Editor

The word "setback" is seldom used when talking about the monster-cap steamroller Genentech Inc., but the company did suffer at least a glitch last week in its further development of the colorectal cancer drug Avastin.

Approved by the FDA in early 2004 for metastatic disease in the first-line setting when combined with 5-FU-based chemotherapy (and cleared in Europe about a year later), Avastin (bevacizumab) is being tested in a Phase III study by Genentech’s partner F. Hoffmann-La Roche Ltd., to evaluate whether adding the drug to chemo as an adjuvant following surgery can reduce the chance of recurrence in patients with Stage II and III disease.

Since the trial began recruiting in December 2004, almost two-thirds of the target number of 3,450 patients has been enrolled, and in January alone more than 250 patients were signed up.

But the work is held up for now.

Last week, Genentech said the study is stalled while the data safety monitoring board reviews safety data - the result of "adverse events" observed at a higher rate in the Xelox plus Avastin arm of the study, compared to the other two arms, which are giving the FOLFOX regimen and FOLFOX plus Avastin. Specifically, in the Xelox/Avastin arm, two cardiac deaths and three of unknown cause were recorded, the company said, and some occurred in younger patients.

Xelox consists of capecitabine and oxaliplatin. FOLFOX is oxaliplatin, 5-FU and leucovorin together. Four deaths were reported in patients getting only FOLFOX, and three in the FOLFOX plus Avastin group.

Wall Street failed to panic at the news - Genentech’s stock was nicked by only a few percentage points - and Avastin’s prospects in other indications continue to look viable overall, even if analysts fretted over the drug’s performance in fourth-quarter earnings.

Sales of the anti-VEGF therapy totaled $359.1 million for the quarter, an 89 percent increase over fourth-quarter 2004 sales of $190.5 million and a 10 percent increase over third-quarter 2005 sales of $325.5 million, but the amount wasn’t what some had hoped for.

Christopher Raymond, analyst with Robert Baird & Co. in Chicago, said a physician survey indicated Avastin appeared to have "hit a wall." First Albany and Merrill Lynch & Co. both downgraded the company’s stock from "buy" to "neutral" after the earnings were disclosed last month, and Rodman & Renshaw dropped the stock to "market perform" from its previous "market outperform" rating.

Genentech aims to make Avastin the treatment of choice for colorectal cancer at all stages - and more. The company, which in December submitted the supplemental biologics license application for the drug against second-line colorectal cancer, is investigating it in a range of clinical trials in more than 20 cancer types, including adjuvant and metastatic colorectal, renal cell, breast, pancreatic, non-small-cell lung, prostate and ovarian. It also is the subject of earlier-stage trials in a variety of solid_tumor cancers and hematologic malignancies.

The Avastin announcement put on the back burner Genentech’s better news: approval of Rituxan (rituximab), its therapy for low-grade non-Hodgkin’s lymphoma, in diffuse large B-cell lymphoma. Rituxan sold $484.4 million for the three-month period ending Dec. 31, and Genentech has bigger plans for it, as evidenced by a push - well ahead of the second FDA clearance - to get the word out to the public about selectively targeting certain types of abnormal B cells.

The approach could be an important new strategy against a range of diseases beyond lymphoma, including rheumatoid arthritis, lupus and multiple sclerosis, and action on the supplemental BLA for Rituxan against RA is pending at the FDA.

"We’re expecting to hear [from the agency] by the end of this month," said Sunil Agarwal, medical director of RA research at Genentech.

"For the past 20 or 30 years, a lot of work has been done to define what drives RA," he said, and during about the past two decades, "there have been a lot of people saying RA is a T-cell mediated disorder," a belief Agarwal called "much too simplistic."

Winning approval for Rituxan against NHL gave Genentech "a tool to evaluate the hypothesis" regarding B cells, he added.

"We’ve now completed three trials, including the Phase III pivotal trial called REFLEX showing Rituxan with methotrexate was highly effective," Agarwal said, which "led to more and more enthusiasm and support" - and is likely to lead to another approval shortly.

Kip Benyunes, medical director in oncology research, said a filing is likely later this year for use of Rituxan as an extended treatment for low-grade indolent NHL patients.

"What we learned about targeted therapy for B-cell malignancies now is being studied in non-malignant disorders," he said. "I think Rituxan is our first example of a drug that’s gone way beyond what we thought."

He compared Rituxan not only to Avastin but Tarceva (erlotinib), which sold $83.9 million in the fourth quarter, and for the full year totaled $274.9 million. Tarceva gained approval in November 2004 to treat patients with locally advanced or metastatic non-small-cell lung cancer who have failed at least one prior chemotherapy. In November 2005, Genentech and partner OSI Pharmaceuticals Inc. chalked up regulatory clearance in another indication - Tarceva combined with gemcitabine for advanced pancreatic cancer in treatment-na ve patients.

"In all of those cases, it was the science of the tumor, the target or both that caused us to pursue studies" leading to approvals, Benyunes said, noting that the science behind Avastin, involving angiogenesis, also led to the development of Lucentis (ranibizumab). In December, Genentech submitted, as promised, the BLA for Lucentis against neovascular wet age-related macular degeneration.

Also last week, the company submitted an sBLA to use Herceptin (trastuzumab) in early stage, HER2-positive breast cancer, and asked for fast-track status. The drug was cleared in the fall of 1998 for use in women with metastatic HER2-positive disease.

"Follow the science" has been the motto of Genentech since the start, Agarwal said.

"From a clinical perspective in general, it’s always good when you have a therapy not to think of it as just for that one disease," he said, returning to the Rituxan example as observers await the next FDA decision.

"To say that Rituxan is an oncology drug is not to follow the science," he said.

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