[Updated 8/15/11 8:00 am. See below.] In mid-July, Cambridge, MA-based Cerulean Pharma began a new clinical trial of its cancer drug CRLX101, which is a “nanoparticle”—a powerful chemical wrapped in a tiny package that can burrow its way into cancer cells and kill them. Cerulean is one of a handful of companies laboring to apply nanotechnology to drug delivery. The trial, which will involve 150 patients with non-small cell lung cancer, should shed some light on the potential of nano-drugs in the cancer setting when top line results are released next year.
But CEO Oliver Fetzer isn’t waiting for proof that Cerulean’s approach works. He’s so optimistic that he has already set his sights on a big new opportunity for the company’s tiny drug platform: RNA interference (RNAi). About a decade ago, the pharmaceutical industry started pouring research dollars into RNAi—a new method for shutting off disease-causing genes and proteins. But there was a problem. “If you just inject RNA into the patient, enzymes degrade it very quickly,” Fetzer told Xconomy in a recent sit-down interview. So last year, Cerulean started testing its nanoparticles to see if they might offer a better way to deliver RNAi therapeutics.
Cerulean isn’t the only company to spot an opportunity for nanoparticles in RNAi. On July 25, Cambridge-based Alnylam Pharmaceuticals (NASDAQ: ALNY)—one of the pioneers in RNAi—announced that it and its collaborators at the Massachusetts Institute of Technology discovered novel nanoparticles that might facilitate the delivery of RNAi drugs directly into cells. Alnylam is developing RNAi approaches for several diseases, including cancer.
The difficulty of translating the promise of RNAi into drugs has been a major downer for the field. Last November, Swiss drug giant Roche unexpectedly pulled the plug on its RNAi program, which included ending a research alliance with Alnylam that once had the potential to earn the Cambridge company $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.”