National Editor

CHICAGO - A lively, data-chocked meeting of the American Society of Clinical Oncology here left analysts and attendees to sort the findings offered and determine their value in the weeks ahead.

Clear standouts were South San Francisco-based Genentech Inc.'s Avastin (bevacizumab) and Tarceva (erlotinib), along with Erbitux (cetuximab), the drug being developed by scandal-ridden ImClone Systems Inc., of New York, and its Darmstadt, Germany-based partner, Merck KGgA.

Jason Zhang, analyst with Independent Research Group, a wholly owned subsidiary of (and formerly with Stephens Inc.), said he found quite a few other things to grab his interest.

"I was impressed by the Avastin data, but the Erbitux data was about [in line with] my expectations," he said. Avastin, a humanized antibody designed to inhibit tumor growth by binding to and inhibiting vascular endothelial growth factor (known to play a role in angiogenesis), proved positive in a Phase III study with previously untreated metastatic colorectal cancer patients. So did Erbitux, in the much-anticipated data from the Merck trial. (See BioWorld Today, June 3, 2003.)

Zhang said he was "still not 100 percent convinced [Erbitux] will be approved in the U.S." There's been speculation that ImClone and partner Bristol-Myers Squibb Co., also of New York, might use the Merck data for an FDA filing.

"All the doctors I've talked with seem somewhat reserved" about Erbitux's immediate prospects in the U.S. at this point, Zhang told BioWorld Today.

Tarceva, which like Erbitux targets the epidermal growth factor receptor, is being developed in Phase III trials against non-small-cell lung cancer in a three-way deal involving Genentech, OSI Pharmaceuticals Inc., of Melville, N.Y., and Roche Holdings Inc., of Basel, Switzerland.

"The only [Tarceva] data I think was new was in glioblastoma multiforme," or brain cancer, Zhang said. "It's very intriguing, but it's only Phase I."

In 49 evaluable patients in the dose-escalation study, researchers found eight partial responses (16 percent), three minor responses (6 percent) and 11 with stable disease (22 percent). Rash and occasional diarrhea were reported as side effects.

OSI and Genentech said they will take Tarceva into Phase II.

"Patients have no alternatives," Zhang said, noting that exploring other indications for Tarceva is a strategy to keep the drug alive if "for some reason" the lung cancer data don't pan out.

Zhang also found appealing palonosetron, the drug for chemotherapy-related nausea and vomiting from MGI Pharma Inc., of Minneapolis, which disclosed positive Phase III data during ASCO.

"Usually you don't hear much about this because it's not a cancer drug," Zhang said. "I was amazed to find out that doctors tend to underestimate the problem of nausea and vomiting."

In one survey, only 10 percent of doctors called chemo-induced nausea and vomiting an unmet medical need, but patients rated it much higher.

"It's not recognized by physicians," Zhang said.

Amgen Inc., of Thousand Oaks, Calif., offered favorable Phase III data with another drug for chemo side effects: palifermin, a recombinant human keratinocyte growth factor, to treat mucositis.

A treatment in the development for the same condition is repifermin (keratinocyte growth factor-2), from Rockville, Md.-based Human Genome Sciences Inc., which is "also supposed to be very good," Zhang said.

"The quality-of-life issue [for chemo patients] is really big, and it's going to be for a long, long time," Zhang said.

There was much ado regarding EGFR, VEGF and anti-angiogenesis drugs at ASCO. Not to be left out was the field of antisense, with two companies reporting data Tuesday.

Antisense Takes Stage On Final Day

Isis Pharmaceuticals Inc., of Carlsbad, Calif., offered details from the Phase III trial in which its compound Affinitak failed earlier this year against NSCLC. The drug is partnered with Indianapolis-based Eli Lilly and Co. Lilly is conducted a second Phase III trial testing Affinitak against the same indication in combination with Gemzar (gemcitabine) and cisplatin, and a decision regarding the drug's future will come after those results are in. (See BioWorld Today, March 18, 2003.)

Isis also disclosed data from two Phase II trials of ISIS 2503, an antisense agent targeting Ha-ras.

