To be announced.
DDTSS Webinar—2022 Paper of the Year: Species-Specific Urothelial Toxicity with an Anti-HIV Noncatalytic Site Integrase Inhibitor (NCINI) Is Related to Unusual pH-Dependent Physicochemical Changes
Friday, May 13, 2022, 1:00 PM ET
Speaker: Ruth Roberts, PhD, ATS, FBTS, ERT, FRSB, FRCPath
Speaker: Leigh Ann Burns Naas, PhD, DABT, ATS, ERT
GS-9695 and GS-9822 are next-generation noncatalytic site integrase inhibitors (NCINIs) with significantly improved potency against human immunodeficiency virus compared with previous drugs such as BI-224436. Development stopped due to vacuolation of the bladder urothelium seen in cynomolgus monkey but not in rat; this lesion was absent in equivalent preclinical studies with BI-224436 (tested in dog and rat). Lesions were unlikely to be attributable to target because NCINIs specifically target viral integrase protein and no mammalian homologue is known. Secondary pharmacology studies, mitochondrial toxicity studies, immunophenotyping, and analysis of proteins implicated in cell-cell interactions and/or bladder integrity (E-cadherin, pan-cytokeratin, uroplakins) failed to offer any plausible explanation for the species specificity of the lesion. Because it was characterized by inflammation and disruption of urothelial morphology, we investigated physicochemical changes in the bladder of cynomolgus monkey (urinary pH 5.5–7.4) that might not occur in the bladder of rats (urinary pH 7.3–8.5). In measurements of surface activity, GS-9822 showed an unusual transition from a monolayer to a bilayer at the air/water interface with decreasing pH, attributed to the strong association between drug molecules in adjacent bilayer leaflets and expected to be highly disruptive to the urothelium. Structural analysis of GS-9822 and GS-9695 showed zwitterionic characteristics over the range of pH expected in cynomolgus monkey but not rat urine. This exotic surface behavior is unlikely with BI-224436 since it would transition from neutral to cationic (never zwitterionic) with decreasing pH. These data provide useful insights to guide discovery and development of NCINIs, related compounds, and zwitterions.
DDTSS Webinar: 2020 Paper of the Year Presentation
Wednesday, October 27, 2021 at 1:00 PM ET
Speaker: Christine Karbowski, PhD, Principal Scientist, Amgen
Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34þ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.
DDTSS Webinar: Understanding Neurotoxicity Assays and Interspecies Differences to Address Attrition in Drug Discovery
Thursday, April 15, 2021 at 2:00 PM ET
Attrition in drug discovery and development due to safety/toxicity issues remains a major challenge with cardiovascular and CNS toxicities predominating. Identifying neurotoxicity in drug discovery and development can improve our efficiency and accuracy of diagnosis. While early identification of neurotoxicity will enable early intervention, utilization of non-invasive biomarkers will also facilitate clinical trials of pharmaceutical interventions for many neurodegenerative conditions. Most guidelines for the evaluation of neurotoxic effects of chemicals/drugs for hazard and risk assessment are based on in vivo studies evaluating effects mainly on neurobehavior and neuropathology that have, to a certain extent, a predictive value. Implementation of in vitro neurotoxicity tests would accelerate the rate at which compound knowledge and mechanistic data are produced, however, no in vitro approaches for evaluating the neurotoxic hazard of compounds have been formally validated to date. First, Dr. Thomas Hartung will go over work using IPSC-derived 3D human brain organoids for neurotoxicity, drug development, and personalized medicine as well as using big data and artificial intelligence for predictive toxicology. Next, Dr. Remco Westerink will cover in vitro neurotoxicity assays with a focus on microelectrode array (MEA) recordings and discuss interspecies differences. These talks will be followed by a question and answer session.
Thomas Hartung, MD, PhD, Johns Hopkins, Professor and Doerenkamp-Zbinden Chairman for Evidence-based Toxicology
Remco Westerink, PhD, Utrecht University, The Netherlands
DDTSS Webinar: Insightful Tips for Career PlanningMonday, October 19, 2020 at 11:00 am EDT
Career planning is important in all stages of your career. During your journey, transitions are key times during which you can take action and decide how you want to grow and progress in your career. It is important to define your interests, build your career development plan, and be prepared for change. Every transition or change will bring other opportunities, new people, and new experiences and will represent a new challenge through which you can grow and increase your knowledge.
CTSS and DDTSS Webinar: Artificial Intelligence in the Design of Safer Medicines—Science or Science Fiction
Thursday, June 25, 2020 11:00 am Eastern Daylight Time (New York, GMT – 4:00)
Artificial Intelligence in the Design of Safer Medicines—Science or Science Fiction?
DDTSS Webinar: Nonclinical Safety Strategies for Gene Therapy
Tuesday, February 25, 2020 11:00 am Eastern Standard Time (New York, GMT–05:00)
Gene therapy has been a hot topic these recent years, with the first approvals allowing patients to be successfully treated. This increased interest in gene therapy resulted in a lot of potential therapies in preclinical and clinical development.
DDTSS Webinar: Lead Optimization Drug Safety Strategies for Small Molecules
Monday, October 29, 2018 at 11 am Eastern Daylight Time (New York, GMT–04:00)
Panelists, Zoe Zhong, PhD, DABT (Associate Director, Head of Small Molecule Discovery Toxicology at Genentech) and Mark Fielden, PhD, DABT (Scientific Director, Comparative Biology and Safety Sciences at Amgen), will provide insights on lead optimization strategies to increase selectivity, minimize off-target effects, and integrate assessments of in vitro and in vivo toxicology studies for rapid identification of clinical candidates. The intended audience is scientists across all career stages interested in deepening their knowledge of drug discovery.
DDTSS Webinar: Careers and Opportunities in Pharmaceutical Discovery Toxicology
Wednesday, April 5, 2017 11:00 am Eastern Daylight Time (New York, GMT–04:00)
This unique 90-minute webinar comprises two distinct presentations in which experts will discuss career development in the pharmaceutical drug discovery space.
Specific topics each speaker will discuss include:
Personal experience and career path development (how did they get here?)
We plan on a 5 minute intro from our president Ray Kemper, followed by a 20–25 minute presentation from each of the 2 speakers, with time for questions at the end.
DDTSS Webinar: Safety Assessment in a World of Expanding Immuno-oncology Approaches
Tuesday, January 24, 2017 11:00 am Eastern Standard Time (New York, GMT–05:00)
No Recording is available for this Webinar.
This unique 90-minute webinar comprises three distinct presentations in which experts will discuss safety assessment in the growing field of immuno-oncology research.
Nonclinical Safety Assessment of Checkpoint Inhibitors and Costimulatory Agonists
Evolution of Safety Assessment for T Cell-Dependent Bispecific Molecules