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product that Cerulean has devised is about 30 nanometers wide, compared with targeted antibody drugs which are about 10 nanometers wide, Fetzer says. The diameter of the molecule is important, because it’s big enough to make it hard to get inside healthy cells as it travels through the bloodstream, but still small enough to slip inside the big leaky holes (about 100 nanometers wide) that are all over the blood vessels that feed tumors.
Once the Cerulean drug gets inside the tumor, Fetzer says, it’s too big for the tumor to be able to pump it out, which tumors often do when encountering chemo agents. Instead of being designed like an antibody to bind with a specific receptor on the surface of tumor cells, Cerulean’s drug uses its physical properties to get into the tumor and then steadily release its toxic payload as the cell engulfs the drug, Fetzer says. For those interested in targets, the drug is supposed to be a potent inhibitor of the proteins topoisomerase 1 and HIF-1 alpha.
The data so far have given Cerulean confidence that it can give its drug safely, in a one-hour infusion that patients get every two weeks. Cerulean was prompted to start its big ongoing trial by a previous study of 38 patients with various tumor types, and which was tilted heavily to enroll 21 patients with non-small cell lung cancer, the most common form of lung cancer. The patients were very sick, having gotten an average of about three prior therapies, Fetzer says. While this study had no control group—so it’s impossible to say whether Cerulean’s drug was better than anything else—the tumors of the lung cancer patients were kept from spreading for a median time of 4.4 months, a measurement known as progression-free survival.
Based on a review of historical studies of similar patients with standard treatments like Genentech’s erlotinib (Tarceva), Eli Lilly’s pemetrexed (Alimta) and docetaxel chemotherapy, researchers would generally expect about 2.5 to 3 months of progression-free survival, Fetzer says. Once the tumors spread again, these patients have a life expectancy of an additional four to six months, he says.
Given that backdrop, Cerulean designed the ongoing study of 157 patients to find out if the Cerulean drug can not only keep tumors in check, but whether it can keep patients alive longer, after they’ve already gotten one or two prior rounds of therapy. The study is designed with the assumption that patients on the best supportive care will live about a median of five months, consistent with historical averages, Fetzer says. The study’s statistics are set up in such a way that it will be a success if patients live just slightly under nine months on the drug, Fetzer says. Even if the control group lives a bit longer than historical averages would suggest—raising the bar for the Cerulean drug—Fetzer says he believes the drug will still be well-positioned to become a product as long as it can deliver nine months of median survival time.
“We’re not going after a squishy endpoint, we’re going after the endpoint that really matters,” Fetzer says. “I completely agree with the regulators,” he says, noting there’s no reason to try to extrapolate survival time based on an earlier read-out on whether tumors have spread.
The study began enrolling patients in July 2011, and was full of patients a year later. The study protocol said that at least 94 patients would have to die in the overall population to get a statistically valid answer about whether the new drug is helping. Based on the study’s enrollment patterns, Cerulean’s contract research firm first expected the 94 death events to be reached in October, then November, and then it delayed it again. While many cancer drug developers have implied that such delays might mean the new drug is working, there have been numerous cases of other trials that took longer than expected, and still failed, because patients in the control group lived longer than researchers forecast. Or, maybe patients who entered the trial were healthier than those who entered previous studies. Those answers won’t be known until the blind comes off the database.
All Cerulean knows for now is that the 94 deaths were reached in early 2013. It also has had a look at the safety data, and so far the drug group and the best-supportive-care-alone group look similar, with slightly more patients complaining of shortness of breath, coughing of blood, and chest pain in the best-supportive care group, Fetzer says. Researchers have seen a few cases of “low-grade” bleeding in patients’ urine, which is consistent with usage of camptothecin, the active anti-tumor agent in CRLX101, Fetzer says. He says there have been “very few” moderate to severe side effects in the study, known as Grade 3 and 4 adverse events.
If the study is positive, obviously, Cerulean and its research collaborators will be motivated to move quickly to prove the result in an even bigger trial to win FDA approval. Cerulean figures that study should require about 700 patients to deliver the kind of evidence the FDA will want to see.
Even before the final results of the mid-stage study are in, Cerulean is charging ahead as if it has already passed the trial. Late in January, the company enrolled the first patient in another study of CRLX101 in patients with advanced small-cell lung cancer, an even harder form of lung cancer to treat. Earlier that month, it started a mid-stage gastric cancer trial, and provided an update on a mid-stage trial of the drug for ovarian cancer.
If the non-small cell lung cancer trial pans out this month, those other studies will look like an aggressive plan to make the most of a promising new kind of treatment. If the first big study fails, the trials will take on a different light, as potential fallback options for Cerulean.
Either way, the company will still have options that come from having raised a lot of money and used it to place a variety of gutsy bets. Fetzer, in talking last week about the strategy, sounded like the sort of guy who fills up a tank of gas and then floors it, rather than tiptoeing around in hopes of getting the best possible gas mileage.
“I want to make sure the drug gets optimally developed. I want to do our studies in parallel rather than what small biotechs typically do, which is run them sequentially, which takes years,” he says. And when he talks about running studies in parallel, it’s not only for multiple diseases, but for multiple countries. To go global, he’ll need help from a partner. So you can be sure several potential partners will be watching for that data readout from Cerulean this month, and that Cerulean will be ready to talk.
“We will be looking for a superb partnership, not just any partnership,” Fetzer says.