EntreMed hoping for success with Panzem/Avastin combo

EntreMed has initiated a phase II trial of Panzem in combination with Genentech's Avastin in carcinoid cancer. The trial will examine how the therapy fares against potential rivals and its possible use in other tumor types. With the blockbuster Avastin possessing the potential to significantly raise the profile of Panzem, the study will prove crucial for EntreMed's lead pipeline drug candidate.

Carcinoid cancer is a rare neuroendocrine tumor that is on the increase. In the US, 6,000 to 7,000 new cases are confirmed each year, with 2,500 tumors at the malignant stage. The majority (85%) of carcinoid cancers develop within the gastrointestinal tract between the stomach and the rectum. Several tumors may develop in the small intestine, which often increases the risk of developing other tumors within the gastrointestinal tract. 

According to the National Comprehensive Cancer Network, 50% of carcinoid cancer patients do not survive beyond five years from diagnosis. There is, therefore, a clear unmet medical need in this market.

Promising partnership

Panzem is an orally active liquid nanocrystal formulation of 2-methoxyestradiol with multiple anti-tumor actions. These include tubulin disruption to halt mitosis (cell division), apoptosis stimulation and, similarly to Avastin (bevacizumab), angiogenesis inhibition. Panzem has shown preclinical activity against taxanes, DNA synthesis interfering agents and tamoxifen-resistant models. 

The aim of the carcinoid tumors phase II trial is to assess Panzem's safety and efficacy profile in combination with Avastin for locally advanced or metastatic carcinoid cancer. The commencement of phase II development follows positive data from recent phase Ib studies, with Panzem meeting endpoint pharmacokinetic anti-tumor activity in addition to demonstrating an acceptable toxicity profile. 

EntreMed is hoping that the addition of Avastin to Panzem will result in a higher response rate than that currently achieved with combination chemotherapy (10-15%) or either agent alone.

As the first approved antiangiogenic agent, Avastin is a monoclonal antibody indicated for the first-line treatment of metastatic colorectal cancer in combination with a 5-flurouracil-based regimen. The drug generated sales of $1.13 billion in the US alone in 2005, and, despite recent safety concerns, looks set to go from strength to strength in the cancer market.

Indeed, Genentech/Roche are currently filing a submission for Avastin with the FDA in non-small cell lung cancer and relapsed colorectal cancer, and are preparing to file for metastatic breast cancer by H2 2006.

Key trials

Although Panzem appears to hold promise as a novel agent, the drug candidate must prove itself in these key trials before its full potential can be realized. In particular, Panzem must not increase the risk of posterior leukoencephalopathy syndrome. 

If positive data is demonstrated, phase III studies must then confirm how this could translate into commercial success for EntreMed, Genentech and Roche. If this was to happen, the drug combination would enjoy orphan drug status and improve therapeutic options for patients beyond standard chemotherapy. 

The duo could also be examined in other tumor types as Panzem is currently undergoing phase II studies in brain cancer and, in combination with Bristol-Myers Squibb's Taxol (paclitaxel), in breast cancer. 

However, a number of challenges remain for Panzem/Avastin. If the therapy is to make any significant impact upon the carcinoid tumor market, it must demonstrate superiority over standard chemotherapy. Further competition could also lie with other phase II candidates such as Bayer/Onyx' Nexavar (soranefib) and Novartis' RAD001.  

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