Despite significant initial interest in angiogenesis inhibitors, they have failed to live up to expectations and are yet to be approved by the FDA for cancer treatment. However, there are a number of drugs in phase III clinical trials that should finally gain US approval. Iressa and Thalomid look set to demonstrate the potential of the angiogenesis inhibitor class and possibly reap the reward.
As a result of the 1970s discovery that angiogenesis is implicated in tumor growth, anti-antigenic, designed to block the formation of new blood vessels thereby 'starving' the tumor's supply of oxygen and nutrients, were identified as one of the most promising drug classes to emerge from clinical research and were hailed as a potential cure for cancer.
However, in recent years, a number of angiogenesis inhibitors have optimistically undergone clinical trials but unexpectedly failed at the last hurdle due to poor results. Consequently, despite nearly 50 angiogenesis inhibitors being in clinical trials in 1999, to date, none have been approved in the major markets for the treatment of cancer.
Despite all angiogenesis inhibitors failing to gain wide approval so far, there are still a number of drugs in late stage development with significant promise, namely Iressa, Thalomid, Tarceva and Neovastat. These four drugs could form the core of the angiogenesis inhibitor market
Fools rush in....
There are a number of reasons why angiogenesis inhibitors have, so far, failed to gain approval, but poor clinical trial design has significantly contributed to the failure of the drug class.
Although it has been known for the last three decades that angiogenesis is implicated in cancer, it is only in recent years that researchers have begun to understand the biology and the role of angiogenesis in cancer. However, because of the new mode of action, many pharmaceutical developers entered the angiogenesis inhibitor market prematurely without intensive preclinical and animal studies.
For example, it is now known that cells can migrate through the cellular matrix by converting themselves to 'liquid' form and squeezing through the gaps, thus circumventing the effects of matrix metalloproteinase inhibitors (MMPIs). Had more diligent preclinical studies been conducted, British Biotech
could have avoided spending unnecessary development costs for its disappointing first-generation MMPI, Marimastat.
In addition, there is growing evidence to suggest that the beneficial effects of an angiogenesis inhibitor are demonstrated after long-term administration of the drug. Currently, an average clinical trial is approximately three months: far too short to evaluate the real benefits of angiogenesis inhibitors.
Extending the length of clinical trials would considerably add to the overall development cost but pharmaceutical companies have no other choice. While the average development cost of a drug is approximately $750 million, a cancer 'blockbuster' can achieve well over $1 billion annually; accordingly, companies cannot afford to jeopardize market potential by cutting corners and not conducting longer clinical trials.
Don't believe the hype?
In 1999, approximately 50 angiogenesis inhibitors were in clinical trials for various cancers. However, by September 2002, only Iressa had been approved in any market (for use in Japan alone) and more importantly, none in the lucrative US market. As a result of the poor performance of the drug class in clinical trials, angiogenesis inhibitors have been written off by many in the industry as just another 'hype'.
However, there are four angiogenesis inhibitors in late-stage development that have significant potential to be approved and achieve considerable sales over the next few years. They are AstraZeneca's
Tarceva and AEterna's
Neovastat. These drugs will form the core of the angiogenesis inhibitor market over the next five years.
Of these drugs, Iressa appears to have the biggest potential despite one recent setback. In widely publicized phase II studies (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] I and II), it was shown that 12% of symptomatic non-small cell lung cancer (NSCLC) patients treated with Iressa monotherapy demonstrated reduction in tumor size at a dose of 250mg daily and 43% of patients experienced symptom relief.
However, it was announced by AstraZeneca in August 2002 that in INTACT (Iressa NSCLC Treatment Assessing Combination Therapy) Iressa in combination with a platinum agent did not show any improvement in survival over conventional platinum-based regimens and only palliative benefits were observed, confounding the notion that angiogenesis inhibitors may be more effective when used in conjunction with traditional chemotherapies.
At the FDA's Oncologic Drugs Advisory Committee meeting on 24th September 2002, the committee voted 11 to three that a 10% response rate plus some symptom improvement is sufficient to suggest that Iressa monotherapy would have a clinical benefit in future confirmatory studies.
Iressa my case...
The stumbling block was the poor phase III combination therapy data, which had been intended to provide confirmatory information for approval. However, the committee suggested that the first-line phase III combination therapy data were not critical to the decision of accelerated approval for Iressa as third-line monotherapy in patients who have failed two types of chemotherapy.
Because the FDA usually follows the advice of the advisory committee, Iressa should be approved for monotherapy use in the US and Europe in 2003 and, as a result of being first-in-market and also due to AstraZeneca's adept marketing, could achieve considerable sales.
In addition, other angiogenesis inhibitors currently in phase III trials (Thalomid, Tarceva and Neovastat) have been well received so far. Their novel modes of action, along with good clinical trial results, have certainly gained the attention of the physicians.
The approval of Iressa should further increase physicians' confidence in the drug class as a whole and as a result there should be high clinical uptake of these drugs for various solid tumors. With more carefully designed clinical trials for the new angiogenesis inhibitor drugs carried out in close consultation with the FDA Iressa should prove to be the catalyst in rejuvenating this class of cancer treatment.
If you found this week's Expert View useful, you may be interested in Datamonitor's reports, all available from www.datamonitor.com/healthcare
· Angiogenesis inhibitors: An Update - Can Iressa and Thalomid Rejuvenate the Angiogenesis Inhibitor Class? priced $1,500
· Market Dynamics 2002: Anti-Cancer Innovatives Series Part 2 - Angiogenesis Inhibitors priced $4,100
· PharmaVitae: AstraZeneca priced $1,100
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