The Thrill of Defeat

Still, Pfizer scientists are tackling an obstacle that has thus far proved insurmountable: Diabetes is a chronic, degenerative disease that develops so slowly that it can take years to determine whether an experimental drug is having any impact. After almost a decade of tests--and vast amounts of data that delivered mixed but encouraging results--sorbinil hit a wall. A small percentage of patients in late-stage trials developed a potentially fatal allergic reaction to the sorbinil molecule. It was then that John Niblack dubbed the entire effort a "Vietnam project."

"It was a quagmire," says Niblack, Pfizer's former chief of global R&D, who retired two years ago. "The regulators and our clinical people were extremely worried. And the results from the trials were still unclear. Some people argued that we were closing in and winning. If we stopped, we'd have to write off millions and millions of dollars. Do we soldier on when some patients are getting sick or do we surrender?"

The decision: surrender. "That's the way it is in this business," Niblack shrugs. "Most of your labor is in vain."

It was a searing disappointment for the researchers at Groton--"a death in the family," Hutson says. Some scientists had spent a decade working on the project; when sorbinil crashed, more than a few switched gears and moved into other research programs. "It was the right decision, but I was heartbroken," says Hutson. It was also a watershed moment for her. "Losing sorbinil taught us that you have to keep some of your emotions in reserve," Hutson says, adding that the defeat transformed her into a professional drug developer, tempering her original starry-eyed optimism with a new sense of realistic, if diminished, expectations. "We were just as determined as ever. But did we still believe we'd change the world overnight? No. That dream was over."

Holy Spaces

"We have to help researchers understand that only a tiny minority of them--over their entire careers--will ever touch a winning drug. We have to lead them through failure."

While sorbinil's death cost Pfizer tens of millions of dollars and more than a decade's worth of time and talent, it still didn't quash the company's quest for a breakthrough antidiabetes drug. Even as sorbinil entered late-stage clinical trials, a Pfizer team of medicinal chemists had synthesized a second aldose-reductase inhibitor. Dubbed zopolrestat, it proved to be 40 times more powerful in the test tube than sorbinil.

Early-stage human trials showed that patients tolerated zopolrestat well, but Pfizer's executives were understandably reluctant to once again lay siege to diabetic complications. They were finally swayed by the old cliche: You can't win if you don't compete.

As with sorbinil, more than a decade of tests and trials followed for zopolrestat. With diabetic rats, zopolrestat halted nerve damage and in some cases even reversed it. By early 1999, the results from human trials were encouraging enough for Pfizer to select a brand name for what it hoped would be its first-ever antidiabetes drug: Alond, the runner-up name for the pill that came to be known as Viagra. That January, Forbes predicted that zopolrestat would be one of a new generation of blockbusters to emerge from Pfizer's lab. But as the months progressed, biopsy data showed little difference between patients who received zopolrestat and those who got a placebo. It had taken years of testing to make clear that the drug couldn't do in humans what it had done in rats. On August 12, most of Groton's scientists heard the news at the same time Wall Street did: Zopolrestat was dead on arrival.

After two spectacular flameouts in two decades, it looked as if Pfizer's antidiabetes program was finished. But once again, Pfizer had hedged its bets. Back in 1985, as zopolrestat was heading out of the lab and into clinical trials, Hutson had asked Oates to take a final look at their aldose-reductase research. His brief: Unless he found a new pathway that was worth pursuing, he was to close the program.

"I badly wanted a winner," Hutson says. "Peter would turn over every stone, and if there was another way for treating diabetic complications, he would find it. I told him, 'Just follow the science.' And he did."

Following the science, in fact, was what Oates lived for. A large photograph dominates a wall in his small, spartan office, just off the diabetes lab in B-220. It looks like a swirling galaxy of stars, but it's an electron micrograph of a human cell, magnified 44,000 times. Oates's blue eyes widen as he points out the cell's DNA. The photograph shows what he and other diabetes investigators are really trying to accomplish: to see into an invisible world and take on diabetes at the molecular level. "I've spent my life in that cell, trying to understand the fundamental biomechanisms of diabetes," he says. "This work is exciting, it's draining, it's daunting. We're on a journey into inner space, and there are false leads and unexpected insights all along the way."