Streamlining the Drug Discovery Process

Caliper Life Sciences’ Mark Roskey and Bioscan’s Staf C. Van Couter tell us how to reduce R&D costs and increase efficiency.

What technologies can companies use to help reduce the cost of drug discovery?

Mark Roskey. One approach to reducing the cost of discovery is to gain more specific pharmacologically relevant information about a candidate drug earlier. Molecular imaging is emerging as a key technique to reduce costs by enabling researchers to test candidate drugs in animal models earlier in the discovery process.

High value and high throughput longitudinal efficacy studies can be carried out in mouse models using cost-effective optical imaging technology, which can provide detailed molecular information on how much compound is specifically modulating a target. The ability to do rapid dosing studies using fewer animals and the reduced requirement for histological follow-up are also key to reducing cost and getting better quality drugs into clinical testing.

Technologies like IVIS deliver molecular imaging data with high throughput and calibrated precision to meet the demands of drug development on a commercial scale. IVIS has aided the discovery and development of more than five FDA-approved therapies and an increasing tally of compounds in clinical trials.

Staf C. Van Cauter. A major factor in the high cost of drug discovery is the high attrition rate of promising drug candidates at a late stage in the process. Today, only about 10 percent of investigational new drug (IND) applications for new molecular entities submitted to the FDA progress beyond the investigational phase I. The success rate is even lower in oncology (less than five percent). The problematic issues that underlie this low rate of approval of new drugs include the lack of tools that can accurately predict the efficacy and toxicity of new agents.

I believe that translational molecular imaging technologies such as PET/CT and SPECT/CT offer the unique ability to improve the efficiency of this process by enabling a seamless transition from pre-clinical animal testing into human clinical trials. The FDA and other regulatory agencies are facilitating this transition with the recognition of the phase 0 micro-dosing clinical trial phase. I believe that the ability of imaging biomarkers with PET and SPECT across the traditional pre-clinical and clinical gap will translate into improved sensitivity in delineation of viable drug candidates, thus reducing the number and costs of failures.

With looming patent expiries, pharmaceutical companies need to be more efficient in R&D to stay ahead of the competition. What tools can they use to help streamline their drug discovery process?

SVC. With the recent introduction of the new nano-nuclear imagers such as the NanoSPECT and NanoPET (Bioscan, Inc., Washington, DC), it is now possible to obtain images from mice - 1500 to 2000 times smaller than humans - with virtually the same detail as can be obtained with human PET and SPECT scanners in the clinic. By combining nanoliter volumetric resolution with picomolar detection sensitivity, these tools can now be used early and throughout the entire drug discovery process. This includes validating therapeutic targets in mouse models of human diseases, optimizing candidate agents and providing proof of concept for these agents in larger animal models, enhancing the mechanistic understanding of drug or drug combinations, and even distinguishing, early-on, responders from non-responders. Therefore, these tools can clearly be used to streamline the entire drug discovery process.

MR. The R&D discovery process can be streamlined by linking early phase target identification and screening with the rapid evaluation of safety and efficacy parameters in animal models. By decreasing the turnaround time between identifying new lead molecules and validating efficacy in vivo, candidate drugs can be triaged much more quickly.

Specific tools to accomplish this include higher quality compound identification and profiling platforms to ensure upfront activity, and tools such as molecular imaging, which can be used to effectively link in vitro activity to in vivo efficacy.

Getting drugs into animals sooner streamlines the development process. A complete in vivo optical imaging platform makes this approach feasible because it is cost effective to use in a high throughput mode early in the discovery process.

Drug firms are facing increasing demands for compliance from regulatory bodies. What tools can they use to help them meet these requirements?

MR. Pharma companies are now starting to implement quality by design (QBD) processes and metrics earlier in the discovery process as an approach to generate the appropriate supportive data and ensure downstream compliance with regulatory standards. These QBD processes are being implemented on standardized laboratory robotics and analytic tool platforms designed for reproducibility and high quality analytical data generation. One specific tool that is being implemented in this format is the LabChip GX platform. This microfludics-based, high-throughput, protein characterization and analysis platform rapidly generates very reproducible and high quality data supporting QBD approaches and generating appropriate data for regulatory submission. Leading biotechnology and pharmaceutical companies have adopted this platform as a component of their QBD systems used specifically to characterize and QC protein therapeutics and follow-on biologicals.

SVC. By pointing to the location in the body of diseased tissue and monitoring the effects of therapeutic agents over time, the non-invasive PET and SPECT imaging techniques allow experimentation in a physiologically relevant tissue context, thereby avoiding the artifacts and pitfalls often associated with tissue processing in ex vivo and in vitro assays.

As the FDA points out, the search for a new drug can only be confined to a laboratory test tube until the point at which research is aimed at discovering "what a drug does to the body." After that, animal testing is required to find out "what the body does to the drug." Given the high failure rate of compounds entering clinical testing, and the ability of PET and SPECT imaging to test drug candidates as they move through the entire development process, I believe that non-invasive testing with these technologies, in combination with biomarkers for efficacy and toxicity, is critical to make the development of medicines faster, better and safer.

How do you see the future of drug discovery developing in the next few years?

MR. Drug discovery scientists are recognizing the multifactorial nature of disease as well as the biological redundancies that have evolved to compensate for inhibition of a particular molecular target. As such, future discovery efforts will be increasingly focused on more complete characterization of the complex biology of a particular disease. Technical approaches to inhibit, activate, and monitor molecular effects on pathways in relevant animal models will drive the more rapid development of successful candidate drugs.

In vivo imaging of cellular pathways using optical reporters is becoming a significant trend in molecular imaging. Monitoring the signaling process in whole animals using IVIS provides the most relevant readout from a complex set of interactions. IVIS data also co-registers with more translational modalities to provide a direct link to dosing regimes and clinical trials.

As new drugs are accelerated from pre-clinical testing into clinical trials it becomes increasing important to establish relevant companion biomarkers, including optical imaging biomarkers, which will be used to monitor dosage, efficacy, development of drug resistance and identify responding patient populations.

SVC. I believe that the concerning downward trend in regulatory approval for new drugs can be reversed by the use of appropriate tools for imaging biomarkers. Many novel drugs fail at a late stage because they have not been tested at earlier stages in a relevant physiological environment of living specimens, or they fail because they may have been tested in inappropriate patient populations, thus not being able to demonstrate the clinical benefit that is required for marketing approval.

Many of these challenges can be overcome by using non-invasive PET/CT and SPECT/CT micro-imaging tools throughout the process. These tools enable to visualize disease biology at the nano-volume level and to monitor and quantify the effect of candidate therapeutics on disease pathology with picomolar sensitivity. Such tools can therefore identify therapeutic and toxic effects early and assist with the selection of optimal patient target populations, thus significantly improving the chances for success in drug discovery.

Mark Roskey is currently Senior Vice President of Biology R&D at Caliper Life Sciences. He has a PhD in Microbiology from the University of Notre Dame and completed a postdoctoral fellowship in Molecular Immunobiology at Harvard Medical School. Roskey has more than 20 years' experience developing tools and technologies design to accelerate drug discovery.

Staf C. Van Cauter is Executive Vice President of Bioscan Inc., Washington, DC. Prior to joining Bioscan, Van Cauter was Corporate Vice President and Chief Technology Officer of Packard BioScience Company until its acquisition by PerkinElmer, Inc.