because biologists at the time didn’t know which molecules were culprits in feeding osteoclasts. Amgen scientists Scott Simonet and Dave Lacey were chasing the same idea, and published a paper in 1995 showing that RANK Ligand was an essential factor for osteoclasts, and that mice who lacked the gene for it had a dramatic increase in bone density, without having other tissues affected, Dougall says.
Dougall’s competing group at Immunex, 2,000 miles north of Thousand Oaks, CA, found that RANK was an essential piece of the puzzle for inhibiting osteoclasts. When Amgen bought Immunex for $10 billion in 2002, it was able to keep both of these programs together in the same company, Dougall says. Although a lot of colleagues left after the takeover, Dougall stayed, and he has worked continuously with four members of his lab for more than 10 years on the program, he says.
This group has been studying cancer, and the role that osteoclasts play in throwing off essential proteins that nourish tumors in bones. By developing a drug that soaks up excess RANK Ligand, and shutting off the spigot of osteoclasts, it’s sort of like starving bone tumors of essential proteins they use as fuel, Dougall says. It’s conceptually similar to Genentech’s Avastin, which doesn’t directly kill tumor cells, but binds with a protein that’s critical for forming vessels that supply them with blood.
Tumors, in one of their more nefarious activities, also trigger signals to rev up bone breakdown. Experiments have shown that if you block RANK Ligand in animals, you see a decrease in bone lesions and tumor shrinkage. A final-stage clinical trial in breast cancer patients, showed that dmab could increase bone mineral density in women who had bone damage from taking aromatase inhibitors, according to research presented last December at the San Antonio Breast Cancer Symposium.
Bigger trials that look at whether dmab can go a step further, by preventing cancer from spreading to bones, and preventing cancer-related bone damage, are the big remaining questions Amgen hopes to answer in 2009. Since cancer becomes extremely painful when it gets inside the bones, and basically starts cracking them from the inside out, this would be welcome news for doctors and patients. The company has placed an enormous bet on this drug, with 19,000 patients enrolled in clinical trials for osteoporosis and cancer. Now that it’s already been proven in osteoporosis, Amgen will see whether its investment in cancer trials will make this an even bigger blockbuster.
I asked Dougall if the story has taken any surprising twists or turns along the way. To my surprise, he said no. Since few scientists ever see their discoveries make it all the way through clinical trials, most of them have built up a tough skin, accustomed to failure. Not Dougall.
“We’ve had great expectations for this from early on,” he says. “I’d be surprised if it doesn’t work.”
