With the dropping of the Avastin (bevacizumab) shoe last week - Genentech Inc. disclosed Phase III data showing the breast cancer drug missed its primary efficacy endpoint - came a renewed focus not only on vascular endothelial growth factor treatments but also on the disease itself.

Genentech's news, characterized as "worse than expected" by analyst Martin Auster with SunTrust Robinson Humphrey, may have put a dent in some investors' faith in the VEGF receptor approach to anti-angiogenesis in cancer. The mechanism "isn't very well understood," Auster noted.

Chrystyna Bedrij, chief investment officer with Griffin Securities, said she wasn't surprised.

"But they're primarily geared toward colorectal [cancer], and there are about 20 other drugs targeting the same growth factor" and being developed by other companies, she added.

Earlier this year, the Phase II failure of Angiozyme in metastatic breast cancer fueled an ongoing debate about VEGF. The drug, from Ribozyme Pharmaceuticals Inc., is also being tested in a Phase II colorectal cancer trial. Colorectal cancer is the lead indication for Genentech's drug, and the company awaits data, due in mid-2003, from a Phase III study in 900 patients. (See BioWorld Financial Watch, May 13, 2002.)

Bedrij said VEGF won't be taken seriously by investors "until someone makes it in Phase III, and then the question's going to be, Who else is playing there?'"

The bigger picture is the disease itself, which is expected to kill about 39,500 women this year, and the American Cancer Society estimates 203,500 women will be newly diagnosed. Except for skin cancer, breast cancer is the most common cancer among women in the U.S., and such sad facts represent a strong opportunity for any firm able to come up with a better treatment, VEGF or otherwise.

Surgery is the most common approach for cases diagnosed early, followed by adjuvant therapy such as radiation, chemotherapy and hormone therapy.

Bedrij, in a recent research report, surveyed the crowded breast cancer-treatment field, and offered to BioWorld Financial Watch her ideas about the future of the sector.

Bristol-Myers Squibb Inc. has 13.8 percent of the chemo market - estimated at upward of $8 billion last year - with its Taxol (paclitaxel), approved for metastasized breast cancer, as well as other indications, she noted.

But sales dipped in 2001, partly because of competition from Taxene, IVAX Corp.'s generic version of the drug, and partly because of market share taken by Aventis AG's Taxotere (docetaxel).

"Taxol has been one of the most successful, obviously, and people don't switch too often," Bedrij said, calling IVAX and Aventis "neck and neck" for shares of the Taxol pie.

Aventis made headlines in April with a potential $480 million oncology deal focused on Genta Inc.'s Genasense, the first antisense oncology product, which is in Phase III trials for melanoma, multiple myeloma, chronic lymphocytic leukemia, and non-small-cell lung cancer, as well as Phase II studies for leukemia, lymphoma and prostate and small-cell lung cancers. Taxol also took a hit from Eli Lilly and Co.'s chemo treatment, Gemzar (gemcitabine).

Impossible to overlook is Genentech's Herceptin (trastuzumab), launched in 1998 and useful in about a third of breast cancers that overexpress the human epidermal growth factor receptor 2. The monoclonal antibody is paired with paclitaxel as a first-line therapy, and used alone as second-line and third-line treatments.

The king player in the breast cancer field is AstraZeneca plc, which has four strong products, most notably Nolvadex (tamoxifen), which was launched in 1973 and is the oldest and most successful breast cancer drug for post-menopausal women, with $630 million in sales last year.

"Tamoxifen rules the roost," Bedrij said. But Nolvadex, like AstraZeneca's others, is a selective estrogen receptor modulator, which block estrogen's growth effect, and works for only about five years.

AstraZeneca also has Faslodex (fulvestrant), approved this spring for hormone receptor-positive breast cancer in post-menopausal patients who have gotten worse despite anti-estrogen treatments such as tamoxifen. Faslodex attacks the estrogen receptors inside the cancer cells.

Zoladex (goserelin) is AstraZeneca's third hormonal treatment. That one is a lutein hormone-releasing drug, aimed mainly at pre-menopausal and peri-menopausal patients. With a market share of 12.7 percent in the hormonal space, Zoladex dipped somewhat after losing patent protection in 1999. Still, the drug reaped revenues of $728 million in 2001.

