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The global cancer market is characterized by a mix of established gold standard therapies and new innovative products rapidly capturing market share. Inhibitors of angiogenesis represent one class that has received considerable attention as anti-cancer agents. The therapeutic importance of angiogenesis inhibitors took a leap forward in 2004 with the US approval of Genentech/Roche's Avastin (bevacizumab), followed closely by European approval. Peak sales of up to $1.7 billion are now forecast. The nearest competitive threat to Avastin is likely to come from Novartis' PTK787, however AstraZeneca's orally active VEGF-2 receptor antagonist, ZD6474 has successfully emerged from Phase I clinical development. In their Clin Cancer Res paper Williams et al report that the efficacy of ZD6474 is enhanced in a schedule-dependent fashion when given alongside radiotherapy. The success of ZD6474 has recently become of even greater importance to AstraZeneca since the recent withdrawal of its European application for Iressa approval.

The global cancer market is characterized by a mix of established gold standard therapies and new innovative products rapidly capturing market share (see “The Cancer Market Outlook to 2009” for a detailed update on the cancer therapy market). Inhibitors of angiogenesis represent one class that has received considerable attention as anti-cancer agents.

The therapeutic importance of angiogenesis inhibitors took a leap forward in 2004 with the US approval of Genentech/Roche's Avastin (bevacizumab), followed closely by European approval. Approval was based on a pivotal, placebo-controlled Phase III clinical trial, which randomized 900 previously untreated metastatic colorectal cancer patients to receive a standard chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan with or without Avastin. Patients in the Avastin arm showed a median survival of 20.3 months compared with 15.6 months in the control arm. The addition of Avastin also resulted in a progression-free survival advantage of more than four months between the two arms.

Fourth-quarter financial results reported sales of Avastin to be approximately $200 million, a figure expected to swell to peak sales of between $845.3 million and $1.7 billion now that European approval has been granted. Avastin is also under investigation for breast cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer and renal cell carcinoma, approvals for which will significantly increase the drug's overall commercial potential. Despite the renewed clinical and commercial confidence that Avastin approval and sales has brought to the angiogenesis inhibitor class there is a lack of late-stage development and the only competitive threat to Avastin is likely to come from Novartis' PTK787 in the short to medium term (see “Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies”). A more distant threat to Avastin is AstraZeneca’s orally active VEGF-2 receptor antagonist, ZD6474.

Although there are multiple opportunities for the development of anti-angiogenic molecules, the most advanced targets are the growth factors. The principal growth factors driving angiogenesis are VEGF, bFGF, and hepatocyte growth factor/scatter factor. Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors. This growth factor binds to a family of receptors including Flt-1 (VEGFR-1), KDR/flk-1 (VEGFR-2) and VEGFR-3/Flt-4. VEGFR-2 is exclusively expressed in endothelial cells and receptor activation induces angiogenesis, endothelial cell proliferation and the elongation, network formation, and branching of nonproliferating endothelial cells.

ZD6474 blocks VEGF pathways but in contrast to Avastin which bind to VEGF, ZD6474 selectively inhibits the tyrosine kinase activity of VEGFR-2 producing inhibition of VEGF-stimulated endothelial cell proliferation. ZD6474 has additional activity at the epidermal growth factor receptor, paralleling the mechanism of action of Iressa. Administration and in vivo, ZD6474 reduces the growth of a wide range of other tumors with a minimally active dose of around 25 mg/kg. ZD6474 successfully emerged from Phase I clinical development and interim results are expected in the next few weeks on a phase II study combining ZD6474 with chemotherapy in the treatment of non-small cell lung cancer patients. In a recent Clin Cancer Res paper Williams et al report that the efficacy of ZD6474 is enhanced in a schedule-dependent fashion when given alongside radiotherapy.

Anti-cancer drugs are generally given in combinations and the sequence in which individual agents are given can often be of crucial importance. Williams et al report that tumor growth delay induced by ZD6474 given before successive doses of radiation was greater than that induced by ZD6474 or radiation treatment alone. When ZD6474 was given 30 minutes after the last dose of radiotherapy, the growth delay was enhanced still further. The use of angiogenesis inhibitors has been known for a number of years to increase the efficacy of radiotherapy, albeit through a mechanism that is not entirely understood. This study demonstrated that this is true for ZD6474 however it also demonstrates that determining the optimal treatment schedule is important. Determining the preferred treatment schedule may be key to the success of ZD6474, if evaluated within a radiotherapeutic treatment regimen.

The success of ZD6474 has recently become of even greater importance to AstraZeneca since the recent withdrawal of its European application for Iressa approval. This epidermal growth factor (EGFR) tyrosine kinase inhibitor was already approved for sale in the United States and Japan, however the release last month of clinical trial data that showed the drug did not increase the lifespan of patients casts the future of Iressa in doubt and places added weight on the shoulders of ZD6474.

Entry date Sunday, January 23, 2005

Clin Cancer Res. 2004 Dec 15;10(24):8587-93