Calistoga Rolls Out More Evidence For Blood Cancer Drug, Sizes Up Pivotal Trial

12/5/10Follow @xconomy

Calistoga Pharmaceuticals has been stirring up buzz at medical meetings for more than a year about how its experimental treatment is shrinking tumors for patients with certain blood cancers that resist other therapies. And today the Seattle-based company is showing still more evidence that strengthens the medical case for its drug, as the tumor shrinkage effect appears to be long-lasting, and the drug looks like it can be safely combined with other standard meds.

The latest data about Calistoga’s experimental drug, CAL-101, is being presented today at the American Society of Hematology meeting in Orlando, FL. The main study has been expanded over time to include 177 patients, and has been adjusted since it started in June 2008 to now focus primarily where it appears to be most effective: patients with chronic lymphocytic leukemia and slow-growing or “indolent” non-Hodgkin’s lymphoma. Even after patients saw their disease worsen following multiple rounds of treatment, the Calistoga drug kept their tumors from spreading for more than a year, researchers said. And an early look at a second study of the Calistoga therapy said it didn’t appear to add any extra side effects when combined with standard drugs like Cephalon’s bendamustine (Treanda) or Roche and Biogen Idec’s rituximab (Rituxan).

“As we’ve added more and more numbers of patients, you can see it’s not a statistical fluke,” says Carol Gallagher, Calistoga’s CEO. “The response rates we are seeing are real, and so is the duration of response.”

Calistoga, which raised its first sizable venture round in 2007, has been emerging for some time now as one of the top private biotech companies in Seattle. The company has attracted another $70 million in venture capital over the past 18 months to drive the development of this drug, which is seeking to attack cancer through a hot avenue known as the PI3 kinase pathway. Scientists are excited about this pathway because it is thought to control critical cell processes like proliferation, migration, and cell survival. When these normal functions get flipped into an overactive mode, it’s a hallmark of cancer cells growing out of control.

Carol Gallagher

Carol Gallagher

Pharma heavyweights like GlaxoSmithKline, Novartis, and Sanofi-Aventis are pursuing this strategy, yet Calistoga is seeking to differentiate itself by aiming for more specific types of PI3 kinase, particularly one known as the delta isoform. By being more specific, it hopes to be more potent against particular blood cancers that overexpress the delta isoform, and minimize side effects.

Calistoga’s first study enrolled a wide variety of patients with blood cancers. More than half of them had relapsed or didn’t respond any more to existing therapies. Without receiving any other combination treatments, people in the study took CAL-101, a twice-daily oral pill, for a 28-day course of therapy, for as many as 12 cycles. Researchers enrolled patients with five different kinds of malignancies in this study, looking for signs in which CAL-101 showed the most promise.

The strongest evidence over time appears to be for two forms of blood cancers—chronic lymphocytic leukemia, and slow-growing “indolent” non-Hodgkin’s lymphoma.

First, here’s what is known about chronic lymphocytic leukemia. There were 54 patients with that disease who enrolled in the Calistoga study who were very sick—having received a median of five prior rounds of therapy and yet still having bulky tumors. Even so, all 51 of the evaluable patients had some degree of tumor shrinkage, researchers said. About 80 percent of patients saw their tumors shrink by half or more. And these partial remissions do appear to last, as about 60 percent of patients still had no evidence their tumors had started to grow again after a year of follow-up, Gallagher says. Details are being presented today at the hematology meeting by Richard Furman of Weill Cornell Medical College in New York.

A similar story played out in patients with slow-growing or “indolent” non-Hodgkin’s lymphoma. About 63 percent of patients had their tumors shrink by at least half, based on results of 30 people who had received a median of four prior rounds of treatment. Again, a majority of patients saw those partial remissions endure for more than a year, and researchers are continuing to follow up patients to see how long they last. Some patients in this group did see an increase in liver enzymes early in their course of therapy—which can be a red flag of liver damage—although researchers said they were able to reverse the build up of liver enzymes by taking patients off the drug, and putting them back on therapy later at lower doses.

Based on this experience, Calistoga has zeroed in on an ideal dose of 150 milligrams taken twice a day, after experimenting as high as 350 milligrams earlier in the study and seeing no extra benefit.

