BY MARK SCHOLZ, MD
Zytiga has rapidly become the treatment of choice for prostate cancer resistant to standard hormone treatment with Lupron. It is effective and well-tolerated. Given the immense success of this product, I find the story of its discovery 22 years ago quite interesting. What follows is a heavily truncated version of Gerry’s story published on the web in 2010.
In 1990, Dr. Gerry Potter, having just finished his PhD, was in his first week of work at the Institute of Cancer Research in London's Royal Cancer Hospital. His colleagues on the drug discovery program, Prof. Mike Jarman and Dr. Elaine Barrie, wanted to target a male hormone-producing enzyme called CYP17 because prostate cancer feeds on testosterone.
A laser-guided bullet to target CYP17 was needed. Block this enzyme and you took away the cancer's exclusive food supply. "The idea was to starve the tumor to death, not attack it directly," explains Gerry.
They asked their new scientist to design a drug that “jammed” the lock of CYP17. Easier said than done. To build a jamming key you needed to know what the lock looked like. No one did. You couldn't see it under a microscope. "You have to work it out from the inside," he says. "It's a bit like a glove. To know its shape, you need to understand the hand that fits it. You have a palm and fingers and thumbs. You have to work out how they all fit together."
Gerry worked on hunches and hypotheses, using his knowledge of the enzyme's basic components to scribble down different possible structures. Then he saw it, or rather he imagined it. "It was a Eureka moment," he says. "You instinctively know when something is right."
Now that he had the lock, he had to build the key to block it. That took a fortnight – a heartbeat in the time scale of hard science. "I developed a new chemical reaction to synthesize it," he says matter-of-factly. "What I was trying was really difficult and couldn't have worked predictably at any stage. Yet everything fitted into place. It worked first time."
Then came the boring part: the making of "analogues" – a hundred near replicas of abiraterone, so no-one could make a copycat variant and claim the idea as their own. "None worked as well as the first," says Gerry, still slightly awed by that fact. "Everything came so easy."
Everyone involved felt the hand of history on their shoulders as abiraterone astonished participants in laboratory tests. The best prostate cancer drug on the market in 1990 – ketoconazole – had a cancer inhibiting activity of 10. "You need that number to be as low as possible," says Gerry. Abiraterone scored 0.001 – making it 10,000 times more potent than ketoconazole.
"It was, indeed, a magic bullet," says the scientist.
He "scaled up" the drug, so it could be produced in kilogram quantities – a requirement for the patent. The patent was eventually filed in 1994 through a venture capitalist company called BTG that had funded much of the supplementary research. BTG then sold on the team's hard work to Boehringer Ingelheim, a German pharmaceuticals giant with the financial muscle to support the fledgling drug through the inevitable years of clinical trials.
The people at Boehringer, however, became concerned when trials of abiraterone suggested it caused the depletion of cortisol, a hormone vital to health. The company cashed in its chips with abiraterone, selling the drug for $40 million to Cougar Biotechnology. Ultimately, pharmaceutical giant Johnson & Johnson (Janssen Biotech) bought Cougar Biotechnology for $1billion.
Zytiga’s impact on lowering cortisol was easily solved by administering it with prednisone, a commercial form of cortisol. Since Zytiga has so few side effects we have found safe ways to combine it with other effective therapies like Taxotere or Provenge.
Gerry and his team overwhelmingly succeeded in improving the lives of thousands of men with prostate cancer.
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