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Biotech / Medical : EntreMed (ENMD) -- Ignore unavailable to you. Want to Upgrade?

To: tnsaf who wrote (1780)	2/21/1999 10:55:00 PM
From: Bear Down	Read Replies (1) \| Respond to of 2135

A direct link biocentury.com

To: tnsaf who wrote (1780)	2/21/1999 10:56:00 PM
From: ztect	Respond to of 2135

Thanks...for the convenience of everyone...Here is the article to which you refer... biocentury.com New this week From BioCentury, February 16, 1999 Technology Focus Why Bristol-Myers returned angiostatin By Ilan Zipkin Staff Writer EntreMed Inc. has decided to push into human trials with a compound that partner Bristol-Myers Squibb Co. believes is not ready for clinical development, reflecting the differing sense of urgency between a biotech company with nothing in the clinic and a pharma company with product sales and a broad oncology pipeline. While the proof of who is right will be seen in clinical trials, the main point of disagreement is whether ENMD's highly publicized anti-angiogenic protein material is potent, scalable and reproducible enough to take forward. Bristol-Myers last week returned development of angiostatin, a cleavage product of the protein plasminogen, to ENMD. The biotech company said it plans to submit an IND for the agent at year end, and also plans to start Phase I trials of endostatin, a fragment of the protein collagen XVIII, during 1999. Both proteins are being produced using the yeast Pichia pastoris. The compounds have generated positive results in mice bearing tumors. But Robert Kramer, vice president of oncology drug discovery at Bristol-Myers, said that angiostatin fails to meet several criteria that the pharma company has for clinical candidates. Kramer told BioCentury that Bristol-Myers is not satisfied with angiostatin's potency (that large daily doses would be required) or the reproducibility of the protein's biological activity (the company has seen different activity from time to time). Kramer added that there is no release assay for angiostatin, meaning there is no easy way to monitor consistency of material from lot to lot. “These are all process chemistry issues relating to making a molecule at scale that can be put into people in large clinical trials,” he said. “We think the material they're making is not ready for clinical development.” John Holaday, ENMD's chairman, president and CEO, said the company has not seen any problems with angiostatin's preclinical anti-angiogenic activity and potential as a cancer treatment. He noted that Bristol-Myers has been using a mammalian cell production system for angiostatin that has yielded some batches with activity and some without, while every batch made with ENMD's Pichia yeast system has shown activity. “They didn't think they could solve that riddle in a timely way,” Holaday said. “They didn't want to take on our process, since they weren't familiar with it. In its present form, it's not ready for clinical trials — the question is, will it be in a form for clinical trials in a timely way? The answer is yes.” Bristol-Myers disagrees. “We determined that the Pichia material also is not ready for clinical trials and in that regard there was a difference of opinion between EntreMed and us,” Kramer said. “The Pichia system might make material but there's still a lot of work to do. Filing an IND is one thing; having material that meets some standards for reproducibility is another. This is a very exciting research tool — that does not a drug make.” Angiostatin and endostatin were discovered in Judah Folkman's lab at Children's Hospital (Boston, Mass.), and there has been some concern over the reproducibility of his results in other labs, concerns echoed by Bristol-Myers' decision. Results with endostatin have been duplicated, both by researchers at Beth Israel-Deaconess Hospital in Boston and last week by National Cancer Institute researchers working in Folkman's lab, although not yet at NCI facilities. While the results may protect Folkman himself from further doubt, they do not ensure success with endostatin and angiostatin in the clinic. “It is likely that differences in storage, handling and purification methods can result in different levels of activity,” the NCI stated. “It is important to define as precisely as possible the reasons for variability in the mouse experiments, since how endostatin behaves in laboratory experiments may have implications for its use in the clinic.” Holaday noted that endostatin has been produced in nearly gram quantities, and that angiostatin is even more soluble, making it easier to produce. However, both proteins may require similar preclinical work before meeting the criteria set by Bristol-Myers. Kramer noted that the data generated with angiostatin so far relate to laboratory-sized batches of the protein, not production-scale quantities. Bristol-Myers (Princeton, N.J.) has retained the option to reassume development and marketing rights after proof-of-principle has been shown in Phase II trials in exchange for a $1 million exercise fee and a “substantially increased” royalty, according to ENMD. Kramer noted that ENMD has different priorities, which is why responsibility for clinical development was transferred back to ENMD. “EntreMed has an interest and urgency relating to getting angiostatin into the clinic,” Kramer said. “It's better that they deal with that sense of urgency — we have a very rich portfolio. Ultimately angiostatin might prove to be everything that it was originally claimed to be. If they succeed, we win, so we wish them the best.” However, ENMD has the option to terminate Bristol-Myers' involvement with angiostatin by notifying the pharma company before the end of Phase II trials that it has found another partner for angiostatin or plans to develop the protein on its own. Bristol-Myers already has agreed to forego its right of first refusal to take a license to endostatin.