Industry Voices: The contributions of immunology translational medicine to clinical pharmaceutical development

Francisco Leon Ian Gourley

By Francisco Leon 
and Ian Gourley,
Janssen Research & Development

Translational medicine, both the mindset and the practical approach, is an important if not essential element of today's successful pharmaceutical development. It deals with building the bridge between the science of the emerging preclinical portfolio and the early development space where molecules are studied in humans for the first time. It ensures that the right translational work is done in the immediate preclinical phase and is continued into early clinical studies.

Translational medicine thinking also applies to many later clinical studies. For this reason, many larger pharmaceutical companies have dedicated a part of their research and development organization to translational medicine. Often, the same group may also be responsible for the conduct of early clinical trials.

"The goal is to maximize the 'learnings' from the translational medicine early development studies, answering key development questions for the project such as understanding the mechanism of action (MOA) of the drug, not just obtaining data on safety and pharmacokinetics (PK)," said Donald Raible, M.D., head of Translational Medicine Development at Janssen R&D.

A key driver for a dedicated group working in this space is the need to foster innovation in the translational approach. Beyond the necessities of learning about a molecule's safety, tolerability and PK profiles under a translational approach, the first clinical studies are considered an opportunity to begin learning about the relationship of the molecule with the disease. The process is a learning continuum, so while the primary purpose of the data is to propel the molecule forward and inform the design of larger proof-of-concept (POC) studies, important added benefit comes from feeding the data backward so that the discovery teams are also informed by the early clinical experiments.

This approach is strengthened by involving patients as early as possible in early development and by harnessing innovative approaches and technologies to maximize learning from these small trials. With this in mind, a goal of Immunology Translational Medicine at Janssen is to include a cohort of subjects with diseases in the multiple-dose study or in a small Phase Ib trial. This can add immensely to the understanding of the drug profile and contribute significantly to the design of a later POC trial in Phase II development. This plans for success but also provides a source of mechanistic data to help understand the reasons for a potential failure in a later trial.

Another goal of including disease subjects in early trials is to establish a proof of mechanism before the drug is studied in a larger Phase II trial setting. Often this will involve using assessments other than the standard clinical endpoints, like blood- or tissue-based biomarkers or imaging modalities. Innovation is also essential here because new approaches are needed to gain confidence in the interpretation and reliability of shorter studies with smaller patient numbers than typical POC studies.

A critical component of translational medicine is dedicating resources to understand the utility of new tools before using them as endpoints in an early trial. This involves a variety of approaches, including conducting observational or Phase 0 trials to evaluate a particular tool or set of tools in the appropriate disease setting, and taking advantage of larger Phase II or III trials to include the assessment in a subset of patients. For example, novel imaging approaches of rheumatoid synovium may one day be key to making early decisions about the future potential of new rheumatoid arthritis drugs, but can't be used in decisional trials until some experience has been gained in a relevant setting to fully understand how predictive the assessment can be.

Through a late-development clinical trial, the ideal setting to generate the necessary data, the imaging approach is being explored in a subset of subjects. While the clinical development teams typically cannot prioritize this type of exploratory work, the translational medicine team can act as the catalyst to bring together the technology within the right clinical trial setting to carry out these first exploratory assessments.

Translational medicine as a successful approach does not happen in a vacuum. A complete translational approach will include collaboration with key partner functions. The first important partnership is with the discovery research team developing the molecule. Within the Janssen Immunology therapeutic area, engagement between translational medicine and the discovery team happens a year or more before the clinical candidate is chosen. This amount of time is required to develop an eventual translational plan which guides the translational work in the preclinical and early clinical space.

In some companies, a biomarker capability is a separate function, while in others it may be part of the translational medicine group. Within Janssen Immunology, this function is a close collaborator in enabling the right clinical biomarkers to be integrated into early studies, especially those that include patients for the first time. Another important partner is the clinical pharmacology or PK/pharmacodynamics modeling group. This team will design a strategy to employ exposure/response relationships using the early trial data to help with ongoing study design and molecule understanding.

Last but not least, another essential collaborator and eventual customer for the work of immunology translational medicine is the clinical development team who run Phase II and III trials. Success requires a team effort in which the clinical development colleagues are involved with planning and decisionmaking at every step. This ensures alignment within the plan and delivery of the best package of data when the molecule leaves early development and plans for Phase II are underway. Coordinating and integrating all of these activities can be challenging, so, within Janssen Immunology, a group called the Experimental Medicine Working Group serves as a forum where members of all of these functions meet regularly to discuss strategies and specific projects.

In addition to studies which evaluate the potential of novel tools and approaches, another important role for the Translational Medicine Science team is to run experimental medicine studies which may be essential at a disease or molecule level to develop the pipeline. These typically fall outside of the scope of the Translational Medicine Development group, which needs to focus on delivering the first-in-human single and multiple-dose studies, and the clinical pharmacology studies needed for specific development programs. For example, Janssen is conducting observational studies to acquire blood and tissue samples from specific patient populations. These studies are driven by collaborations between Translational Medicine and colleagues in the research organization who need clinically characterized samples to help with target validation and identification. Another example involves a study to understand the MOA of a drug, running in parallel with the development program, but focusing more on sampling of appropriate tissues and application of the best technologies to generate the information.

Translational medicine within Janssen Immunology is a discipline that aims to unlock the potential of every molecule using innovation and collaboration, and is most successful when resources are dedicated specifically to the implementation of the translational medicine strategy.

Francisco Leon, M.D., Ph.D., Head, Translational Medicine, Immunology Therapeutic Area, Janssen Research & Development, LLC

Ian Gourley, M.D., Senior Director, Translational Medicine Science, Immunology Therapeutic Area, Janssen Research & Development, LLC