Blueprint Medicines Combs Through Genome for the Next Gleevec(s)

3/20/13Follow @xconomy

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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.

One of those drug programs is aimed at the D816v mutation of the c-Kit gene, Varma says. It’s a specific mutation that is known to be a driver of at least three different malignancies.

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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  • Suhaib M. Siddiqi

    “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. ”

    That is a dream, not possible with current DNA sequencing instruments. Most of the current DNA sequencing technologies provide short reads. It will be humongous task (nearly impossible) to sequencing cancer genome for a more accurate picture of copy numbers, orientations of amplified regions and SNPs present in cancer. Even if accomplished, it certainly not be cheap, not super fast and certainly not super cheap.
    To accomplish what Blueprints Medicine wants, one desperately needs very very long reads. Even long read, claimed by Pac Biosciences will not good enough. Oxford Nanopore is one option but NGS community have started developing serious doubts about it, due to lack of data. ZS Genetics may offer the longest reads suitable for Cancer genome, but its technology is being developed.