Since this study wasn’t designed to randomly assign patients to the Calistoga therapy and something else, it’s impossible to say for sure how much of an improvement this treatment represents over the standard of care. While it’s always a bit dubious to compare one clinical trial to another because each uses different criteria, Calistoga’s main benchmark will probably be GlaxoSmithKline’s ofatumumab (Arzerra). That drug has shown that it can shrink tumors in about 42 percent of relapse patients with chronic lymphocytic leukemia, with a median duration of response of 6.5 months, according to the drug’s prescribing information.

The combination study is still in its very early days, but like the other Calistoga study, it is showing encouraging results right off the bat. The first 20 out of as many as 84 patients have been enrolled to get the Calistoga pill in combination with rituximab (Rituxan) or bendamustine (Treanda). The patients had relapsed or treatment-resistant forms of chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma.

All six of the first patients with indolent non-Hodgkin’s lymphoma who had gotten two prior rounds of therapy saw their tumors shrink at least by half (one had a complete eradication of tumors) when they got the Calistoga drug in combination with bendamustine. Just like in the other trial, some patients saw increases in liver enzymes, which came down after therapy was halted and re-initiated at a lower dose. Four of the first five patients with indolent non-Hodgkin’s lymphoma who got the new Calistoga drug in combination with rituximab had their tumors shrink by half, researchers said.

“The preliminary results from this trial suggest that CAL-101 can be safely combined with current standard-of-care therapies and may provide more improved and durable responses, without added toxicity, for patients with relapsed and refractory indolent NHL or CLL,” said Ian Flinn, a researcher at Sarah Cannon Cancer Center in Nashville, TN, in a statement from Calistoga.

Encouraging as it all seems, every shred of the evidence has to be filed under the header of exploratory or hypothesis generating. It’s not strong enough for the company to bundle up and ship off to the FDA for review. That’s what comes next.

Calistoga is in the midst of developing the protocol for a pivotal study that it hopes will form the basis for FDA approval of CAL-101, Gallagher says. The trial will put together a network of 35 to 40 sites in the U.S. and Europe, and will enroll a total of 100 patients with indolent non-Hodgkin’s lymphoma, she says. The plan is to start enrolling patients later this month, or early in 2011. By the end of 2012, Calistoga hopes to have generated data to show that it can reach its primary goal of tumor shrinkage and receive FDA approval by the end of 2013, Gallagher says.

While that study is going on, Calistoga is working up the protocol for a similar pivotal study in chronic lymphocytic leukemia patients. Calistoga has met with the FDA and sought its advice on proper study design, and it has examined the regulatory pathway that competitors have followed before. The company hasn’t sought a written agreement from the FDA on the study design—what’s known as a Special Protocol Assessment—because that could take six months or more, and the company is racing to stay ahead of competitors, Gallagher says.

“We don’t want to slow down and let them catch up,” Gallagher says. “We think we’re about three to four years ahead.”

That’s the scuttlebutt she’s been hearing at the ASH meeting, referring to a number of Big Pharma companies developing PI3 kinase inhibitors that are specifically tailored to the delta isoform, like Calistoga’s lead product. All of the Big Pharma contenders in that class are still thought to be in animal studies, Gallagher says. Other PI3 kinase inhibitors in clinical trials tend to be more broad-reaching against a number of isoforms, and aren’t really direct competitors, she says.

Besides the data presentations, lots of other stuff, of course, happens behind the scenes at medical meetings like ASH. Gallagher says she was happy to see during one of the medical education sessions that thought leaders spoke openly about CAL-101 as one of the important future agents to watch. “We’re seeing broader awareness, and that’s good,” she says.

Calistoga has also been talking with investigators who are showing interest in participating in its next clinical trials, in order to get access to the drug for their patients, Gallagher says. And Big Pharma’s dealmakers are there, still holding meetings with Calistoga. Gallagher wouldn’t say if she plans to bring on a partner to help take CAL-101 all the way through the FDA approval process. With the recent hiring of new R&D head Langdon Miller and finance chief Andrew Guggenhime, Calistoga has the people in-house to go it alone, she says.

“We haven’t decided yet if we’ll go further along with our assets being wholly owned, or whether we’ll get help,” Gallagher says. “We are well prepared to go our own way if that’s what we decide to do. We have the team now in place.”

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