Although the tested indication was non-small-cell lung cancer rather than breast, AstraZeneca ran into trouble that had an industry-wide impact in August, when the firm's Iressa - an endothelial growth factor receptor inhibitor - yielded discouraging trial results. The company found that adding Iressa to standards of care (gemcitabine/cisplatin and paclitaxel/carboplatin) did not provide a survival advantage, but might work as monotherapy and with chemotherapy when given sequentially, but not at the same time.

A growing segment of the hormonal-treatment market includes drugs that block aromatase, which boosts the production of estrogen in the first place. AstraZeneca has Arimidex (anastrazole) in this class, which competes with Novartis AG's Femara (letrozole). The drugs sold $191 million and $125 million last year, respectively.

Arimidex entered the market in 1995 and is deployed as a second-line treatment for breast cancer that has failed tamoxifen. Earlier this month, it won approval from the FDA for adjuvant treatment of hormone-receptor positive early breast cancer in post-menopausal women - the first hormonal drug other than tamoxifen approved for that indication.

Bedrij said the race between Arimidex and Femara "changes weekly. I thought Femara would take sales away, but now maybe not, because of the new indication."

Arimidex was approved in 1996 as the first non-steroidal aromatase inhibitor for treatment of hormone-receptor-positive advanced breast cancer in postmenopausal women. In 2000, it gained the FDA nod for first-line treatment of hormone-receptor positive advanced breast cancer in postmenopausal women.

"Right now, everyone's super hot on aromatase inhibitors, so you're going to have to beat them," Bedrij said.

Novartis came into the market with Femara, the second-leading aromatase inhibitor, in 1995 as a second-line therapy after tamoxifen, and this year the drug was approved as a first-line therapy for post-menopausal women with advanced disease.

Comparing Femara with Arimidex in a head-to-head study, Novartis has showed advanced breast cancer patients are more responsive with the former than the latter, and Bedrij expects Femara to keep advancing on Arimidex and, to some extent, tamoxifen.

Pharmacia Corp. (whose acquisition by Pfizer Inc. is expected to complete this year) has entered the fray with its aromatase inhibitor Aromasin, launched in 2000 for second-line treatment of advanced breast cancer and now approved in 49 countries. The company is pursuing a label for first-line use.

In such a marketing melee, what looks especially hot? Bedrij was quick to answer: Bioenvision Inc.'s Modrenal (trilostane), also known as Modrastane, already approved in the United Kingdom for advanced post-menopausal breast cancer. She has "no money, no interest, no nothing" in Bioenvision, she added.

A recent publication in Cancer Cell Biology showed Modrenal works on estrogen receptors, particularly on the second, or beta, receptor. Most treatments have focused on the first, or alpha, receptor, Bedrij noted.

The currently available anti-estrogens drugs, such as tamoxifen, are competitive inhibitors that bind to the ligand-binding sites of estrogen receptors. Modrenal, instead, works at a different site. It inhibits the receptors from binding to estrogen-response elements in the cell and stops estrogen-stimulated gene transcription.

Writes Bedrij in her report: "Clinical trials show more effective than currently available hormonal treatments in specific breast cancer types, such as those who have become refractory to therapy with tamoxifen." She cited "clinical crossover studies establishing no cross-resistance between Modrenal and aromatase inhibitors, coupled with more recent data suggesting Modrenal acts specifically as an agonist of estrogen receptor beta," as good evidence of the drug's promise.

Others must agree, she added, pointing to the May placement in which Bioenvision raised $17.75 million, which she finds "incredible for a small company in this marketplace."

Bedrij said "the [estrogen] receptor area is going to be hot," adding that AstraZeneca and Merck KGaA are "trying to find these selective receptors," too.

"I think Bioenvision really has a shot at it," Bedrij said. Having won approval in the UK, "they're going to go back and do a Phase IV for this receptor [beta]," and the company intends to seek approval in the U.S. as salvage therapy for hormone-sensitive breast cancer.

With so many drugs available, the eventual treatment approach may be similar to that used in AIDS, she believes.

"I think cocktails might be an answer in order to try to manage it," she said, adding that "it's the normal state of affairs" to use in a sequential way whatever might work, until it quits working. While effectiveness in an individual patient is not disputable, opinions vary on the marketed drugs as more tests are done - and the pendulum may swing.

"Just now you're having papers coming out in scientific journals [showing that] tamoxifen beat the aromatase inhibitors," she said. "There's a lot of action."

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