genes in those samples that seemed to be causing those tumors to fight off the treatment.
He found several intriguing candidates. To test their effects, Gleave ran experiments in which those genes overexpressed the proteins they produced. In some cases, those proteins made tumors resistant to chemotherapy, he found. He then blocked the genes or proteins to see if the tumors would again be sensitive to treatment.
This process turned up two highly promising leads. Blocking either clusterin, a protein linked to cell death, or a heat-shock protein called Hsp27, made tumor cells much more sensitive to chemotherapy.
Gleave and Cormack co-founded OncoGenex in 2000 to develop drugs like these that are supposed to impact treatment resistance. The company cut a deal with Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: [[ticker:ISIS]]) to create antisense drugs based on that thesis. One drug—now known as custirsen—blocks the RNA that codes for clusterin. Another, OGX-427, or apatorsen, grabs onto Hsp27, blocking its action.
Of the two, custirsen came first. But the company faced a decision. Clusterin is overexpressed in a whole variety of solid tumors, so OncoGenex could test it in a number of different cancers. The company decided to start with prostate cancer, though, because it was Gleave’s area of expertise. So OncoGenex set up a Phase 1 study testing the drug in men with early-stage prostate cancer to see if the drug was getting to its target, and blocking the production of clusterin. Mission accomplished: weekly infusions of custirsen knocked down levels of the protein in patients’ prostate tumor cells by a dramatic 92 percent, and in lymph nodes by an even more impressive 98 percent. OncoGenex picked a dose, 640 milligrams, and eagerly started human clinical trials in 2006.
The key questions: Would patients live longer if given custirsen along with chemo? And would the drug work in different cancers? OncoGenex launched five Phase 2 trials in prostate, lung, and breast cancer, testing the drug with chemotherapies like docetaxel and mitoxantrone. All the while, OncoGenex was relatively obscure, a lightly-traded stock with a miniscule price—until December 2008.
That’s when Oncogenex reported the top-line results of one of those Phase 2 trials. In the study, 82 men with terminal forms of prostate cancer were broken into two groups and given either docetaxel and custirsen, or the chemo drug and a placebo (docetaxel, at the time, was the standard of care for prostate cancer). OncoGenex’s drug seemed to be extending the lives of prostate cancer patients, and its stock doubled from about $2 to $4, starting a steady climb over the course of the year. Once the full data from the Phase 2 prostate cancer study were released in May 2009, OncoGenex said that its drug helped men live a median time of 23.8 months, about 6.9 months longer than those on placebo, and even showed it might reduce bone pain—a big side effect men suffer when prostate cancer tumors migrate to the bones. Shares of OncoGenex closed as high as $40.16 on Aug. 31, 2009.
OncoGenex was now in the prostate cancer discussion with more widely-known players like Dendreon (NASDAQ: [[ticker:DNDN]]), Johnson & Johnson (NYSE: [[ticker:JNJ]]), and Medivation (NASDAQ: [[ticker:MDVN]]). And Cormack says the company wanted to make absolutely sure it hadn’t been fooled before forging ahead with a multi-million dollar Phase 3 trial. The company “tore that dataset down to a fairly high degree,” examining things like patient discontinuations, the number of chemotherapy cycles received by each arm, and other baseline characteristics, looking for any biases in favor of its drug.
The conclusion: The drug must have worked. “We looked at that and said ‘wow, that’s worth further development,” says Cormack.
OncoGenex, of course, didn’t have the financial firepower to take custirsen into lengthy pivotal trials. But after its Phase 2 victory, it did have the credibility to shop itself to a partner. So OncoGenex cut a deal with Teva in December 2009. The little Washington State company got $60 million up front, including a $10 million equity investment from the big drugmaker. It handed over worldwide rights to custersin—though it had an option to co-promote the drug in the U.S. and Canada—but in return, Teva agreed to foot the bill for a series of large Phase 3 clinical trials, and pay OncoGenex up to $370 million in potential milestone payments, and additional royalties if custersin could make it to market.
The clinical plan was to essentially hedge a bet on clusterin. The idea was to test the drug at two different times—during the initial chemo and then after patients had failed treatment because their tumors had developed resistance. In addition, trials were planned not just in prostate cancer, but also in lung cancer as well. The two companies ultimately designed three studies for those tasks: Synergy, Affinity, and Enspirit. (OncoGenex and Teva dumped a fourth study called Saturn that was supposed to judge bone pain.)
By far, the trial with the most riding on it was Synergy—which tested
