Cerulean Shows Progress in Cancer, Tests Nano-Drug Platform in RNAi

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$1 billion. The move came just months after Roche’s neighbor Novartis axed its alliance with Alnylam.

Fetzer believes those disappointments signal an urgent call to work out RNAi’s delivery challenges. “I would argue that if no one figures it out in the next two years it’s really going to get the field stuck,” he says.

Cerulean originally designed its nanoparticles to exploit a unique characteristic of tumor tissue. There are pores in tumors that are much larger than pores found in normal tissue, Fetzer explains. Cerulean’s nanoparticles travel through those pores, get absorbed into the cancer cells, and release the drug from inside the cells. But the nano-drug doesn’t travel anywhere else in the body, which helps minimize side effects, Fetzer says.

The ability of Cerulean’s nanoparticles to zero in on tumors explains the safety signals the company has seen in Phase 2 trials of its CRLX101, Fetzer says. The active ingredient is camptothecin, a potent anti-cancer chemical discovered years ago but never developed because it was too toxic to be given as a therapy. So far, Fetzer says, none of the patients in the Cerulean trials have had to reduce their doses or take the drug less frequently because of side effects. They don’t lose their hair, or complain of fatigue, Fetzer says. “These patients have already been exposed to a lot of toxic drugs, so they’re pretty beaten up,” he says. “But they comment to us, ‘I’m feeling great. What are you giving me?’ Ironic that it’s camptothecin—the compound that was once too toxic to be given alone.”

Now Cerulean is branching out into RNAi. Cerulean’s nanoparticles are polymer chains linked to drug molecules. Once the particles have arrived in a cell, naturally occurring enzymes clip the links, releasing the drug. What’s left of the nano-machinery gets flushed out of the body naturally. Cerulean is testing a second nanoparticle platform to see if it can be a carrier for what’s known as “small interfering RNA,” or siRNA, which can bind to other RNAs to either increase or decrease their activity. In mouse studies, says Fetzer, “We can put siRNA on our particles, we can get it into cancer tissue, we can release it, and we can knock down a protein.” [Paragraph revised to clarify that Cerulean is developing a separate nanoparticle technology for RNAi use.]

Alnylam is also developing its nanoparticles as siRNA delivery vehicles. Alnylam CEO John Maraganore (who is also one of our Xconomists) said in an e-mail that Alnylam’s nanoparticles employ different materials than those used by Cerulean and other companies. The Alnylam technology, called “core-shell,” may allow scientists to tweak the size of the nanoparticles to accommodate different siRNA therapies, according to a paper the company published in the Proceedings of the National Academy of Sciences.

Cerulean’s Fetzer says that rather than developing RNAi therapies in-house, the company plans to license out its technology. Cerulean raised $24 million in a Series C in November, bringing its total funding to $56 million—plenty to continue the development of CRLX101, while simultaneously building more of a case that the RNAi platform works, Fetzer says. “We want to make sure we have really robust data before we start talking to people” about licensing the nanoparticle technology for RNAi therapeutics, Fetzer says. “Because of the fact that there are so many companies that haven’t succeeded in RNAi, the bar is pretty high out there.”

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