Research and Markets: New Lines of Attack in Cancer Anti-Angiogenesis.

DUBLIN, Ireland -- The American Cancer Society estimates that approximately 1.2 million new cancer cases are diagnosed each year in the US

Research and Markets (http://www.researchandmarkets.com) has announced the addition of New Lines of Attack in Cancer Anti-Angiogenesis to their offering.

Development of an adequate blood supply is one of the essential factors that dictate malignant growth and cancer development. An extensive number of companies seek to affect tumor growth by targeting angiogenesis and neovascularisation via techniques aimed at inhibiting new blood vessel growth or destroying already existing tumor vasculature. Despite early enthusiasm for angiogenesis inhibitors as safe and effective anticancer drugs, results of several completed Phase III and Phase II trials have been disappointing. New strategies have been developed to overcome these previous mistakes. Since the early failure of drugs such as Avastin, Erbitux, SU5416, Marimastat, Endostatin and Angiostatin, new clinical trials have commenced that will define whether the anti-angiogenetic strategy will hold.

The American Cancer Society estimates that approximately 1.2 million new cancer cases are diagnosed each year in the US. According to International Union Against Cancer (Iuac), approximately $164 billion is spent globally on cancer control annually and the numbers continue to grow. The oncology market is expected to increase in overall size and in the variety of available therapies, driven by the emergence of innovative drugs such as growth inhibitors, antisense, gene therapies, antisense and antiangiogenesis agents. The oncology market experienced substantial expansion during 2001, with a host of new products in development the market grew by 11% in 2001 to US$12bn (IMS Health MAT).

Despite important advances in understanding the molecular basis of cancer, few treatments have been devised to specifically target the known defects in tumor cells. Standard chemotherapy or radiation treatments are inherently non-selective and kill normal cells along with malignant ones. Effective future treatments depend of developing drugs that target individual abnormalities in specific tumor cells. Specially promising new drug classes under development for treatment of cancer include monoclonal antibodies and angiogenesis inhibitors.

This highlight report provides an update on the most recent advances and the ongoing struggle for improved anti-angiogenesis and vascular targeting cancer therapeutics, with a central of attention on achievements and pitfalls that have been experienced. The different strategies are believed to be necessary today are outlined in order to achieve maximum clinical efficacy of the anticancer angiogenesis inhibitors.

This analysis highlights the areas regarded as the "hottest leads" at the moment. The main focuses include vascular endothelial growth factor and epidermal growth factor and their respective receptors, which are in Phase II to III trials. Followed by agents that target matrix metalloproteinases and integrins. A special interest is also given to the new vascular-targeting agents, which aim to disrupt existing tumor endothelium, and Cyclooxygenase-2 inhibitors that have been found to play a role in tumor angiogenesis. Further, the specific therapeutic strategies adopted are examined, namely small molecular drugs, monoclonal antibodies, endogenous inhibitors and antisense therapy.

Report Contents:

Table of Contents

Executive Summary 1

Methodology 5-7

Information Sources

Table of Contents 7-8

Introduction 9-11

Box 1. Anti-angiogenesis strategies

Angiogenesis: still questions to be answered 12-18

Box 2. Problems facing anti-angiogenesis

--Table 1. Therapeutic interventions for exploiting differences between normal and tumor endothelium 14 ongoing phase III trials

--Table 2. Summarizes 14 phase III clinical trials (company, drug, indication, target and technology)

--Figure 1. Number of R&D Projects in phase II and III clinical trials for eleven different cancer indications

--Figure 2. Number of drugs in phase III in relation to their mechanism of action Anti-Angiogenesis Cancer Drugs Close to or Already on the Market 19-21

Gleevec

Erbitux

Neovastat

Tarceva

Avastin

Table 3. Status and sales for anti-angiogenetic drugs

Orphan Drug Approvals 22

Endostatin / Squalamine

Neovastat / ENMD 0995

Investigational New Drug 23-29

Drugs that targets VEGF are less likely to be effective

Figure 3. Strategies for VEGFr/EGFr inhibition

A potent VEGF blocker

Alternative approach to VEGF monoclonal antibodies

Receptors 30-54

Novartis & Schering together

Antibodies vs. small molecules

A small light in the tunnel

A continued faith for receptor tyrosine kinase inhibitors

A new Tyrosine Kinase Inhibitor 

Table 4. Summarize 80 R&D industry related projects targeting receptors involved in angiogenesis (company, drug, indication, target, technology and status)

Negative clinical data

AstraZeneca continues with ZD6474

Is this the end for VEGF receptor inhibitors?

What can be learned from this and other failures?

New targeting possibilities

Stimulating endogenous anti-angiogenesis

Targeting endothelium cells using Endogenous/Natural Inhibitors 55-59

Angiostatin in new phase II study

Other "statins"

Squalamine, a focus on later stage programs

Vascular Targeting, Damaging existing tumor vasculature 60-89

Figure 4. Number of R&D projects in early or late stage clinical development for nine different therapeutic strategies

Big Pharma on the move

Table 5. Summarizes 26 Industry related R&D projects in the field of vascular targeting (company, drug, indication, technology and status)

Figure 5. Number of vascular targeting R&D projects in relation to their development status

Vasopermeation Enhancement Agent (VEA) technology

A need to develop new mouse models

RNA interference-mediated inhibition

Progress in Assay Development

Early Discovery

Monoclonal antibodies and anti-angiogenesis

--Table 6. Summarize 36 industry related R&D projects utilizing Mabs as a therapeutic strategy for anti-angiogenesis (company, drug, indication, therapeutic target and status)

The addition Cyclooxygenase-2 inhibititors: industry progress

Attacking Integrins 90-100

--Table 7. Summarize 16 industry related R&D projects attacking integrins (company, drug, indication, therapeutic target, technology and status)

--Figure 6. Integrin vs. Technology

New anti-adhesion strategy goes clinical

A more effective method developed by Pharmacia?

New light on MMPS 101-108

--Table 8. 16 industry related R&D projects targeting MMPS for the treatment of cancer (company, drug, indication, therapeutic target, technology and status)

A good possibility for kidney cancer marketing

--Table 9. Kidney cancer late stage clinical trials with respect to; company, drug, indication, therapeutic target, technology and status

Antisense

Table 10. Company Activities in the Antisense Field with respect to; company, drug, indication, therapeutic target, technology and status

Angiolytic treatment / P13K pathway

Zn-finger proteins a new possible target for anti-angiogenesis

Conclusion

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