Johnson & Johnson (NYSE: JNJ) and Medivation (NASDAQ: MDVN) shook up the prostate cancer world the past couple years by introducing two important new FDA-approved treatments. Now Cambridge, MA-based Tokai Pharmaceuticals is looking to see if it can go a step further, by combining the best features of each of those drugs into a single pill.
Those two companies, along with Seattle-based Dendreon (NASDAQ: DNDN), consume most of the time and attention of those who follow what’s innovative for the treatment of prostate cancer. But privately held Tokai has been quietly sneaking up on the leaders. This year, Tokai is recruiting patients into a 170-patient clinical trial that should give it a sense of whether it has a drug that can compete with the bigger companies.
Tokai, which has raised $57 million since its founding in 2004, has gotten this far through investment from Apple Tree Partners and Novartis Venture Fund. While it toiled away for the last decade in R&D, the hurdles it has had to clear have gotten nothing but higher. Dendreon won FDA approval for its first-of-its-kind immune booster for prostate cancer in April 2010. J&J followed a year with FDA approval of its drug, an oral pill. Then last August, Medivation and its partner Astellas Pharma won FDA clearance for their new pill.
Each of those companies showed in its own company-sponsored clinical trials that it could help men live longer with prostate cancer, with much milder side effects than chemotherapy. Each drug represents an important step ahead in scientific understanding of prostate cancer biology. And each product should be a tough, well-entrenched competitor that Tokai—or any other new entrant—will have to tangle with in the future.
“The bar is really high now in prostate cancer,” says David Miller, president of Biotech Stock Research, which covers the prostate cancer field for investors. “When was the last time you saw a successful late-stage oncology drug that had a lower rate of serious adverse events in the drug arm of the study, compared with the placebo arm? That’s the kind of safety bar [Medivation’s enzalutamide] has set.”
Tokai CEO Martin Williams, not surprisingly, takes an optimistic view. The success of J&J’s abiraterone (Zytiga) and Medivation’s enzalutamide (Xtandi) has provided scientific validation for the path his company has been on for years. While each of those drugs has been an important advance, most cancer needs to be treated with combination therapy because of the propensity tumors have for developing resistance to any one drug.
“The concept for our drug is ‘combination therapy in one pill,’” Williams says. “When you go now to prostate cancer meetings, many of the [key opinion leaders] say the best way to treat prostate cancer is to add enzalutamide to abiraterone and prescribe them together. Then you’re hitting the cancer in multiple different ways. It’s the exact rationale for our drug.”
The concept for Tokai’s drug, galeterone, comes from research done by Angela Brodie and Vincent Njar at the University of Maryland School of Medicine. Brodie, a professor of pharmacology, is best known for her work developing aromatase inhibitors, which are now commonly used for the treatment of breast cancer.
Given that scientists know prostate cancer tumors use male sex hormones for fuel, the scientists sought to cut off the fuel source in three ways. One is by blocking an enzyme called Cyp17 lyase, which is involved in testosterone synthesis, and which J&J’s abiraterone works against. The Tokai drug, an oral steroid analogue, was also designed to block the androgen receptor, which enables cells to process testosterone, and which Medivation’s drug works against. The third way Tokai’s drug is supposed to work is through degrading the androgen receptor itself, so it can’t siphon up whatever trace amounts of testosterone might still be lurking in the blood.
Tokai isn’t the only company exploring possibilities of different drugs that seek to build on the work done by the J&J and Medivation drugs. Cambridge, MA-based Millennium/Takeda has one called orteronel in the third and final stage of clinical trials, which is made to bind selectively with a member of the CYP17 enzyme family. San Diego-based Aragon Pharmaceuticals is also in mid-stage clinical trials with another drug seeking to bind with the androgen receptor, like Medivation’s.
It’s hard to say yet what advantage Tokai’s drug may have, if any. Data from a first-stage clinical trial of 55 patients on a variety of doses of the treatment were presented last spring at the American Society of Clinical Oncology meeting. The drug was considered well-tolerated, although six of the 55 dropped out of the 12-week study because of toxicity, researchers said. Still, researchers were encouraged that about half (24 of 49 patients) saw some sign of improvement in their disease with at least a 30 percent drop in their prostate-specific antigen (PSA) scores.
That finding was enough to encourage Tokai to design the more rigorous, 170-patient study called Armor, which is currently recruiting patients. The study is enrolling patients whose prostate cancer has spread after the usual chemical-castration therapy, and those whose disease has worsened after getting J&J’s abiraterone. That trial is being designed to look at PSA scores, and tumor shrinkage rates, to provide a sense of how effective the drug is.
But before Tokai charged ahead, it had some work to do to sharpen up its competitive standing. The company’s original clinical trial was with a capsule, and Tokai went to work on reformulating it into a tablet in order to get more efficient distribution in tissues, Williams says. For that reason, the Armor study will have a short lead-in period so that Tokai can select the best dose of the tablet before it starts enrolling larger numbers of patients, he says.
The tablet should have at least two important advantages over J&J’s abiraterone, Williams says. The Tokai drug doesn’t need to be taken in combination with prednisone, a common immune suppressor that has significant side effects, and it doesn’t need to be taken on an empty stomach. The Tokai drug should also have an advantage over Medivation, Williams says. That’s because Medivation’s drug needs to find a binding pocket against the androgen receptor to work, and there’s a type of androgen receptor sometimes found in prostate cancer patients that doesn’t provide a binding pocket for the drug. Tokai believes its drug’s third way of working, which degrades the receptor itself, could be useful in combatting resistance.
The proof, like everything in biotech, will be in the patient data. In Tokai’s case, the final data from the Armor study should be available by June 2014. But that won’t be the definitive trial. J&J, Medivation, and Dendreon all showed in various types of trials that their drugs helped men live longer—the gold standard measurement of success in cancer drug development. Those kinds of studies take a long time, especially for patients with slow-moving malignancies like prostate cancer tends to be.
So Tokai clearly has a long road ahead, and it could run into some significant challenges at the FDA, which has set high expectations for prostate cancer, Miller says. For example, the agency will likely want to see new prostate cancer drugs in the late stages of treatment that can beat existing treatments in head-to-head studies, not just beat a placebo. Medivation’s drug has shown such a clean safety profile that it will be hard for anybody to beat it on the grounds of safety, Miller says.
The competition of the future, he says, could come down to pricing strategy. J&J’s drug is priced at about $5,400 a month, while Medivation’s is at about $7,500 a month. While it’s hard to imagine Tokai could double that price because of its three-way mechanism of action, it could gain traction by undercutting one of the rivals on price, or by showing superior effectiveness in a head-to-head study, Miller says. “Where it fits in will probably depend heavily on price,” Miller says.