Plexxikon Shows How New Drug Hits Molecular Target for Deadly Skin Cancer

Xconomy San Francisco — 

Plexxikon has just landed a one-two punch in a couple of the world’s top medical and scientific journals.

Just a couple weeks after the Berkeley, CA-based biotech company delivered some eye-opening results in the New England Journal of Medicine on its drug candidate for a deadly type of skin cancer, it is following that up with a study being published today in Nature. Today’s paper is the first to show the method Plexxikon’s scientists used to develop their drug, PLX4032. The new publication also shows that when the drug is given in high doses and is inhibiting its target at the molecular level, patients see the greatest benefit in tumor shrinkage and remission time.

The findings are an important step for Plexxikon as it seeks to prove to scientists and physicians that it has created the next big thing for treatment of melanoma that has spread through the body. The experimental drug is thought to be useful for about half of the patients with metastatic melanoma who have a mutated form of a protein called BRAF that enables the uncontrolled cell division that is a hallmark of cancer. Initial results from a study of 32 patients, published last month, showed that 81 percent of them had partial or complete tumor shrinkage, and they stayed in remission for a median time of seven months.

There was no control group in the trial, so it’s impossible to say how much of an improvement that really represents, but other drug combinations usually only cause tumor shrinkage in 10 to 15 percent of patients. Bristol-Myers Squibb made headlines back in June when it said its drug candidate, ipilimumab, was able to extend lifespan from a median of six months to about 10 months.

Plexxikon hasn’t yet gathered data on how its drug affects survival time. So there’s plenty of room for people to wait for more confirmation from other studies that might rule out whether other factors that may have contributed to the better performance of those patients. That’s why today’s Nature paper is important for the company, because even though it’s still in a small patient population, it shows the link between what its drug is doing at the molecular level, and how patients end up faring.

Gideon Bollag

Gideon Bollag

“We think this really validates the target,” says Gideon Bollag, Plexxikon’s senior vice president of research. “This shows for the first time that the target is absolutely critical to the survival of the cancer cells. People in the field have called this oncogene addiction, in which the tumor cells are addicted to this BRAF gene. But you don’t know it’s the case until you see a single agent that targets BRAF protein, and is effective on its own to cause tumor regression.”

The findings were a bit surprising to the Plexxikon scientists. Based on their method of structure-based drug design, they selected their lead compound PLX4032 for its combination of potency, selective ability to home in on the BRAF target, and its potential to be given as a tolerable twice-daily oral medication.

Still, as potent and selective as the drug was, it didn’t appear to help shrink tumors or slow them down at the lowest doses in this clinical trial. When Plexxikon took a look at tumor biopsies from patients, taken before and after they got treatment, the scientists figured they would see a connection between their drug’s mechanism and tumor shrinkage early on.

They figured that if a drug could inhibit half of the available BRAF targets on cells, then it ought to make a significant impact on tumor shrinkage, Bollag says. But Plexxikon really only saw the tumor shrinkage benefits in patients when it was able to inhibit 80 to 90 percent of the chosen targets, Bollag says. “That surprised us,” he says. “If you inhibit 50 percent that should be enough. But it’s not enough.”

So while the researchers started seeing an effect at 240 milligram doses, the company ended up picking 960 milligrams as the ideal dose for future clinical trials, Bollag says.

More definitive results are expected to come fairly soon. Plexxikon and its partner, Roche, have completed enrollment in a mid-stage study of about 100 patients with metastatic melanoma and expect to have preliminary results from that trial by the end of the year. The companies are also recruiting people into a pivotal Phase III trial of about 700 patients, which will compare the Plexxikon drug to a common chemotherapy drug, dacarbazine. That study started enrollment in late 2009 and early 2010, Bollag says.

Promising Phase I results certainly are the kind of thing that can help speed up clinical trial enrollment, as patients with melanoma seek some kind of hope. That may help Plexxikon move this program along quickly, which it will have to do if it wants to hold onto the upper hand in the field. Novartis, GlaxoSmithKline, and South San Francisco-based Exelixis are all thought to be developing their own drugs to block the BRAF target, and other companies are also thought to have been encouraged to get into the race based on Plexxikon’s success so far, Bollag says. It’s safe to say that this is going to be an increasingly competitive niche to watch in the cancer drug development world.

“Our data has encouraged other companies that this is indeed an attractive target,” Bollag says. “Other efforts are escalating.”