Computer-Assisted Drug Development
The pharmaceutical world agrees that better development decisions need to be made faster. Research and development departments are under continual pressure to produce rapid results in the form of marketable drugs.
To that end, many companies are integrating information collected in preclinical toxicokinetic, pharmacokinetic, pharmacodynamic, and metabolism studies to create a knowledge-based drug development framework in humans.
Xiao Feng, senior scientist, global preclinical development at Johnson & Johnson Pharamaceutical Research & Development (J&JPRD; Raritan, NJ), says, "The search for biomarkers has to be a large-scale collaborative effortno one group can get this done."
Hans Winkler, head of functional genomics at J&JPRD in Beerse, Belgium, adds, "We tend to do global profiling for biomarkers using a combination of higher throughput technology and bioinformatics. We're set to cover the whole spectrum from lead optimization to pharmacokinetics and pharmacodynamics."
The team at J&JPRD in Beerse conducted an MTB mode of action study for their tuberculosis (TB) compound (R207910). J&JPRD sought the new antituberculosis compounds by selecting prototypes of different chemical series and testing them for inhibition of growth of mycobacterium smegmatis, which was used for experimentation because of safety issues.
R207910 is active against Mycobacterium tuberculosis and other species of Mycobacteria, including multidrug resistant strains. However, it is not active against a range of other bacteria. The mode of action of this investigational drug was discovered by comparative genomics.
The experimental approaches to discover the mode of action of R207910 included drug cross-resistance and growth inhibition studies with radioactively labeled metabolites.
The genomics approaches included: comparing the common genes of the sensitive bacteria with the common genes of the resistant bacteria; examining gene expression of sensitive Mycobacterium species to resistant mutants in the presence of the drug; and sequencing complete genomes of sensitive and resistant Mycobacterium species and identify resistance-conferring mutations.
"I think one thing we can all agree on is that the heightened attention being given to biomarkers is driven by the confluence of new technology and resources, and the drive by pharmaceutical companies to make better decisions, sooner," says Christopher J. Godfrey, senior pharmacometrician, clinical pharmacology at Vertex Pharmaceuticals (Cambridge, MA).
Vertex has a broad-based drug discovery effort targeting the human protein kinase family, which consists of approximately 500 members. Protein kinases are enzymes that play a key role in transmitting signals between and within cells.
Kinases exert their effect by phosphorylating other proteins, which then become activated and perform a specific function. Kinase activity has been implicated in most major diseases, including cancer and autoimmune, inflammatory, cardiovascular, metabolic, and neurological diseases. Thus, kinases can be ideal targets for therapeutic intervention.
In November, Novartis Pharma selected Vertex' small molecule protein kinase inhibitor, VX-322, for clinical development. VX-322 is a novel compound targeting the key mechanisms implicated in leukemia and other cancers. Vertex and Novartis collaborate on the discovery, development, and commercialization of small molecule drugs directed at protein kinases.
In June 2004, Vertex and Merck entered a global collaboration to develop and commercialize VX-680, a small molecule inhibitor of Aurora kinases, for the treatment of cancer. Aurora kinases are three closely-related proteins required in rapidly dividing cells.
Inhibition of Aurora kinase activity with a small molecule may provide a means of slowing or reversing the uncontrolled cell growth observed in cancer. VX-680 is currently being evaluated in cancer patients as part of a Phase I study initiated in January 2005.
Vertex has advanced drug discovery efforts targeting several other kinase targets, including targets that play a role in the development and progression of cancer, inflammation, and autoimmune disease.
Vertex is also conducting a broad-based drug discovery program targeting the ion channel family. Ion channels are a gene family of more than 650 proteins that act as cellular gatekeepers, controlling the flow of ions across cell membranes.
The ion channel target family contains numerous druggable targets representing potential intervention paths for indications including cystic fibrosis, pain, and inflammatory, cardiovascular, and metabolic diseases.
Existing therapies such as amlodipine and nifedipine, calcium channel blockers for the treatment of hypertension, and lamotrigine and carbamezepine, sodium channel inhibitors for the treatment of epilepsy, provide a strong basis for developing drugs targeting ion channels.
Vertex' ion channel research extends across several ion channel subfamilies, including sodium and calcium channels, and is principally focused on the design and development of small molecule drugs for the treatment of pain and cystic fibrosis. Specific sodium channels in peripheral nerves are particularly attractive targets for novel pain treatments.
In 2004, Vertex advanced a novel drug candidate, VX-409, a selective sodium channel inhibitor, into preclinical development for the treatment of pain. Ion channel modulators also could be important therapeutic agents for cystic fibrosis, since the primary genetic defect responsible results in a defective ion channel.
Vertex is collaborating with the Cystic Fibrosis Foundation in targeting this ion channel, the cystic fibrosis regulator protein (CFTR). The hope is that a drug that increases the activity of CFTR will be beneficial in lessening the buildup of mucous in the airways that otherwise leads to chronic infection and inflammation and progressive lung deterioration.
"We can generate significant amounts of biomarker data, which is very useful, but researchers need to be able to integrate this information into a coherent package to best inform decisions," Godfrey says.
"Developing appropriate models for biomarker responses allows us to interpret that data and create knowledge, which is then converted to understanding when individual models can be integrated into one system. The integrated model can put responses into context and help us see higher-level implications."
Godfrey adds, "Simulation is the critical tool that converts our understanding of the system into wisdom. It enables us to ask the What if?' questions to test our system and see the results of our decisions. This is the role our research plays in capitalizing on biomarkers."