AstraZeneca's Nuanced View of Cancer Drug Development
With its small-molecule signal transduction inhibitor Iressa, the first approved drug targeting the EGF receptor, AstraZeneca became an early mover in the development of molecularly targeted cancer drugs. But Iressa also became the poster child for the difficulties associated with targeted therapies when a Phase III trial failed soon after the drug was approved. Iressa's ups-and-downs has brought home the need for "guided empiricism" to link targets in the clinic to markers and dosing. Yet even as AstraZeneca and others make connections linking target biology to disease propensity or status, clinical drug development continues. And if history is a guide, industry should expect more Iressa-type missteps.
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Despite the success of Gleevec, developing drugs that inhibit complex signaling pathways, while simultaneously trying to understand the biology around a drug's target, remains a challenge. Without biomarkers to help establish dosing and identify likely responding patients, clinical development of targeted cancer drugs will remain challenging. AstraZeneca's recent experience with Iressa bears this out. It's likely that single markers will not be sufficient to stratify patients by their tumor types; rather, patterns of gene and protein expression will be required. The technology to take these measurements is making its way from academia to industry, but the process is slow, and needs encouragement and better coordination between academia, regulators, and industry. Meanwhile, clinical trials themselves remain the best target validation tools. When all is said and done, efficacy is the best biomarker.
For the second time since the summer, a Top-Ten pharma company with an established oncology franchise has enlisted the aid of a biotech to give it a leg up in the development and manufacturing of therapeutic antibodies. In July, it was Aventis. Now, AstraZeneca is teaming up with human antibody producer Abgenix.
As companies move into development of drugs against novel targets, including a host of genomically derived drugs, they are assuming a new kind of target risk. The heightened risk exists largely because the targets revealed by genomics techniques for the most part have not been validated by linking them empirically to the initiation or maintenance of a disease state, nor through the use of biomarkers during clinical development. Stumbles in the pursuit of drugs against EGFR are symptomatic of this new pharma industry problem. In this context, the cancer drugs Herceptin and Gleevec, widely touted as the first examples of rapidly developed, rationally designed molecular medicines, will prove to be much more the exception than the rule. And importantly, the emerging pattern of EGFR drug development suggests that pursuit of novel targets will do little to ameliorate the industry's R&D productivity problem.