There’s a biotech startup called Plexxikon in Berkeley, CA, where executives and investors are probably mirroring this week’s sunscreen-worthy Bay Area weather with some sunny faces of their own. That’s thanks to encouraging news about Plexxikon’s lead drug candidate, which goes by the prosaic label PLX-4032, and its ability to reverse tumor growth in patients with a specific genetic mutation commonly linked to metastatic melanoma, one of the deadliest types of skin cancer.
In a paper published Wednesday in the New England Journal of Medicine, researchers at Plexxikon and partner institutions reported that nearly all of the patients in a small Phase I clinical study—designed primarily to test the drug’s safety rather than its effectiveness—showed a reduction in tumor size. In 24 of the 32 patients, tumors shrank by at least 30 percent, and in two patients they disappeared completely. While the results are preliminary, that kind of response rate is unheard of for a disease where the best drugs on the market are ineffective in 80 to 90 percent of patients.
“Any significant response would have made the news, but the 81 percent that we are reporting is just hitting the ball out of the park altogether,” Peter Hirth, Plexxikon’s CEO, boasted to Xconomy yesterday. Others apparently agree: “This is the most important breakthrough in melanoma, ever,” University of Pennsylvania physician Lynn Schuchter, who worked on the study, told USA Today.
The drug appears to work so well that even before the Phase I study was completed, Plexxikon had launched Phase 2 and Phase 3 studies that could garner the data needed to support an application for FDA approval. Those studies are still in progress, but Plexxikon expects to present data from the Phase 2 study at a conference later this year. “We expect to get an accelerated review process, so we might get approval next year if everything goes well,” says Hirth. “And that means potentially having a drug on the market next year.”
Patients were chosen for the PLX-4032 study because their tumors were linked to mutations in a protein called BRAF. This so-called “protein kinase” is involved in stimulating cell growth, and normally its action is regulated by other proteins. Researchers discovered in 2002 that about in about half of patients with metastatic melanoma, there’s a specific mutation in BRAF that disrupts this regulation, causing out-of-control cell proliferation. PLX-4032, which Plexxikon is co-developing with Roche Pharmaceuticals, is designed to bind to and shut down the mutated form of BRAF, while leaving BRAF molecules in healthy cells untouched.
Hirth and others are saying that the Phase I results help to validate Plexxikon’s proprietary strategy for designing so-called selective kinase inhibitors. “The study highlights the potential power and importance of this type of approach,” Alexis Borisy, an entrepreneur in residence at Boston’s Third Rock Ventures, told Technology Review yesterday. “In a short period of time, we’ve gone from the discovery of the mutation to the design of a drug that is selective for that mutation, and which leads to dramatic clinical effects.”
There are many companies testing selective kinase inhibitors as potential cancer therapies. But nine-year-old Plexxikon is closest to bringing a drug to market, Hirth claims, and he attributes the company’s lead to its “structure-based” approach to drug discovery.
“We started Plexxikon with a concept of using co-crystallography as a screening tool,” Hirth says. “We take targets and complex them with potential drug candidates, we make them into crystals, we place the crystals in an X-ray beam, we look at the differential geometry, and we use that to determine the atomic structure of the complex. That tells us where the compound binds to the target, and what we can do in terms of chemistry to build upon that.”
Using structural data to guide the search for lead drug candidates, Hirth says, is significantly accelerating drug discovery at the company. “In most big pharma companies running a program like this, it’s not unheard of to make 5,000 different compounds. We have, in this case, made maybe 100 to get to our lead compound. That translates into enormous time and cost savings. It’s a revolution in drug discovery at work.”
So if Plexxikon has been doing structure-based drug discovery since 2001, why has it taken until 2010 to find a promising disease therapy? That’s partly a story about the benefits and hazards of working with Big Pharma. In 2004 Plexxikon and Wyeth struck a $372 million deal—$22 million up front, and $350 million in milestone payments—to use Plexxikon’s technology to develop compounds to treat metabolic conditions such as diabetes and obesity. But after working with the startup to get a lead compound all the way to clinical trials, Wyeth decided to drop the program, Hirth says, leaving Plexxikon partner-less and payment-less.
So in 2006, Plexxikon started over, establishing a new partnership with Roche, which was interested enough in PLX-4032 to provide $40 million in up-front fees and up to $660 million in milestone payments. Roche is also backing research on another Plexxikon compound, PLX-5568, to the tune of $60 million up front and $275 million in milestone payments.
The licensing fees the startup has collected—$170 million in all—have allowed it to grow on a relatively small base of venture capital. The company has raised only $67 million in venture financing, from a group that includes Advanced Technology Ventures, Alta Partners, Astellas Venture Capital, CW Ventures, Daiwa SMBC Capital, GIMV, Kumho Asiana Group, NIF SMBC Ventures, Pappas Ventures, and Walden International.
“The last round was in 2006, prior to our BRAF deal with Roche, and was a relatively small round,” says Kathleen Sereda Glaub, Plexxikon’s president. “$67 million, for a biotech at our stage, is incredibly low, and that tells you a little bit about our business model, which has been very capital efficient. We have raised money through the pharma collaborations, and we have been able to do them largely around programs that were at the IND [investigational new drug] or Phase I stage, so we have been able to do very attractively priced deals.”
The only bad news, Glaub says, is that the company is doing well enough financially that it has had to pay taxes for the last several years.
If the promise of PLX-4032 pans out, it might send those taxes even higher. Melanoma, after all, affects more than 50,000 people in the U.S. every year, killing 85 percent of them within 5 years of diagnosis. A safe drug that worked more effectively against cancer cells than current drug treatments—chemotherapy drugs such as Dacarbazine and immunotherapy agents such as interferon—could be a very big seller.
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