In an open-label trial of ISIS 2503 with Gemzar in 48 chemo-naive patients with locally advanced or metastatic pancreatic cancer, six-month survival (the primary endpoint) was achieved with 57.5 percent of patients, with a median survival of 6.6 months.

The response rate, defined as percent of patients who experienced either a confirmed complete or partial response, was 10 percent (5 of 48), and a total of 71 percent of patients showed clinical benefit with either a response or stable disease.

In the second trial, an open-label study of 26 patients with metastatic breast cancer, subjects received ISIS 2503 in combination with paclitaxel. The response rate was 54 percent (13 of 24 evaluable patients), with the most frequent adverse events being complications related to the in-dwelling catheter used to administer the drug. Investigators concluded that additional trials of the drug with paclitaxel against breast cancer are warranted.

Isis' shares (NASDAQ:ISIS) closed Tuesday at $5.83, down 32 cents.

Zhang said he had not seen the Isis data, but noted a broad skepticism about the technology.

"Antisense is a beautiful science, but it's going to be difficult to become a business, because of toxicity and manufacturing," he said.

Also reporting antisense data was Genta Inc., of Berkeley Heights, N.J., whose lead drug Genasense (oblimersen sodium) was the focus last year of a $480 million deal with Strasbourg, France-based Aventis SA. (See BioWorld Today, April 30, 2002.)

Genasense, which targets the Bcl-2 protein to boost the effectiveness of chemotherapy, is in four Phase III trials. Joy Schmitt, associate director of corporate communications for Genta, stressed the importance of the target and "how effective we are in blocking the target and permitting apoptosis in order to enhance chemotherapy."

Among its offerings at ASCO, Genta reported results from a Phase II study with it in combination with Taxotere (docetaxel) for patients with advanced, hormone-refractory prostate cancer, and said a new, randomized, multicenter trial with the pair for that disease will be started by the European Organization for the Research and Treatment of Cancer.

Data were presented from 29 evaluable patients who had received extensive prior treatment. All were refractory to standard hormonal therapy; six had failed prior chemotherapy, and 25 had been previously treated with radiation therapy. A total of 164 cycles of combined Genasense-Taxotere therapy was administered.

Overall, 48 percent (14 of 29) of patients achieved greater than 50 percent reduction in blood levels of prostate-specific antigen. Of the group of patients who had measurable disease on physical examination or by X-ray, 31 percent (4 of 13) showed an objective partial response.

The planned EORTC trial will randomly assign men with the disease who have not previously received chemotherapy to Taxotere alone or Taxotere plus Genasense.

Men in the trial from which Genta reported results Tuesday "were a tough group of patients, no doubt," given that they had been heavily treated before the study and their average age was 66, Schmitt told BioWorld Today.

She said the three main Phase III trials have completed accrual and top-line data will be available by the end of summer, with a new drug application possible if the numbers are good.

Genta's stock (NASDAQ:GNTA) closed Tuesday at $10.96, down 52 cents.

Zhang said the challenges of antisense may prove especially daunting in light of advances in RNA interference research, known as RNAi. That approach "silences" gene expression by deploying small interfering RNA, called siRNA, to degrade messenger RNA, which is the link between DNA and proteins.

The journal Science voted the discovery of small RNA molecules and their role in RNA interference the 2002 scientific breakthrough of the year. Companies such as Ribozyme Pharmaceuticals Inc., of Boulder, Colo., and Sequitur Inc., among others, recently have turned in that direction.

The latter recently broadened its antisense deal with Bristol-Myers to include RNAi, and the former entered an agreement for $48 million in financing as part of its changed focus to that technology. (See BioWorld Today, Feb. 13, 2003, and March 4, 2003.)

Zhang predicted companies "are going to quickly switch. If you have a choice, you'll probably use RNAi at this point."

In the months ahead, he said, more efforts will concentrate reducing side effects of cytotoxic cancer drugs, and attacking tumors with the anti-angiogenesis approach. The promise of EGFR and VEGF drugs will be further explored. Gene therapy, Zhang said, "will probably take a back seat."