Amgen Scientist, After 13-Year Push, Sees Bone Cancer Work Paying Dividends

10/29/08Follow @xconomy

Amgen had the worst year in its history in 2007, according to CEO Kevin Sharer. If you’re wondering why the world’s largest biotech company has mounted a comeback this year, one good place to look is in the lab of Bill Dougall, an Amgen scientist in Seattle. He’s been pursuing a bone cancer program for more than 13 years that has become a critical component of Amgen’s next big drug.

“This is the biggest thing to come out of this company since Aranesp, since Epogen, since Enbrel,” says Carol Pawlak, an Amgen spokeswoman, referring to drugs that generated more than $9 billion in worldwide sales last year. “People here are very excited.”

The new excitement is about denosumab, or “dmab” for short. It’s a targeted antibody drug that reached its goal of reducing fractures in women with osteoporosis, according to research presented at a medical meeting last month. This drug could generate $2.2 billion in annual sales in 2012, said Christopher James, an analyst with Rodman & Renshaw in New York, in a note to clients last week. The projections are based mostly on dmab’s growth potential for osteoporosis, but Thousand Oaks, CA-based Amgen (NASDAQ: AMGN) is eager to see clinical trial results next year that could prove dmab’s effect is much broader, for seriously ill patients whose prostate or breast cancers have spread to the bones.

The treatment for osteoporosis “has the potential to redefine the space, much the same way in which Enbrel re-defined rheumatoid arthritis,” James wrote. But for cancer patients, he added, “dmab continues to be under-appreciated.”

Much of the excitement stems from clinical trial results presented last month at the American Society of Bone and Mineral Research in Montreal, Quebec. Scientists said a study of 7,808 patients, followed for three years, showed a 68 percent lower risk of spinal fractures for those who took dmab versus those on a placebo. The drug didn’t appear to cause increased rates of serious side effects.

But that’s not where the story ends. Dmab is designed to work unlike any other treatment on the market for osteoporosis, or for bone tumors. It is meant to block the action of a protein called RANK Ligand, which activates osteoclast cells that lead to the breakdown of bones.

This requires a little basic biology to understand. Healthy people maintain a constant balance of what’s called bone remodeling, in which bone cells die and re-grow. Cells called osteoclasts work to break down bone, while osteoblasts build up new bone, Dougall says. When that cycle falls out of balance—like when people develop too many osteoclasts or those cells become too overactive—then it can lead to bone loss, Dougall says.

This is the part of biology that Dougall has been working on for so long. He started at what was then Seattle-based Immunex in 1994, after a postdoctoral fellowship at the University of Pennsylvania. The next year he was put to work on a team that looked at inflammatory proteins like TNF, which was plays a key role in rheumatoid arthritis, and which etanercept (Enbrel) was created to block. He found RANK, a protein receptor that binds to RANK Ligand, which plays a key role in stimulating osteoclast cells. This was a big deal, 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.”

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