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FDA Nears Ruling On Use Of Avastin For Breast Cancer February, 2008





Genentech Inc. has been waging an uphill fight to add breast-cancer treatment to the approved uses of its blockbuster drug Avastin, whose sales growth is slowing.

The biotech company's push to market Avastin for breast cancer has split the cancer community, which remains divided despite an 11th-hour boost last week from news of a study involving the drug by Genentech's majority shareholder, Roche Holding AG.

Approved to treat colon cancer in 2004 and lung cancer in 2006, Avastin had sales last year of $2.3 billion. But analysts say the biotech company needs to add a breast-cancer niche to refuel the drug's growth. Avastin has been "a pipeline unto itself," says William Tanner, an analyst with Leerink Swann & Co. "If breast [cancer approval] doesn't happen, it's going to be tough" for the company to generate growth that satisfies investors.

Genentech's pursuit of so-called label expansion is a favorite strategy of biotech and big pharmaceutical makers seeking to turn a drug into a multiuse blockbuster. Securing Food and Drug Administration permission could add an extra $2 billion a year to Genentech's coffers.

The FDA is due to decide on Avastin by Saturday, but the outcome is far from assured. Members of an agency advisory committee voted 5-4 against approval in December. While the FDA isn't required to follow the panel's recommendations, it usually does. European regulatory authorities approved Avastin for breast cancer last March.

Adding to the uncertainty, biotech newsletters and blogs have reported in recent days that two members of the FDA advisory panel have tried to change their votes to affirmative, tipping the balance toward recommending approval. The FDA had no immediate comment. Despite speculation that such a shift would have a positive effect on the FDA's final decision, the December vote remains on the record. FDA officials, as a matter of policy, don't publicly discuss their intentions in advance of a ruling.

The study Genentech submitted to the FDA found that using Avastin in combination with Taxol, a breast-cancer drug made by Bristol-Myers Squibb Corp., delayed the growth of patients' tumors for 11.3 months - 5.5 months longer than Taxol alone. However, despite this, the women on Avastin in the study didn't live significantly longer than those on Taxol, and they experienced more bad side effects, such as high blood pressure, blood clots and bowel perforation. Six deaths were linked to Avastin's toxicity, and none to Taxol's.

A major issue for the FDA advisers was whether slowing cancer for an extra 5.5 months is a benefit that merits market approval. Maha Hussain, an oncologist at the University of Michigan and the chairwoman of the FDA's Oncology Drugs Advisory Committee, voted that such data don't clear the bar. But her fellow panel member, Duke University oncologist Gary Lyman, says a 5.5-month halt in tumor growth is the best response he has seen in patients with metastatic, or spreading, breast cancer. "That translates -- during whatever time they have left -- into better quality of life," he says.

Even patient advocates, who often support swift drug approval, are divided. "No data showed that Avastin improved survival and quality of life. It shouldn't be approved for breast cancer yet," says Barbara Brenner, executive director of Breast Cancer Action in San Francisco. "It should be approved," counters Robert Erwin, an activist in Davis, Calif., who lost his wife to breast cancer in 1994.

Meanwhile, after years of heady Genentech stock prices, shareholders are discovering that profitable drug-label extensions don't come easy. "You're not batting out blockbusters at every turn," says Mr. Tanner, the analyst. In 2007, revenue growth cooled to 26% from 40% in 2006. Investor zeal cooled too, and the stock is hovering near $73 a share, down from a 52-week high near $88 a year ago.

Breast cancer is often curable in its early stages through surgery, radiation and drugs. But once it has metastasized, it is considered treatable but not curable. An estimated 45,000 women die of metastatic breast cancer each year. Of those, Genentech estimates that 38,000 have tumors that might respond to Avastin. Some already use the drug, which their doctors can prescribe off label. The cost for an 11-month cycle is $84,700, which many insurers have been willing to cover.

Because Genentech agreed to cap annual charges for authorized treatments, FDA approval would limit Avastin's cost to $55,000 a year. But if the FDA turns Genentech down, insurers may stop covering its off-label use.

"It'll be a disaster," says Mr. Tanner, the analyst. Sales growth "could go flat or negative if people get yanked off the drug."

Susan Desmond-Hellmann, Genentech's president of product development, says Avastin is a test case for how much the FDA will weigh tumor suppression, as opposed to survival, in drug approvals.

Marketing Avastin to fight breast cancer is "important from a business perspective," Dr. Desmond-Hellmann says. But, she says, it also offers women more treatment options, her goal since her days treating cancer patients in Lexington, Ky., in the early 1990s. Few drugs were available then. Now there are more, but none are yet specifically approved as a first-line treatment for metastatic breast cancer.

Avastin is a so-called biologic drug that replicates the body's own weapons -- antibodies that block the growth of blood vessels that feed tumors. But just because Avastin mimics a natural function, that doesn't mean it is benign. "We're all catching up to the fact that just because they're what the body would make, antibodies are no less powerful," says Dr. Desmond-Hellmann. A biotech drug like Avastin causes different -- but not necessarily fewer -- side effects than a drug concocted from chemicals in a test tube.

Kay Yow, the head women's basketball coach at North Carolina State, experienced Avastin's pros and cons. It, plus a cocktail of other drugs, helped her return to courtside after being sidelined in November 2006 by Stage IV breast cancer that invaded her bones and liver. She endured fatigue, pain and cracked skin on her hands and feet, her doctor says.

But by January 2007, her tumor had retreated. The 65-year-old coach rallied to lead her team to the regional semifinals of the national-championship tournament, "an incredible run for us," she says. She said late last month that she's still coaching and has a lot more energy than she had last year.

In its bid for FDA approval, Genentech offered a single study, conducted by the independent National Institutes of Health-affiliated Eastern Cooperative Oncology Group. Unlike some studies in which treatments are masked to avoid bias -- the "gold standard" of research -- doctors and patients in this study knew which patients got Avastin.

Meanwhile, Roche, which co-markets Avastin, conducted a more rigorous trial due out in March. In a surprise early announcement this past week, Genentech disclosed that Roche's study confirmed that Avastin delays breast cancer's progression. Genentech's press release offered no data, and the company declined to elaborate pending scientific peer review. So while the news buoyed believers, it didn't convert skeptics.

Thus, analyst Joel Sendek of Lazard Capital Markets hailed Roche's study as supporting Genentech's bid. But Michael Abermann of Credit Suisse pointed to a lack of a survival benefit.

Indeed, the most divisive issue facing the FDA is which yardstick to use: survival or delayed cancer growth. Genentech notes that many breast-cancer studies now focus on slowing tumors, and it argues that the FDA recently approved two breast-cancer drugs -- GlaxoSmithKline PLC's Tykerb and Bristol's Ixempra -- using that yardstick.

The study cited by Genentech included 722 patients observed for three years. Nailing proof-of-survival benefits would require studying 2,000 to 3,000 patients for another three years, and that would unacceptably slow the pace of cancer-drug development, argues Dr. Desmond-Hellmann. "Does that 5.5 months outweigh toxicity? I think it does."

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