This is the second article in a five-part blog series about TransCelerate’s data sharing initiatives. Future topics in this series will include our work on data sharing to support a robust response to COVID-19, patient privacy, and historical trial data sharing, among others.
The value chain of developing new medicines to treat complex diseases in humans begins with research in the lab. This “bench-side to bedside” approach ensures we collect as much information on the safety and mechanisms of a new molecule before it is used in a first-in-human clinical trial. Starting by identifying and isolating the molecules that may one day help a patient recover from a once-devastating disease, researchers then must develop understanding of the toxicology profile of a molecule using various forms of non-clinical research.
TransCelerate’s subsidiary BioCelerate aims to make the operations of nonclinical research more efficient, with seven sponsors as members of the organization. The group began with data sharing as its first initiative, specifically the sharing of toxicology and background control data in animals, due to its early-stage importance for high-quality therapeutics development. The Toxicology & Background Control Data Sharing Initiative supports companies in the biopharma research ecosystem to make data-driven decisions on compound progression. Sharing this data among researchers in the biopharma community can help to greatly improve early-stage decision-making. The design of the data sharing initiative has been described in detail in our manuscript “Toxicology Data Sharing: Leveraging Data Sharing to Enable Better Decision Making in Research and Development.”
BioCelerate’s Toxicology and Background Control modules within DataCelerate® are used to store, analyze, and visualize toxicology data and unstructured data formats. The database solves many of the pain points in early-stage therapeutics development by enhancing the community’s overall understanding of target-related toxicity. Datasets within individual companies are limited and the lack of a centralized, searchable repository makes it difficult for investigators to answer questions related to on-target or off-target toxicity. There is also often a lack of published toxicity study results, further reducing the ability of researchers in the ecosystem to find what they need in the literature. Pooled toxicology and background control data can help to identify flawed compounds earlier in the process, optimize future study design, and provide greater context on the significance of rare or incidental findings.
By sharing these data among participating companies, BioCelerate has provided biopharma researchers with increased confidence in early-stage decision-making. As data volume increases over time, new insights can emerge to enhance the biopharma community’s collective understanding of toxicology. Finally, the toxicology database can reduce animal use by optimizing toxicity study design, thereby improving efficiency and speed of nonclinical development.
The BioCelerate team has already seen many successes in the biopharma research community due to implementation and use of the toxicology and background control database. Among other organizations that have utilized the database, TransCelerate Member Companies Shionogi and Bristol Myers Squibb (BMS) have demonstrated its utility, which will be discussed in more detail in the following sections.
Shionogi: Using Toxicology Data Sharing to Identify Adrenal Toxicity
Pre-clinical researchers at Shionogi used the toxicology database to search for a target of interest using the Pharmacologic Class (PCLASS) parameter that is populated for each study in the Toxicology Module within DataCelerate®. The team found two studies that had targeted the relevant enzyme of interest. Combined with Shionogi’s own data, a total of four studies were analyzed. In all studies, adrenal toxicity findings were observed. The consistent adrenal findings could indicate a target-based toxicity rather than a structural compound class-effect toxicity for this pharmacological target. In the future, Shionogi plans to use DataCelerate® to find similar pharmacology targets and analyze or investigate the toxicity to develop its risk assessment strategy before development.
Bristol Myers Squibb: Comparing Toxicity Profiles
Using the BioCelerate database, the BMS team gained a better understanding of the toxicity profile for one of its compounds by comparing its data to studies conducted by another sponsor against the same target. Combined with BioCelerate’s own toxicology data, a total of six studies were interrogated and results compared in terms of doses, systemic exposures, and target organs of toxicity in both species. The results showed similar key target organs, suggesting an on-target toxicity rather than a chemotype-specific, off-target toxicity for this pharmacological target. Additionally, the microscopic findings partially overlapped with findings with the BMS compound, suggesting that they may represent an evolving spectrum of the same type of lesion.
Working with the data available in the database gave the team greater confidence that its compound might be well tolerated by patients. Moving forward, sharing data from the chronic studies can be extremely valuable for the biopharma research community and could help research sponsors make more informed decisions on the risk/benefit profile for this target.
Looking ahead, the BioCelerate team looks forward to continuing to grow the capabilities and impact of nonclinical data sharing. The team is focused on enhancing the volume of data and functionality of the database to provide a truly integrated solution that brings together toxicology, background control, and future nonclinical data types where appropriate. The collaborative approach to solving the challenges related to data-sharing and toxicology has allowed the team to make an impact across the biopharma development community.
By John Kozlosky, PhD, DABT, Toxicologist in Nonclinical Safety at Bristol Myers Squibb
John Kozlosky is a Toxicologist in Nonclinical Safety at Bristol Myers Squibb. He received his Ph.D. from Rutgers University and is a Diplomate of the American Board of Toxicology. In his current role, he manages, trains, and develops of a team of Study Directors and Study Monitors responsible for the non-clinical safety assessment of new drug candidates. He has been a Full Member of the Society of Toxicology (SOT) since 2001 and is a member of the Drug Discovery Specialty Section and Regulatory and Safety Evaluation Specialty Section where he serves on the Program Committee. Over the past several years, he has also been actively involved in the SOT Mid-Atlantic Regional Chapter where he currently serves as President.