Keynote Lecture: Janssen’s Effort in the Development of a COVID-19 Vaccine
Hanneke Schuitemaker, Janssen Vaccines and Prevention of J&J, Leiden, The Netherlands

In January 2020, when the genetic code of SARS-CoV-2 was published, Janssen started to work on a vaccine against COVID-19. A lead vaccine candidate, Ad26.COV2.S, was selected from 12 different spike protein designs, and leveraging the adenoviral vector platform. A single dose of this vaccine gave full protection in the lungs of challenge non-human primates and near complete protection in the nose. A first-in-human phase 1/2a study initiated in July 2020 and based on interim safety and immunogenicity results, a large (n=~44,000 participants) phase 3 efficacy study (ENSEMBLE), testing the protective efficacy of a single dose vaccine against moderate to severe COVID-19, was initiated in September 2020, in 8 different countries on 3 continents. End of January 2021, the primary analysis revealed the vaccine was safe and well tolerated, with an overall efficacy of 66% against moderate to severe COVID-19. A vaccine efficacy of >80% was observed against severe/critical COVID-19, with full protection against COVID-19 related hospitalizations and death, also in South Africa and Brazil where new SARS-CoV-2 variants of concern (B.1.351 and P2 lineage, respectively) were highly prevalent in COVID-19 cases in the trial. Ad26.COV2.S received Emergency Use Authorization from FDA in February 2021, conditional Marketing Authorization in EU and Emergency Use Listing from the WHO in March 2021, and conditional emergency use authorizations in countries worldwide.

Symposium 1: Latest Developments for Assessing the ADME of Biologics
Co-chairs: Dhaval Shah, University at Buffalo, Buffalo, New York, USA and Vittal Shivva, Genentech Inc., South San Francisco, California, USA

Disposition of Biologics is a very complex process, which depends on numerous drug and system related interactions. To facilitate the investigation of the key determinants responsible for the ADME of biologics, it is essential to develop novel analytical and experimental methods that can overcome the technical challenges associated with accurate and quantitative assessment of their disposition. Emerging techniques in this regard will not only help in establishing quantitative relationships between molecular properties and systemic exposure of biologics, but will also help in accurately characterizing and predicting the exposure of biologics at the site-of-action. In this session speakers will discuss novel state-of-the-art methods developed to assess the ADME of biologics.

Symposium 2: State of the Art Strategies to Enhance Brain Penetration of Small Molecules and Therapeutic Proteins 
Co-chairs: Marilyn Morris, University at Buffalo, Buffalo, New York, USA and Xiaoyan Chu, Merck & Co., Inc., Rahway, New Jersey, USA

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) separate the brain and cerebrospinal fluid (CSF) from the systemic circulation, representing a barrier to the permeation of endogenous compounds and both small molecules and therapeutic proteins into the brain.  Drug transporters at the BBB and BCSFB are involved in the brain uptake and efflux of many drugs.  This symposium will 1) provide an overview of current knowledge and perspectives on roles of transporters at the BBB and BCSFB;  2) present novel in vitro, in vivo animal and clinical approaches applied in the elucidation and characterization of brain penetration, as well as clinical translation; and 3) provide an in-depth discussion of physiologically-based pharmacokinetic models to describe brain distribution and time course of therapeutic drugs and proteins, as well as the influence of dosing regimens and potential alterations with disease.

Symposium 3: Identifying Biotransformations of Next Generation Biologics
Co-chairs: Mark Cancilla, Merck & Co., Inc., Blue Bell, Pennsylvania, USA and Brooke Rock, Amgen, South San Francisco, California, USA

The increased complexity of biologic drug modalities has changed our understanding of their pharmacokinetic and metabolic assessment. The overall stability of a chemically modified or engineered proteins upon administration has been demonstrated to be linked to its efficacy. This session will focus on identifying biotransformations of complex biologics to further understand their metabolic fate as well as to aid in their design for the assessment of their therapeutic potential.

Symposium 4: Epigenetics in Drug Disposition and Drug Therapy
Chair: Ann Daly, Newcastle University, Newcastle Upon Tyne, United Kingdom

Epigenetics including DNA methylation, miRNA expression and histone modification contributes to the global gene expression including those relevant to xenobiotic metabolism and transport as well as disease processes including cancer. Though considerably progress has been made in this area, this is still a relatively poorly understood area with changes in epigenetic regulation due to disease and environmental factors of particular importance. Drugs that modulate epigenetic modification of gene expression are increasingly available and are especially relevant to oncology. This symposium will aim to cover both the drug disposition and drug discovery aspects of this area.

Plenary Lecture 1: The Economics of the Pharmaceutical Industry
Joseph DiMasi, Tufts Center for the Study of Drug Development, Boston, Massachusetts, USA

The new drug development process is highly costly, very lengthy, and fraught with risk.  This presentation will show data on the trends in drug development and regulatory approval cycle times, transition probabilities for clinical phases, approval success rates for clinical development, and pharmaceutical R&D costs.  Drug development metrics vary by therapeutic area and for classes within therapeutic areas, and this will be demonstrated through a number of analyses, including for drugs to treat infectious diseases and cancer.  The extent to which firms compete in development of therapies within therapeutic classes will also be examined through empirical analysis.

Symposium 5: Driving Innovation in Qualitative and Quantitative Bioanalysis
Co-chairs: Lucinda Hittle, Merck & Co., Inc., Rahway, New Jersey, USA and Valerie Kramlinger, Novartis, Cambridge, Massachusetts, USA

As a partnership between the ISSX Bioanalysis in ADME Science and Biotransformation Mechanisms and Pathways Focus Groups, this session will present various aspects of quantitative and qualitative analysis. Topics include novel informatics, instrumentation and imaging; approaches will be presented with an emphasis on application to both small and large molecules. The objective of this session is to highlight state-of-the-art methodologies that are being applied to continuously improve bioanalytical and biotransformation capabilities for xenobiotics.

