A record number of personalized medicines were approved by the FDA in 2017, and now account for approximately one in four New Drug Approvals. Conducting research and development in prevalent diseases can be difficult; rare disease research comes with a whole new set of challenges.
 
When studying rare diseases, it often proves difficult to identify study participants for clinical trials due to low prevalence. As a result, animal models are used to study the effects of investigative therapies during preclinical trials. However, having the right animal model is key – it paves the path for conducting the right clinical trial by understanding a potential drug’s mechanism of action, its effects on relevant biomarkers and when and how it can be used effectively in humans. 
 
Antti Nurmi, Ph.D., MSc, Managing Director, Discovery Services, at Charles River Laboratories (CRL) discusses how the growth of orphan drug research impacts preclinical services and how early research in rare diseases can provide the crucial evidence needed to conduct clinical trials. –KB
 
Contract Pharma: How has the growth of orphan drug research impacted preclinical services?
 
Antti Nurmi: The growth in orphan drug discovery has resulted in a need to review the overall drug development process from a new perspective. There is typically no good starting point for in vitro or in vivo biology of a given orphan disease, which means that drug development programs are often highly tailored and customized. This requires partners to harness capabilities and technologies from across therapeutic areas and customize them to the readouts and conditions of a specific rare disease.
 
Charles River has successfully provided rare and orphan disease drug development services, with Huntington’s disease as one of the most comprehensive examples. Charles River helps to design custom approaches for rare and orphan diseases by combining target agnostic platforms, including disease biology relevant biochemical assays, in vitro and in vivo models and assays.
 
CP: What is the significance of animal models in rare disease research?
 
AN: Discussions about rare and orphan diseases typically surround single gene mutations, which result in a disease phenotype at the cellular and tissue level. While in vitro animal models can mimic the human disease biology at the cell and tissue levels, in vivo models can be more challenging. The disease phenotype in the animal model may significantly differ from the human disease manifestation.
 
Therefore, it is critical to understand the limitations of the animal models, and identify the specific scientific questions that can be answered reliably. Although limited, animal models of disease are essential in understanding disease biology, as they contain the full interactive physiology of an animal, which would be very difficult to reliably simulate in in vitro systems.
 
CP: What are the challenges of finding the right research model?
 
AN: Often there is a disconnect between the underlying disease biology and disease phenotype in an animal model. It may be that we can see the effects of single gene mutations at the biochemical and cellular/tissue level, but we do not see the consequences of such pathology in the animal’s behavior and abilities in the same way as in human patients. Also, it is worth mentioning that the life span and disease evolution in humans compared to animal models is different, making translation of animal model work into the clinic more challenging.
 
CP: How do you help clients address these?
 
AN: Through our expertise across various rare and orphan diseases and historical collaborations, we bring a unique understanding about both opportunities and limitations of animal models. We continuously engage with key opinion leaders, pharma/biotech and foundations to provide the best possible tools available to be used in drug programs. We consider ourselves more as partners than service providers to our clients.
 
CP: How does this early research method impact clinical trials?
 
AN: Early research provides the crucial evidence needed to conduct clinical trials. If there is not a sufficient amount of evidence about the efficacy and safety of novel therapies, there is no point of advancing drugs to clinical trials. Besides ethical justifications, thoroughly and reliably conducted early research reduces the risk of failure related to expensive clinical trials at later stages. Development of a given therapy is increasingly becoming more expensive, and easily requires several years of work to get the therapy to the patient.