Gleevec is like the proverbial shining city on the hill in the pharmaceutical business. When it was first approved in 2001, it beat the long odds of drug development, becoming one of the first targeted cancer therapies. It lived up to the hype, turning a deadly form of cancer into a chronic illness. Even though fewer than 6,000 people get chronic myeloid leukemia each year in the U.S., the drug still made billions of dollars.
Plenty of people in the pharma industry tried to duplicate or iterate on what Novartis did in the imatinib (Gleevec) story. Lots of drugs came next, seeking to inhibit kinase enzymes like Gleevec did. Few had such a profound impact on patients.
But now, more than a decade later, a little company in Cambridge, MA, called Blueprint Medicines has reunited a scientific trio who gave the world Gleevec — Nick Lydon, Brian Druker, and Charles Sawyers. The startup, backed with a $40 million Series A financing from Third Rock Ventures and Fidelity Biosciences in 2011, is making a bold bet that the time has finally come for a team to start cranking out more precisely targeted cancer drugs like Gleevec.
The idea, described by CEO Chris Varma, is to use today’s superfast/supercheap DNA sequencing instruments to systematically comb through the genomic abnormalities that give rise to cancer. Once new potential drug targets have been found, Blueprint’s chemistry team quickly builds libraries full of specific, and potent, small-molecule drugs to hit kinase targets like the one that Gleevec blocks so well.
In its first two years in business, Blueprint has scanned broadly across the 500 or so known kinase targets in the “kinome” and synthesized its own libraries of proprietary drug candidates that can selectively inhibit about three-fourths of them, Varma says. This week, the company took another small step ahead, striking a partnership with the U.K.-based Sanger Institute and Massachusetts General Hospital to see how legit some of these candidates are. Blueprint and its collaborators are now going to test Blueprint’s drugs against 60 different kinase targets, in 1,200 different human cancer cell lines in the lab. Blueprint has already run its drugs through a few cell lines in its own lab, but this is a tougher test, to see just how many of its drugs have promise against such a diverse set of tumor types.
Blueprint doesn’t expect to come away from this collaboration with a one-size-fits-all widget for a common condition like breast cancer. While drug developers of the past might have shied away from rare malignancies, Blueprint’s great hope is to find treatments for a couple types of cancer with names few people have ever heard of.
Pfizer’s crizotinib (Xalkori) is one of these kinds of drugs. It works for 4 percent of non-small cell lung cancer patients with a mutated ALK gene. Before this drug came along, the ALK gene didn’t exactly roll off the tongue of people in the business. But it does now, because it’s a mutation that’s easy to screen for, the Pfizer drug is highly effective for ALK-mutated patients, and sales have been good for the company.
That’s the kind of story Blueprint is hoping it can tell over and over again, for cancer patients with strange gene mutations.
“If you look at what’s been going on in cancer the past 10 years, when you selectively inhibit genetic abnormalities, you can get to substantial responses in patients,” Varma says. “We want to create a company to do that systematically.” He doesn’t shy away from Gleevec comparisons. “We started the company thinking about how we can get to durable responses in cancer? We want to enable patients to live a normal life with the aid of our medicine.”
One might think that the pharma companies would have already created systematic approaches to come up with more Gleevecs. Varma says it’s not the case. Pharma companies are known for their massive libraries of chemical compounds that could be drugs, but most of those compounds are designed to hit the 30 or so most validated of biological targets. Many companies spent years wondering whether it was better to make kinase inhibitors that were super-precise, or maybe not so precise. Essentially, the debate was over whether cancer drugs might need to cause some collateral damage to be effective.
Some small companies—like San Diego-based Ambit Biosciences and Boulder, CO-based Array Biopharma (NASDAQ: ARRY)—have sought over the years to look broadly across the 500 or so kinase targets, although both have placed more of their focus in recent years on individual drugs in late development.
But by the time Blueprint got started in 2011, the underlying discovery technologies had changed. They have gotten cheap enough and good enough that a small company like Blueprint can take a serious shot a comprehensively analyzing the kinome. Besides the improvement in DNA sequencing instruments, genomic data analysis has improved, Varma says. Part of Blueprint’s team works to separate the signal from the noise in the massive genomic data files it reviews.
The company has built up a team of about 30 employees so far, with skills in molecular biology, structural biology, chemistry, and computational chemistry and biology, Varma says. At a time when a lot of startups are attempting to do everything lean and mean, and rely on outsourcing, Blueprint has been going the other direction, building up a serious multi-disciplinary drug discovery engine. “In the past couple years, we opened our labs, we brought in centrifuges, we hired people. One FTE [full-time-equivalent employee] can’t do it alone,” Varma says.
All this work is still very much in the earliest part of the pharma R&D continuum. Blueprint is still several years away from moving its first drug candidate into clinical trials, where investors tend to pay more attention. But in just two years, Blueprint says it has built a pipeline of five drug programs, including two that it could consider “lead programs,” Varma says.
Brace yourself for some thorny terms here, but that’s life in cancer research these days. The mutation is thought to play a role in systemic mastocytosis, in patients with gastrointestinal stromal tumors that resist existing therapies, and in patients with acute myeloid leukemia with mutations to the T821gene.
Blueprint isn’t the only company that has looked down all these different molecular alleys of cancer biology. Novartis has a compound in clinical trials, called PKC412, which inhibits a broad array of kinases and is being studied as a treatment for systemic mastocytosis and acute myeloid leukemia, Varma says. Blueprint believes its candidate is different in that it’s more selective to the D816v mutation, Varma says.
It will be years before researchers know if the Blueprint drug has promise for these patients, or some other subgroup of patients whose tumor type is being redefined. Work like this is helping patients and physicians change the way they think and talk about cancer. If, for example, you had a drug that was exquisitely effective for patients with a D816v mutation, suddenly people will start classifying their cancer based on its molecular hallmarks, rather than whether the tumor happens to come from the breasts, the prostate, or the lymph nodes.
Varma readily admits that the biology is amazingly complex, and to even come up with one drug that’s effective for a small group of cancer patients is a huge achievement. But it’s not such a big challenge that it’s impossible to imagine creating a series of effective drugs for well-defined groups of patients. “This is where I think cancer is going,” Varma says. “What really matters is what’s happening at the genetic level. Cancer is a disease of the genome.”
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