Calistoga Pharmaceuticals Builds Stronger Case for Blood Cancer Drug

Calistoga Pharmaceuticals has come a long way in one year.

The Seattle-based biotech company made its first ripple on the national scene last year at the American Society of Clinical Oncology (ASCO), when it showed its novel drug for blood cancers caused tumor shrinkage in half of the first dozen patients tested. This year at the same confab, researchers led by Richard Furman of Weill Cornell Medical College in New York, had a much meatier set of results to show off. The early hint of effectiveness—and it was really just a hint last year—has much more solid confirmation now that 106 patients have been studied, and some longer-term follow up data is trickling in.

About 57 percent of patients with a slow-growing form of non-Hodgkin’s lymphoma had their tumors shrink by half or more, two-thirds with mantle cell lymphoma did that well, while 30 percent of patients with chronic lymphocytic leukemia had that response, researchers said yesterday at ASCO. Still, like any drug, this one has side effects. Researchers saw increasing rates of certain liver enzymes in the blood of patients who took high doses of the drug, which can be a warning sign of liver damage, something the FDA often monitors carefully. Calistoga says the side effect didn’t cause any observable liver symptoms in patients, and the enzyme levels returned to normal after doctors reduced the doses. (For a look at the detailed presentation slides, click here.)

“We have a clear signal now in terms of efficacy,” says Calistoga CEO Carol Gallagher.

Calistoga bears watching as one of the most promising privately held biotech companies in the Northwest. It raised $30 million in venture capital just a few weeks before it released the first glimpse of data at ASCO last year. The company is pursuing one of the prime targets in cancer biology today—the PI3 kinase pathway. Researchers 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 spiraling out of control, or an immune system gone wild so that it attacks healthy tissue.

Carol Gallagher

Carol Gallagher

Calistoga was founded in 2006 with some intellectual property from Icos to develop drugs against the PI3K enzyme. There are plenty of competitors in this hot field—including GlaxoSmithKline, Novartis, Roche, Exelixis, Oncothyreon, and Intellikine. Many of the rivals make drugs that hit a broad cross-section of PI3K enzymes, and Calistoga claims to be different because its lead candidate is made to hit a specific subtype of PI3 kinase, known as the delta isoform. The hope is that Calistoga’s lead drug, CAL-101, may have a better profile for blood cancers that express the delta isoform, and that it may have milder side effects, a useful feature if Calistoga wants to treat chronic conditions like inflammatory diseases.

The last time Calistoga talked publicly about CAL-101 was back in December at the American Society of Hematology meeting, when it had results from 57 patients. The easiest way to look at this updated data from 106 patients is through a chart, so that’s what I’m providing below. But a little background is required first. This 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 cycle of therapy, for as many as 12 cycles. Here is how patients responded in each group.

Slow-growing “indolent” non-Hodgkin’s lymphoma13/2357 percent
Mantle cell lymphoma8/1267 percent
Chronic lymphocytic leukemia10/3330 percent
Acute myeloid leukemia0/110 percent
Multiple myeloma0/110 percent

Response rates like that beg an obvious question: How long did the effect last? Cancer is a notoriously tough disease to treat, and tumors that get shrunk by some drugs often show an amazing resilience to bounce back and kill people just as if they received no drug at all. Calistoga is still collecting data on the “durability” of effect from its drug, and doesn’t have enough information yet to say how long its drug can keep tumors in check, much less whether it can help people live longer. So far, the company can say that 12 patients have shown they respond to the drug for more than six months.

Importantly, Calistoga has learned from this small study where its drug doesn’t seem to help. The company enrolled 31 patients with multiple myeloma, acute myeloid leukemia, and diffuse large B-cell lymphoma, and saw zero instances of 50 percent tumor shrinkage or greater.

All of this has provided a rich set of data for Calistoga to craft a strategy for the next round of clinical trials, Gallagher says. This trial will probably grow to a total of 150 patients, as Calistoga experiments with getting the right dose, and enrolling a few more people with slow-growing non-Hodgkin’s lymphoma.

Once that database is complete, Calistoga plans to sit down with the FDA to talk about the best design for a pivotal clinical trial that could pave the way for the company to start selling its drug in the U.S. Such a study will be bigger, and will likely enroll patients with indolent (slow-growing) lymphoma, and chronic lymphocytic leukemia, Gallagher says. It will likely not be required to randomly assign patients to directly compare the new drug against a standard treatment, and it won’t need to show the new drug helps people live longer, Gallagher says. Calistoga’s main benchmark will probably be GlaxoSmithKline’s ofatumumab (Arzerra), which has shown in relapsed patients that it can shrink tumors in about 42 percent of patients, with a median duration of response of 6.5 months, according to the drug’s prescribing information.

When used as a single agent, the Calistoga drug has shown in this small study that it can cause tumor shrinkage rates in the 50 to 60 percent ballpark, which gives the company confidence that it can provide an advance over the existing standard of care, Gallagher says. But one trial obviously isn’t enough to prove that. If the company can get the FDA to agree on its pivotal trial plan, it should start that study in the second half of 2010, Gallagher says. Before the end of June 2011, it hopes to start a more rigorous study that randomly assigns patients to the Calistoga drug or another treatment to strengthen the body of evidence it will need to persuade physicians to prescribe the product. Calistoga is also looking to raise the bar on tumor shrinkage rates by combining its treatment with a couple of proven therapies in the world of blood cancers—Roche and Biogen Idec’s rituximab (Rituxan) and Cephalon’s bendamustine (Treanda). There are also possibilities of combining the Calistoga drug with other drugs designed to block other enzymes like mTOR and Akt, Gallagher says. She’s been running through a full slate of meetings at this year’s ASCO conference with doctors and prospective pharmaceutical industry partners, to talk about all the options on the table.

“It will be interesting to see all the data here at ASCO,” Gallagher said on Friday, on the eve of the meeting. “I think this is one of the most active single-agent studies being presented. We’ve seen quite a robust response rate.

Of course, Calistoga’s not the only company touting a drug at ASCO with an encouraging response rate in a preliminary study. It will mean a lot more if Calistoga, and its competitors, can advance through the final stage of development and get their new drugs on the market. “The good news for patients is we are starting to get targeted therapies that are effective and less toxic than traditional chemotherapies,” Gallagher says.

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