CytomX Therapeutics Seeks to One-Up Lilly, Amgen Cancer Drugs

3/2/12Follow @xconomy

There are lots of little biotech companies with dreams of beating the big boys, and one of those classic storylines is playing out in South San Francisco at CytomX Therapeutics.

CytomX has fixed its attention on making an engineered antibody drug (which it calls a Probody) that is more precisely targeted to cancer cells, and packs more wallop, than Eli Lilly’s cetuximab (Erbitux) and Amgen’s panitumumab (Vectibix). This program is still in early development, with a goal of filing regulatory paperwork for clinical trials by the end of 2013, but CytomX has hit enough of its technical milestones to start talking publicly about this bold new initiative, says CEO Sean McCarthy.

The biomarker on cancer cells that the Lilly and Amgen drugs are designed to hit—the epidermal growth factor receptor (EGFR)—is “one of the most clinically and commercially validated targets out there in oncology,” says McCarthy. Lilly’s Erbitux was first approved by the FDA in February 2004 for patients with colorectal cancer, and was later cleared for cancer of the head and neck. Along with Amgen’s rival product, these two drugs collectively generate almost $2 billion a year in worldwide sales. But they have their limits, as the EGFR target is found on skin and gut cells, which means many patients who get these drugs suffer from moderate to severe rashes, and severe gastrointestinal effects like nausea. And while the side effects are unavoidable, scientists have learned that the drugs don’t work for about 40 percent of patients who have mutant forms of a gene called KRAS.

CytomX, founded in 2008 with technology from UC Santa Barbara, is wagering that its technology will make it possible to make a drug that only hits the EGF receptors found on tumors, and that such a drug can be combined with a toxin to get it extra tumor-killing punch. Third Rock Ventures and Roche Ventures bet $30 million back in September 2010 that CytomX could turn this concept into a reality. If CytomX is ultimately proven correct, it could crack open a much bigger market for EGFR inhibitors, by getting rid of the nasty rashes, and offering a new treatment for the 40 percent of KRAS mutant patients who don’t benefit from today’s drugs.

Sean McCarthy, CytomX Therapeutics CEO

Quite a lot happened behind the scenes at CytomX in 2011, McCarthy said during a meeting at the JP Morgan Healthcare Conference back in January. For starters, he was promoted from chief business officer to the CEO job in September, after Nancy Stagliano left for iPierian. While the leadership changed, the company made progress on its operations and technical goals, McCarthy says. The company added a lot of capabilities during the year, growing from eight to about 20 employees, and settling in to a new 13,000 square foot facility in South San Francisco. They worked on the company’s basic concept, which is to combine a peptide with the antibody, so that the drug only gets activated in the presence of certain enzymes (proteases) in diseased cells. This way, the antibody will remain inactive while it circulates in the bloodstream, and then get activated when it comes into contact with these disease-related proteases.

CytomX’s big technical step in 2011 was when it found what McCarthy calls a “relevant animal model” to test its concept. The company showed it was able to inject one of its “Probody” drug candidates into rodents that had EGFR-overexpressing cancer that mimics what is seen in humans, both in the tumor, and the surrounding microenvironment, McCarthy says. CytomX scientists saw that their drug was able to hit the desired target in the rodents’ tumors, while remaining stable and inactive while circulating through the bloodstream. So the company ended the year by showing its drug could be active in a living organism (instead of just tumors in a lab dish), and that they could be locally activated by specific disease-related enzymes in the vicinity of an EGFR-overexpressing tumor.

“We tied it up with a nice little bow for the December board meeting,” McCarthy says.

Of course, having some early success means that a lot more work needs to be done to carry the program forward. This spring, CytomX is working on various engineering tasks to come up with an optimized version of a targeted EGFR inhibitor, McCarthy says. The company has more toxicology studies to do, and has to test its drug in non-human primates. And while CytomX’s core intellectual property is in making the Probodies, it is looking for a partner with different skills to help soup up the molecules by binding them with potent toxins.

If CytomX can check those items off its to-do list soon, then it will be ready to plow ahead toward the clinic with an eye on raising the bar for safety and effectiveness in a very tough population of patients—those with EGFR-positive malignancies that also have mutant KRAS genes that fuel tumor growth too powerful for today’s drugs to handle. Presumably, if CytomX can make a drug that works for these patients, and doesn’t have the rash and gastrointestinal side effects of the others, it could have a best-in-class drug for a quite lucrative class.

It would be big news if CytomX, or anybody else, can pull off such a feat. Amgen’s former head of R&D recently told me that one of his biggest disappointments of the past decade was that Vectibix didn’t have as big an effect as he hoped, and didn’t help as many cancer patients as envisioned. But CytomX is so bullish on its approach that it is already thinking about how to avoid becoming a one-product company, by seeing if its technology can be exploited against other targets on cells that aren’t as validated by drugs like Erbitux and Vectibix. McCarthy says he’s excited by the idea of starting with EGFR, and building from there. “Once we hit our milestones, and we headed into the second half of the year, we had to look out three, four, five years and ask ourselves, what kind of company are we trying to build? We want to focus on areas where we can say, ‘without a Probody, you couldn’t do it.”

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