Symposium 6: Beyond Rule of 5
Co-chairs: Per Artursson, Uppsala University, Uppsala, Sweden and Dehua Pei, The Ohio State University, Columbus, Ohio, USA

The drug space beyond rule of five (bRo5) is populated with drug molecules that are substantially larger than traditional drugs. These include macrocycles, cyclic and stapled peptides as well as PROTACs (degraders). bRo5 drugs can interact with promising intracellular targets that are “difficult-to-drug” using traditional membrane permeable molecules. For instance, bRo5, but not traditionally sized molecules can target protein-protein interactions, which typically have large, featureless, flat or groove-shaped interfaces. While bRo5 drugs offers the opportunity to expand the number of “druggable” intracellular targets, they have well known drawbacks, including poor membrane permeability and oral bioavailability. This has stimulated the search for solutions that improve intracellular uptake and transcellular permeability, respectively. In this session, factors that influence the uptake and permeability of bRo5 compounds will be presented. Innovative approaches that increase intracellular target access will be covered and case stories from ADME and DMPK optimization of cyclic peptides and degraders in the pharmaceutical industry will be reviewed.

Plenary Lecture 2: The Projection of Drug Interactions Caused by Time-Dependent Inhibition of CYP3A

Drug interactions (DDI) caused by cytochrome P4503A time-dependent inhibition (TDI) are common. In vitro assays to study TDI for new drug candidate molecules are employed in an effort to predict the magnitude of DDI or, better still, to aid in the design of alternate molecules that lack this property. A challenge has been that in vitro TDI assays appear to be very sensitive and approaches used to scale these data frequently result in over-predictions of DDI. Research results will be shared that address this problem, including a comparison of TDI data generated in human liver microsomes and primary human hepatocyte suspensions. Alternate proposals of the most appropriate estimates for in vivo concentrations of TDIs for reliable projections DDI will be discussed.

Symposium 7: ADME Success Stories
Co-chairs: Marcel Hop, Genentech Inc., South San Francisco, California, USA and Dermot McGinnity, AstraZeneca, Cambridge, United Kingdom

Scientists from a range of companies will present both preclinical and clinical ADME data that have not been presented in detail before. They will describe the process of identification of a clinical candidate with optimal ADME properties and the struggles encountered and necessary compromises throughout the process. Human PK predictions and the corresponding clinical PK, metabolism and DDI data will be included as well.

Symposium 8: New Strategies for Overcoming ADME Hurdles for Nucleic Acid
Co-chairs: Jessica Hawes, Food and Drug Administration, Silver Spring, Maryland, USA and Donglu Zhang, Genentech Inc., South San Francisco, California, USA

This symposium will cover the most recent advances in the development of new nucleic acid therapeutics, including ASO, siRNA, mRNA, and miRNA drugs. Areas of discussion include the principles, promise, and challenges of developing nucleic acid-based therapeutics, with special focus on new strategies for improving ADME, pharmacokinetic and pharmacodynamic (PK/PD) properties of nucleic acid drugs. Four leading investigators in the fields will present the most recent findings and lead the discussion of new nucleic acid medications. Attendees are expected to learn the fundamental principles and new strategies in discovery and development of nucleic acid therapeutics.

Symposium 9: New Approaches to Improve the ADME Kinetics of Biologics
Co-chairs: Joseph Balthasar, University at Buffalo, Buffalo, New York, USA and Greg Thurber, University of Michigan, Ann Arbor, Michigan, USA

Biological agents such as siRNA, mRNA, peptides, and proteins often exhibit poor in vivo absorption, distribution, and elimination kinetics. This symposium highlights recent advances in the development of optimization strategies for the ADME of biologics, including approaches to enable improved oral and subcutaneous bioavailability, new methods to extend persistence / half-life, and strategies to improve tissue selectivity / targeting and within-tissue distribution. Speakers will review ADME challenges and discuss optimization methods, with in-depth discussion of solutions that have been recently advanced within their laboratory.

Symposium 10: Non-invasive Approaches for Drug Disposition Prediction: Biomarkers, Liquid Biopsies and PBPK Modeling
Co-chairs: Bhagwat Prasad, Washington State University, Spokane, Washington, USA and A. David Rodrigues, Pfizer Inc., Groton, Connecticut, US

Characterization of variability in drug disposition is important for clinical study design and for individualized drug treatment. Because variability in drug disposition cannot be completely described by genetics, characterization of phenotypic variability is ideal. The use of non-invasive exosomes (i.e., isolated from biofluids) and endogenous biomarkers are emerging tools for prediction of drug metabolism and transport. Integration of metabolomics and proteomics data from tissue, blood, urine or exosomes into PBPK modeling provides a translational tool for better prediction of drug disposition. This symposium will provide an update on various non-invasive and in silico approaches of in vivo drug disposition prediction.

Plenary Session: Predicting the Unpredictable – Idiosyncratic Drug Toxicity
Co-chairs: Amit S. Kalgutkar, Pfizer Inc., Cambridge, Massachusetts, USA and Kaushik Mitra, Janssen Pharmaceutica

Cumulative research over several decades has implicated the involvement of bioactivation (formation of electrophilic reactive species) in idiosyncratic drug toxicity. Consequently, “avoidance” strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds. The symposium will focus on the recent progress on the limitations of the structural alert avoidance strategy and novel strategies to assess idiosyncratic toxicity in preclinical/clinical drug discovery paradigm.