custirsen along with first-line chemo, docetaxel. “For the most part,” Cormack says, the trial was the same study OncoGenex carried out in Phase 2, just with a bigger sample size. All it had to do, executives thought, was recreate the same type of results, and OncoGenex would likely have a marketable drug for prostate cancer.
So OncoGenex enrolled patients, and waited…and waited. And a few key things happened along the way. The field for prostate cancer drugs became intensely competitive. Johnson & Johnson’s abiraterone (Zytiga) and Medivation and Astellas Pharma’s enzalutamide (Xtandi) seeped into the marketplace, first showing benefits for prostate cancer patients after chemotherapy, and then before. The paradigm for prostate cancer treatment started to change. Even if OncoGenex were to succeed, the potential market size for its drug became less clear. The share price began to drop. Investors became less convinced that custirsen really had big potential.
Still, any company would prefer market potential questions to efficacy questions, and OncoGenex could at least show its drug had real value if Synergy held up. Even with the other new prostate cancer drugs, custirsen would have a place, Cormack argued, since all drugs eventually lose efficacy .
And then the results came in. On April 28, OncoGenex delivered the bad news. Patients on its drug and docetaxel had a median survival rate of 23.4 months, compared to 22.2 months for patients dosed with chemo and a placebo. The results were “unexpected,” OncoGenex said in a press release, given the “wealth of scientific evidence” supporting targeting clusterin in prostate cancer.
“The hazard ratio part of it was probably the most surprising,” Cormack says.
What went wrong? Cormack and his team now are searching for answers, tearing down the data just as they did in the Phase 2 trials. Among the questions: Was the study “balanced” appropriately? Did the introduction of new prostate cancer meds after the study began have an impact, and if so, what kind? Is there an imbalance in the patients that received one of those therapies? An imbalance in the timing of when they went on to those therapies? Does the changed paradigm of treatment options, for example, mean that chemotherapy is being introduced earlier or later than it was in the case of OncoGenex’s Phase 2? And did all that completely change the dynamics of the study’s control group? Cormack says, for instance, that if docetaxel isn’t used earlier on, then clusterin levels in those patients probably aren’t that high. As a result, the tumors might not have been as resistant to chemotherapy as in the original population OncoGenex thought it was studying.
Of course, regardless of what OncoGenex finds, it can’t change the past. Cormack is adamant OncoGenex isn’t hunting for data that would turn a failed study “somehow into a positive trial.” Instead, the company just wants to better understand what happened.
“The result is the result,” he says. “What we’re trying to do is understand why is this different than what we saw in Phase 2, and [if] it informs anything else we want to do with the drug.”
In looking back, there isn’t anything in particular Cormack would change about the Synergy study given what OncoGenex saw in Phase 2. If anything, he says, an argument could be made that the company should’ve charged right into Phase 3 after it got the Phase 2 data, instead of halting everything while it tried to find a partner. By doing so, OncoGenex might not have had to worry about the abiraterone or enzalutamide effect it’s surmising might have affected the results, because those drugs wouldn’t have been on the market then.
Easier said than done, however. Cormack says OncoGenex would’ve needed a large amount of cash from Wall Street during the peak of the financial crisis to kick off a Phase 3 on its own.
“We couldn’t have found a couple hundred million dollars in the capital markets like today,” he says. “So it wasn’t really a choice to start it earlier—we had to do partnering.”
Where does this all leave OncoGenex? In all likelihood, custersin is probably done as a first-line drug paired with chemotherapy for prostate cancer. But if the scientific hypothesis still holds water—if clusterin is an important target, and if custersin knocks it down—then, Cormack says, then patients whose cancers have built a resistance to one chemotherapy, progressed, and moved to another, should respond. Meaning, at minimum, Oncogenex is hoping that the drug has a future in that niche and that the ongoing Phase 3 studies (Affinity, second-line prostate cancer with cabazitaxel; and Enspirit, second-line non-small cell lung cancer with docetaxel) will prove it.
Still, those are tinier opportunities than what OncoGenex was hoping for. What’s more, the failed study has forced the company to change its strategy. Had custersin succeeded, OncoGenex could count on Teva milestone cash and royalties (though Isis is entitled to a portion of those milestone payments under its licensing deal with OncoGenex). The company’s stock price would’ve jumped, and OncoGenex would’ve had the option to raise cash on Wall Street at a good price, and develop apatorsen from a position of strength.
“You would’ve had different financing opportunities, and you’d probably be less pushed into making earlier decisions on what you do with the apatorsen program, because you have the cash to make decisions and take more time to consider different alternatives,” Cormack says.
No longer. With custirsen’s future uncertain, and OncoGenex’s cash reserves dwindling, its fate now rests heavily on the results—expected later this year—of the first Phase 2 trial of apatorsen, in bladder cancer. The company may have to quickly finance or find a partner.
But despite the big setback, Cormack is steadfast that OncoGenex can pull through.
“It’s biotech and these things happens, and from our perspective, the good thing is, it’s not a single binary event for us,” he says. “You go ‘ok, obviously not what we wanted to see, it’s a surprise, but we do have nine other trials, and we believe in the concepts of what we’re doing with addressing treatment resistance. Let’s go get the answers and carry on.’”
