A hedged bet to kill cancer

Risky game: EntreMed must decide whether to build a factory to make anti-cancer drugs still in the experimental stage. The variables involved include whether the drugs work.

EntreMed Inc.'s David Jackson is under the gun.

The small Rockville company is moving its anti-tumor drugs into more tests in ever larger groups of patients, and Jackson is at the fulcrum of a multimillion-dollar balancing act.

His task: ensuring that the company has enough of the delicately made protein drugs.

For the past two years, the EntreMed vice president in charge of manufacturing has scrounged increasingly scarce space at contract manufacturers to make the drugs. Sometimes, he has nailed down an agreement just in the nick of time.

"Tell him your butt's out there," Ed Gubish, now the company's president, advised Jackson to tell a manufacturing contact earlier this year as EntreMed raced to get enough of its drug Angiostatin made for 2002.

Jackson got a contract, and EntreMed spent millions of its precious dollars to stockpile enough of the drugs for next year, knowing it might be impossible to obtain manufacturing space later.

Now, Jackson and his superiors at EntreMed are weighing an even more momentous decision, one that would greatly diminish the company's reliance on outside manufacturers: when to turn plans for its own 200,000-square-foot plant into reality.

A decision to build, based in part on how well the drugs do in more advanced human tests, would be tantamount to a gamble that its experimental drugs will succeed. It isn't clear at this point that they will work.

Timing is key. Starting construction too soon could waste enough money to threaten the 10-year-old company's existence. Waiting too long could be nearly as injurious: Contract manufacturers may be unable to make enough of the drugs, resulting in lost profits if the drug is approved, and depriving terminally ill patients of a medicine that might help them.

The decision is the latest challenge EntreMed faces as it moves Angiostatin and its other drugs toward the market.

Scientists at the Boston laboratory of cancer researcher Judah Folkman discovered Angiostatin - designed to cut off a tumor's blood supply - in EntreMed-paid experiments. They purified it from mouse urine.

But it was EntreMed scientists who genetically engineered a version safe for humans, then found a way to manufacture it - in a living soup that must be warmed, coddled and fed.

And it was company experts who designed ways to harvest the drug from the soup, store it and ship it without causing the medicine to break down.

Now, the drug is undergoing tests in patients, including a clinical trial at Thomas Jefferson University Hospital in Philadelphia, which The Sun has been following as part of this series of stories on the development of an anti-cancer drug.

But even with the drugs in human testing, the scientists aren't finished.

A drug is no good to anyone if it's too expensive to make, or too cumbersome to use. So EntreMed remains under pressure to improve its drugs. Already, company scientists have increased yields from the manufacturing process 10-fold.

Such challenges are common in the drug-making industry. But large pharmaceutical companies have the luxury of drugs for sale, cash in the bank and their own manufacturing plants. Scientists at young biotechnology companies labor in a different world.

Scientists at small companies are under "lots of pressure," said Dale Cumming, vice president of discovery at GlycoDesign Inc., a small publicly traded biopharmaceutical company in Toronto.

"The issue for a small company is you have limited resources," he said. Their major experiments "have to work. There's less room for mistakes."

Jackson knows that but feels energized by the challenges at EntreMed. A former research chemist at a larger company, he switched to manufacturing after tiring of doing experiments at the bench.

"The hardest steel is forged in the pressure of defining moments," he said of situations in which the company must make quick, critical decisions. "We do get some of the best decisions coming out of this."

Key EntreMed scientist Kim Lee Sim, the company's vice president of preclinical research and development, puts it this way: "Some people thrive on pressure."

Blank slate

When Sim arrived at EntreMed for her first day on the job in 1993, one of a dozen co-workers directed her to her laboratory. Other than sinks and a hood for conducting experiments, it was virtually empty. A figurative blank slate.

It was here that she would begin working to produce the world's first version of Angiostatin that could be manufactured in large quantities and given to people in small amounts.

EntreMed Chief Executive Officer John W. Holaday hoped Angiostatin eventually could be concentrated enough for cancer patients to give themselves shots of the nontoxic drug at home, controlling tumor growth much as diabetics regulate blood sugar with insulin.

Over the next eight years, Sim and her team - which now numbers more than 40 - would run hundreds of experiments aimed at reaching that goal.