While major progress has been achieved in cancer research and development, the majority of new therapies continue to fail in human trials, despite showing promise in preclinical testing. Charles River Labs is working to help combat this issue with novel animal research models to address the challenges cancer drugs face in development.

Aidan Synnott, Ph.D., Executive Director, Discovery Oncology at Charles River Laboratories, discusses the latest developments in oncology research models, as well as the R&D trends impacting drug discovery and the greatest motivators for preclinical outsourcing in today’s market. – KB
 
Contract Pharma: What are the most significant pharma/biopharma R&D trends impacting drug discovery and development?

Aidan Synnott: The industry is undergoing something of an immunological awakening because of the success of immunotherapies in treating cancer. We have seen a redirection of resources and investment into oncology research at the expense of other indications. The revolutionizing impact of this breakthrough and the consequent increased investment has broadened drug makers’ horizons and emboldened them to try out new paradigms that go way beyond the traditional chemotherapeutics and targeted therapies that were dominant. Although it started in cancer, the trend has spread to metabolic diseases, CNS and other therapeutic areas. This seismic shift has created a need for more varied and specialized preclinical assays and models.

Another massive trend is the attempt to harness big data to increase the translatability of therapeutic assets identified in early drug discovery. We see an ever-tightening relationship between preclinical research and the clinic.

CP: What service areas are you seeing an increased demand for and from what sectors?

AS: As the Big Pharma model of producing a drug from soup to nuts has proven to be less effective at getting novel drugs to market, the drug discovery and development process has become fragmented. This has led to an increased need for experts who know how to move a drug from one phase to the next and provide integrated, consultative guidance. Additionally, as the science and regulatory requirements get more complex there is a need for more depth of expertise in each of these segments, which plays to the strengths of large CROs, that work with most of the industry at some stage of the process. The shift in the types of companies who are being truly innovative in the industry has led to a diversification of sectors to include venture capital-funded start-ups, academic spin-offs and “Two Men and a Molecule”-type companies.

CP: What do you see as the greatest motivators for preclinical outsourcing in today’s market?

AS: Biopharma companies have long been comfortable outsourcing clinical and preclinical toxicology work, but they are also starting to understand that they can trust earlier stage work to CROs as well. Their historic reluctance has stemmed from the greater need for secrecy and a belief that no one can do the work as well as their scientists. With an increase in the quality of outsourcing options, even drug makers with in-house capabilities are learning that it can be a lot more efficient and cost-effective to work with a CRO. A benefit of working with a large CRO is that they run hundreds more of the niche assays needed to identify novel drugs and prove their efficacy than even Big Pharma due to greater experience and expertise with those tools. An added spur has been the increase in start-ups and virtual companies due to increased investment in biotech and the recent downsizing trends in the industry, freeing up scientists to pursue their own innovative projects.  

CP: What are some of latest developments in oncology research?

AS: Immuno-oncology research is still leading the preclinical space. A lot of the work being done focuses on combining therapeutic agents that are not necessarily immunomodulatory with proven immunotherapies, such as checkpoint inhibitors. Drug makers are looking either to enhance immunogenicity of tumors to make them more susceptible to immunotherapies or to mitigate their toxic side-effects. A considerable number of these combination drugs are being repurposed either from another therapeutic indication (e.g. autoimmune diseases) or from a frozen or terminated pipeline that already has associated clinical data. Cellular therapies are more niche due to the complex risk factors associated with them but still a strong R&D interest.

Other strong niches in the non-immune space include epigenetic approaches and HDAC inhibitors. Targeted therapies including ADCs are still getting their fair share of attention too, but everyone is more aware of the immune environment and its potential impact than they used to be.

CP: How can these research models help streamline/advance drug development?

AS: The most dramatic increase in demand since last year’s AACR has been for mouse models with a humanized system, imaging and in vitro assays.

Imaging demand tends to be for bioluminescent and fluorescent modalities and has been stimulated by the belief that running tumor models orthotopically rather than subcutaneously allows a greater, more clinically relevant interaction with the immune system. In vitro assays have seen renewed interest because of improved technology such as high-content imaging, which allows meaningful observation of the mechanism of action of biologics. Another point of interest is the co-culturing of immune cells with tumor cells prior to research moving to the in vivo stage.

Historically, the biggest barriers to the advent of humanized models was the high price point and unrealistic expectations about their potential to be a “human in a mouse.” We have reached a point where the industry is starting to understand the potential of humanized models, while accepting their limitations. The increase in the variety and availability of the models has lowered the price point. Meanwhile, researchers are starting to understand the scope and nature of the questions they can be used to answer. We are still seeing a rising demand for syngeneic mouse models but it is only a matter of time before they are overtaken by humanized models.