Over the last 20 years, the landscape of drug discovery has changed dramatically. Historically, research and development took place within large pharmaceutical companies with a collection of smaller biotechnology companies doing the innovating, and eventually being acquired by larger companies. However, given the ever-increasing drive to deliver value quickly and more cost-effectively, the environment is now filled with a dynamic mixture of large pharma, biotechs and virtual organizations.
The timelines for delivery of a candidate compound, irrespective of the therapeutic area, has consistently averaged between two and a half and four years from the initial hit identification effort (see image above). The number of U.S. Food and Drug Administration (FDA) approvals is lower today compared to 1996, which has led to an increased quest for better validation of targets, and higher quality candidates with a greater chance of success.
Pressure is mounting on pharmaceutical companies to both fill their internal pipelines as well as deliver value to shareholders. The trend toward a reduction in internal R&D spend within pharma worldwide coupled with increased outsourcing of research has enabled pharma to reduce its fixed cost-base and allow increased capital flexibility. Increasingly, the R&D market has observed significant increases in the number of small virtual companies with limited budgets being expected to progress compounds to the point of candidate nomination under the shortest timeline possible. This paradigm shift towards virtual research has also resulted in an increase in the number of experienced drug discovery scientists now working for contract research organizations (CRO).
The main aim of the integrated CRO is to act as an extension of the sponsor company and drive projects to the point of nomination. Toward this end, Charles River Laboratories (Charles River) has established a discovery division focused solely on delivering pre-clinical candidates across multiple therapeutic areas. One unique aspect of Charles River’s strategy is to robustly validate the target at an early stage of the project, confirming expression and link to disease, as well as identification of a response biomarker. Their track record of delivering clinical candidates has been analyzed internally and compares favorably with industry standards. In the last 15 years Charles River has delivered 79 preclinical candidates, with over 30 of these molecules progressing to Phase I and beyond (see chart below).
Charles River has achieved these high delivery metrics by pioneering and implementing a translational integrated drug discovery platform which allows their partners to effectively increase their lab size by contracting a complete drug discovery team, including medicinal and computational chemists, in vitro and structural biologists, DMPK scientists and in vivo pharmacologists. These dynamic teams, managed by an experienced project lead—usually a drug discoverer who has delivered preclinical candidates coupled with a specialist in the particular therapeutic area—strive to rapidly transition projects through the phases of drug discovery.
The project leader is responsible for all elements of project management, operating a single point of contact policy with his or her counterpart in the partner company. This ensures clear communication, efficient delivery of objectives and prompt data sharing through Charles River-curated data portals and shared electronic laboratory books. An additional benefit is that an integrated CRO can coordinate all activities under a single Master Service Agreement, thereby streamlining the contracting process for potential partners.
The relationship between the partner and Charles River is absolutely key, and trust is developed through regular face-to-face meetings, supplemented with regular teleconferences and email communication. The shared vision for the project is paramount as it allows dynamic decision-making, and combined input on direction and agreement on the key parameters required to transition the project through the various phases of drug discovery.
Charles River also recognizes that flexibility is crucial to the delivery of preclinical compounds and has adjusted their integrated offering to support this. Charles River will happily contribute one or two disciplines to the project and form part of a project team with the partner organization. For example, Charles River could provide the chemistry and structural biologist for the project, working closely with the partner’s biology and DMPK team. Charles River is equally comfortable working in a collaborative network, interacting with multiple touch-points which could include the partner organization, academic collaborators or a charitable foundation. Charles River firmly believes this flexible working arrangement allows access to our expertise and knowledge – regardless of budget – and focuses on the specific project needs.
As drug discovery evolves, Charles River is focused on embracing new technologies through strategic partnerships and internal development, to allow our partners access to the most up-to-date information and technology with the aim of shortening delivery times of preclinical candidates.
It is becoming clearer within the industry that robust validation of the target expression in the human disease state and the tractability of the target are key to the delivery of successful projects. Charles River can provide due diligence on the project by evaluating the expression of the data in diseased tissues, assessing the current literature, proposing chemistry strategy based on assessment of the target crystal structure, and virtual screening over three million ligands. Investing time in these activities at the initiation of the project has resulted in shorter timelines to reach candidate nomination. In addition, ensuring early identification of target engagement and efficacy biomarkers early in the process will ensure a seamless transition from preclinical to clinical development and ensure a clear line of sight between compound exposure and effect. Charles River is dedicated to continually reviewing the working practices of an integrated project to identify areas of white space which could be removed. A recent initiative reviewing the timelines for compound synthesis to testing in vivo during a lead optimization project resulted in a six-week timeline from synthesis to PK study; this truncation of timeline lead to the successful achievement of project transition ahead of the agreed timeline.
The creation of the integrated drug discovery model has allowed Charles River to offer partners internal expertise, project management skills and the seamless integration of multiple disciplines into a translational project package fully enabled with a biomarker strategy across species, thereby reducing the partner’s delivery timelines for transition of compounds and potentially reducing the cost of delivering a preclinical candidate.
Martin O’Rourke, PhD, is a senior director of Oncology In Vitro Biosciences, Integrated Drug Discovery at Charles River Laboratories and Jane Hughes, PhD, is a senior director of In Vitro CNS Research, Integrated Drug Discovery at Charles River Laboratories