This analysis of the comprehensive E&L dataset showed 5% of chemicals (20/407) had experimental results demonstrating or were predicted to be potent (strong or extreme) sensitizers, supporting the previous conclusion, that potent sensitizers are of low prevalence and are not routinely observed as leachables in pharmaceutical products. By accounting for prevalence of sensitization in the overall E&L dataset, the probability of any potential leachable being more potent than the less than lifetime ICH M7 (10, 20, and 120 μg/day for human exposure of >1-10 years, >1-12 months, and 10 years to lifetime, >1-10 years, and ≤1 year respectively) (Masuda-Herrera et al., 2022) was considered. The M7 and ELSIE thresholds are anticipated to provide ≥95% coverage of induction of sensitization, supporting the use of these thresholds to set the Safety Concern Threshold (SCT)
PretoxtTM: a text mining system for extracting treatment-related findings from preclinical toxicology reports
No full textOver the last few decades the pharmaceutical industry has generated a vast corpus of knowledge on the safety and efficacy of drugs.
Much of this information is contained in toxicology reports, which summarise the results of animal studies designed to analyse the
effects of the tested compound, including unintended pharmacological and toxic effects, known as treatment-related findings.
Despite the potential of this knowledge, the fact that most of this relevant information is only available as unstructured text with
variable degrees of digitisation has hampered its systematic access, use and exploitation. Text mining technologies have the ability
to automatically extract, analyse and aggregate such information, providing valuable new insights into the drug discovery and
development process. In the context of the eTRANSAFE project, we present PretoxTM (Preclinical Toxicology Text Mining), the
first system specifically designed to detect, extract, organise and visualise treatment-related findings from toxicology reports. The
PretoxTM tool comprises three main components: PretoxTM Corpus, PretoxTM Pipeline and PretoxTM Web App. The PretoxTM
Corpus is a gold standard corpus of preclinical treatment-related findings annotated by toxicology experts. This corpus was used to
develop, train and validate the PretoxTM Pipeline, which extracts treatment-related findings from preclinical study reports. The
extracted information is then presented for expert visualisation and validation in the PretoxTM Web App
Reversible Covalent Reactions of Aldehydes and Salicylaldehydes Using a Lysine-Model Substrate.
No full textCovalent modification of lysine residues has gained significant attention due to its potential application in drug development and chemical biology. Lysine is an essential amino acid, abundant in proteins, and plays a critical role in many biological processes. In this study, we investigated aldehydes for imine-based chemistries and their reactivity profiles using a lysine-surrogate. By monitoring reactions of various aldehydes and salicylaldehydes over time, we determined dissociation constants (KD) for each warhead, reflecting the binding affinity towards the surrogate substrate. Strikingly, our data revealed remarkable differences in affinity depending on the substitution of the warheads. Additionally, we analyzed the kinetic profile of selected aldehydes and salicylaldehydes, which revealed significant disparity in their reaction kinetics. Aldehydes reacted quickly, reaching equilibrium rapidly, whereas salicylaldehydes exhibited considerably slower reaction times, in some cases requiring several hours to reach equilibrium. These differences emphasize how the nature of the warhead structure influences the kinetics of covalent binding to lysine residues. Overall, our study provides valuable insights into the application of reversible covalency to target lysines with reactive warheads that can further inspire development of innovative chemical modifications for drug discovery and chemical biology
Identification and characterization of binders to a cryptic and functional pocket in KRAS.
No full textRAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors
Role of restraints on hydrogen atoms in Hirshfeld Atom Refinement: the case of tri-aspartic acid trihydrate
No full textTwo polymorphs of L-Asp-L-Asp-L-Asp (DDD) trihydrate were investigated with the quantum-crystallographic refinement technique Hirshfeld Atom Refinement (HAR) as model compounds for biologically important proton-shuttle reactions. With HAR, hydrogen atom positions were refined freely against the X-ray diffraction data and yielded X-H bond distances close to those from neutron diffraction. However, the X-ray data of DDD trihydrate do not carry enough information to refine hydrogen atom anisotropic displacement parameters (ADPs), while they are considered to be of similar quality as normal oligopeptide or protein datasets, including disordered fragments. Therefore, ISOR, SIMU, DELU, and RIGU restraints were tested for the hydrogen atom ADPs. Although it was found that there is no significant influence of the restraint weights and corresponding ADP values on the X-H distances, some recommendations on hydrogen atom ADP restraint weights to be used in HAR are given. For ISOR, the suggested values are 10 times smaller (stricter) than the default values for non-hydrogen atoms in IAM refinements, whereas those for RIGU are suggested to be less strict
A Call To Action: Developing an Agile Global Regulatory Affairs Workforce for the Future.
No full textAs leaders of biopharmaceutical regulatory affairs organizations, we must learn from the past, thrive in the present and strive for an even better future. We understand the strategic role regulatory affairs professionals play in biopharmaceutical companies, one that uniquely spans the entire continuum of drug development. Our professionals must navigate the increasingly complex regulatory environment, strengthening company engagement with global regulators and other stakeholders to successfully deliver innovative products to patients. Our organizations are only as strong as the people on our teams. As the future of therapeutic development changes in response to technological and scientific advances, we have an obligation to develop, recruit and retain top talent, and build a competency framework to not only meet today’s demands, but to better equip the workforce of the future to improve patients’ access to treatments. There is a great opportunity before us–upskilling our current professionals, attracting individuals with a diversity of expertise into the profession, and setting up the next generation for dynamic and successful careers. This is a call to action for professional societies, academic organizations, regulators, biopharmaceutical companies, and other interested stakeholders to prepare and develop the Global Regulatory Affairs workforce of the future
Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules.
No full textSmall-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2-4 chimeric channel in Ca2+-bound and Ca2+-free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3-S4 linker forms a hydrophobic constriction at the extracellular opening of the pore. Apamin binds to this extracellular constriction and blocks the exit of potassium ions. Furthermore, we identified a structurally related SK2 inhibitor and activator that bind to the transmembrane domains. The compounds exert opposing effects on gating by differentially modulating the conformation of the S6 helices. These results provide important mechanistic insights to facilitate the development of targeted SK2 channel therapeutics
Isolated oral CD30+/CD4+ CAR+ T cell lymphoma in long-term remission after radiotherapy.
No full textA chimeric antigen receptor (CAR)+ CD30+/CD4+ T cell lymphoma (TCL) manifested as a single oral ulceration 22 months after treatment with tisagenlecleucel (tisa-cel), an anti-CD19 CAR T cell-based therapy. The TCL showed lentiviral integration in ANKHD1-EIF4EBP3, loss of function of TET2, and NTRK1 copy number gain, suggesting that genetic alterations unrelated to insertional mutagenesis contributed to lymphomagenesis. The patient remains in remission 2 years after radiotherapy. This is the only CAR+TCL case reported at the Ohio State University James Comprehensive Cancer Center out of 288 patients treated with CAR-T cells
Cell-Specific Functions of the BAI/ADGRB Subfamily of Adhesion G-Protein Coupled Receptors.
No full textAdhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and to establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly evident. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in the field and provides a comprehensive assessment of the current understanding of aGPCR biology here. This includes a focus on human and mammalian aGPCRs, their evolutionary origins, methodological approaches and model systems for their investigation, as well as emerging approaches for their therapeutic targeting