Washington Editor

The much-anticipated arrival of Sutent (sunitinib) in the oncology space occurred last week - and did so with a bang: It received FDA approval for two indications at once, an agency first for a cancer product.

The drug is being brought to market by Pfizer Inc., which also received another long-waited clearance to sell the inhaled insulin product Exubera.

Sutent, a multi-tyrosine kinase inhibitor, was approved for gastrointestinal stromal tumors and advanced kidney cancer, and its clearance comes just a month after a similar drug was granted FDA approval - Onyx Pharmaceuticals Inc.'s Nexavar. Pfizer obtained its rights through its Pharmacia Corp. acquisition almost four years ago. Sutent, which received a priority review and was cleared in less than six months, works through multiple targets and is aimed at halting tumor cell proliferation and angiogenesis.

"That's the direction where Pfizer is heading as we move into the future," explained Charles Baum, the global clinical leader for the New York company's oncology group, explaining there is going to be "less of an emphasis of the older cytotoxic mechanisms that are toxic to all dividing cells and more specific for the tumor cells, as much as possible."

Sutent's approval is Pfizer's first that stems from its buyout of Pharmacia, a deal that included several already-approved products. Baum told BioWorld Today the double approval is "a confirmation of the fact that we're targeting different mechanisms."

Richard Padzur, the director of the FDA's Office of Oncology Drug Products, told BioWorld Today the dual blessing was "more administrative," since Pfizer submitted its application for two indications simultaneously. However, he added that the filing's proof of activity in two diseases "confirmed" that the drug was efficacious and safe in both cancers.

The drug received accelerated approval for kidney cancer based on its ability to reduce tumor size, which stems from its inhibition of the angiogenesis targets VEGF and PDGF. In a single-arm study, an overall response rate ranging from 26 percent to 37 percent was found in metastatic kidney cancer patients whose tumors had progressed following cytokine-based therapy.

Those older treatments include interferon and interleukin-2, neither of which are delivered orally and both of which have harsher side effects than Sutent. Also, patient response rates on tumor size are not as favorable, and Padzur classified both as less-than-optimal, "both from a toxicity and from an efficacy perspective."

In advanced kidney cancer, Sutent enters the same market as the recently approved Nexavar (sorafenib, from Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp.). Its clearance a month ago was the first new therapy to receive FDA clearance in that setting in a decade. (See BioWorld Today, Dec. 21, 2005.)

While both Sutent and Nexavar exhibit anti-proliferative and anti-angiogenic properties, they inhibit different targets and Baum said Sutent generates better tumor-shrinkage rates.

Padzur, who made it clear that the FDA's role is not to hype one over another, said both drugs represent an "advent" for patients who had limited options. The drugs both "truly meet an unmet medical need," he added, calling them "major advances."

Both have broad labels, despite being studied in refractory patients, which Padzur said was "deliberately done" because the cytokine-based therapies exhibit poor efficacy and toxicity profiles. There have been no head-to-head studies of the two, but because they were approved on different endpoints, physicians might choose one over the other based on a need to reduce tumor size (Sutent) or stabilize progression (Nexavar).

"I think it's important that the approval of these drugs does not represent the end of their development," Padzur added. "I look for both of these drugs, Nexavar and Sutent, as well as other drugs that we have approved recently, to be really the first step in their development. I expect to see more sNDAs coming in on them."

Sutent's approval for the rare stomach cancer is indicated for patients whose disease has progressed because of resistance to first-line treatment, Gleevec (imatinib, from Novartis AG), or for the more rare subset of patients unresponsive to Gleevec from the start.

Gleevec resistance develops when the KIT receptor mutates, most of the time, a change that occurs within one and a half years to two years after treatment begins.

Enter Sutent, a once-daily pill that works against mutated KIT. The FDA based its decision on interim data from a randomized study showing that Sutent delayed patients' median time-to-tumor progression to 27 weeks, compared to six weeks for untreated patients.

"It's pretty strong evidence that in addition to the clinical responses, you can look at the mutations in those tumors and see that they have changed, and that is the target for Sutent," Baum said.

Continuing studies are evaluating whether Sutent resistance is on the horizon, and if so, the reasons for it. Uncovering such data "will help advance the field further and understand how these tumors change over time," Baum said, adding that proposed investigator-sponsored studies will examine Sutent's use as a first-line or combination therapy with Gleevec instead of the now-approved complementary setting.

According to the American Cancer Society, about 32,000 new cases of advanced kidney cancer and 5,000 cases of gastrointestinal stromal tumors are diagnosed each year, although Pfizer declined to make any sales projections. Sutent is under review in Europe - the filing was submitted last fall - and the company plans to market it worldwide following regulatory clearances abroad.

More than 1,700 patients already receive Sutent through an expanded access program, and U.S. distribution of the pill is expected to begin later this week.

Treatment cycles last for six weeks, with patients taking Sutent for four weeks followed by a break of a fortnight before cycling back onto treatment. Its side effects, which Baum said "are generally well tolerated," primarily include fatigue and gastrointestinal symptoms such as nausea and vomiting.

The drug's roots go back to Sugen Inc., which Pharmacia bought for $650 million about seven years ago. Pfizer then gobbled up Pharmacia in 2002 for almost 10 times that amount, $60 billion. (See BioWorld Today, June 16, 1999, and July 16, 2002.)

Further studies of Sutent will continue through cooperative arrangements between Pfizer, the National Cancer Institute, patient groups and independent investigators. Among them are Phase II trials of Sutent as monotherapy in breast cancer and neuro-endocrine tumors, as well as Phase I and II trials in colorectal, prostate and non-small-cell lung cancers.

Other targeted cancer therapies in development at Pfizer include additional angiogenesis inhibitors, as well as products that block other intercellular pathways for tumor genesis.

The large pharmaceutical firm's biotech-based drug portfolio got another boost late last week when Exubera received FDA and European approval.

Developed in collaboration with Nektar Therapeutics Inc., it was cleared separately for treating adults with Type I and Type II diabetes and called a "first-of-its-kind medical breakthrough." The FDA's decision had been delayed following a positive panel hearing held late last summer. (See BioWorld Today, Sept. 12, 2005.)

The product is a rapid-acting, dry powder human insulin that is inhaled into the lungs prior to eating using a handheld, four-ounce inhaler. In its chamber, it produces a cloud of insulin powder designed to pass rapidly into the bloodstream.

San Carlos, Calif.-based Nektar is due a royalty on sales per terms of its agreement, and is responsible for all the inhaler devices that deliver Exubera and half the powder processing.

On Friday, Pfizer's shares (NYSE:PFE) gained 94 cents to close at $25.99. Nektar's stock (NASDAQ:NKTR) climbed 13 cents to close at $20.75.

Shares in Onyx (NASDAQ:ONXX) were off 20 cents Friday to $27.50. It was traded flatly but heavily Thursday, at a volume nearly four times its average, after the Sutent news hit the market.

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