By Randall Osborne

Editor

It's the disease that won't go away.

Not AIDS although that affliction fits the bill, too, and would have been the first coming to many minds, a few years ago when the HIV scourge (still rampant) made headlines.

Cancer.

It attacks practically every site in the body, and often moves with a virulence that chills even the most experienced of medical personnel, debilitating and sometimes disfiguring its victims before death, which can be cruelly slow.

On the list of most common fears, "getting cancer" tends to finish near the top, especially since dying of various forms remains an unnerving possibility, despite advances in many zones of research.

That research was the focus last week of the meeting in San Francisco of the American Society of Clinical Oncology. But "focus" may be the wrong word, since the annual event became the site, this time around, of a veritable avalanche of data that scientists, analysts and corporate onlookers may have been hard pressed to sort.

Things, in general, are looking up.

"For the first time in 25 years, the cancer mortality rates are going down," noted Franklin Berger, co-head of biotechnology research for JP Morgan H&Q in San Francisco, an attendee of the ASCO meeting.

A clear winner at the meeting was Amgen Inc., of Thousand Oaks, Calif., with its recombinant erythropoietic protein Aranesp, which yielded positive Phase III data showing the drug can reduce red blood cell transfusions for chemotherapy patients and treat anemia in cancer patients, those who are "on chemo" as well as those who are not.

Amgen may have found another EPO vein of gold.

In an ironic situation that's becoming almost typical of biotechnology, the company hopes to use Aranesp to capture a piece of the anemia market now held by New Brunswick, N.J.-based Johnson & Johnson, which gained an edge in that market with Procrit, licensed from Amgen, which markets it for other indications as Epogen.

Aranesp, in fact, is an extended-release version of the red blood cell booster Epogen. That's where the drug's advantage lies, Amgen says. Flexible dosing once every two weeks or even once every three weeks, as compared to Procrit's once-weekly administration means a better fit with chemo regimens, which means happier patients among a population that has had little medical cause for rejoicing.

"It was as impressive as everyone thought it would be," Berger said.

Data from a Phase I/II study of Aranesp showed it was effective in dose ranges of 1.5 micrograms/kg to 4.5 micrograms/kg once weekly and 3.0 micrograms/kg to 9.0 micrograms/kg every two weeks.

There was more. In a 314-patient, double-blind, placebo-controlled, randomized Phase III study in lung cancer patients receiving multicycle platinum-based chemo, the number who needed a transfusion went down more than 50 percent over the course of treatment phase.

With potential in cancer and in chronic anemia (where the patient is not taking chemo treatments and where Epogen use is comparatively scarce), Amgen could have its hands on a multibillion-dollar drug. The first regulatory filing is expected this year. Trials are ongoing, meanwhile, in chronic anemia patients who are dosed only once every three weeks, and even once every four weeks.

Others had encouraging data to report, too. Among them was ImClone Systems Inc., of New York. The company said its monoclonal antibody IMC-225, designed to target and block the epidermal growth factor (EGF) receptor expressed on the surface of certain cancer cells, proved effective when combined with gemcitabine in pancreatic cancer patients. It gave them a one-year survival rate of 32.5 percent, with 21 patients stabilizing and five more achieving a partial response. The median time to disease progression worked out to about 3.5 months, with an overall median survival of 6.75 months.

Berger told BioWorld Financial Watch the ImClone research was among the most promising but much of the powerful data, he added, derives from the same area: EGF.

"[EGF] is where the light is starting to illuminate in the dark warehouse," Berger said. The first major wattage that made it to market was Herceptin (trastuzumab), South San Francisco-based Genentech Inc.'s monoclonal antibody treatment for metastatic breast cancer that overexpresses the HER-2, or EGF receptor-2, protein.

ImClone's drug with cisplatin against head and neck cancer in patients who had been refractory to cisplatin alone tested 63 patients. Of 41 with stable disease, one responded completely and nine partially, with a median duration of response reaching 24 weeks. Of 22 patients with progressive disease in another cohort, five showed partial response, and the median duration was 12 weeks.

A similar Phase II test was tried with colorectal cancer, refractory to irinotecan. Again, the drugs were combined. Of 120 patients, 27 achieved partial response, with nine more achieving stabilization. Median duration response was 186 days.

Genentech and OSI Pharmaceuticals Inc., of Uniondale, N.Y., said their drug, Tarceva, gained a 13 percent response rate in Phase II studies in non-small-cell lung cancer and a 6 percent response in head and neck cancer.

EGF drugs might end up not working well by themselves against cancer, but . . . so what? "There is no 'best,' and we're probably going to end up requiring several modalities, because everybody's cancer is different," Berger said. "[Cancer is] a personal clone."

Kinases (the enzymes involved in transmitting the signals between cells) have come to make up "one of the hottest areas," he said, with players such as Vertex Pharmaceuticals Inc. and Novartis Pharma AG, of Basel, Switzerland, conducting major programs together. A year ago, the companies formed a kinase inhibitor-focused alliance that could mean $800 million for Vertex.

"There are at least 40 families of kinases in the literature, and they are probably underestimated," Berger said. "There's not a clarion call as to exactly what is the right thing to do [with them]."

Thomas Dietz, senior analyst with Pacific Growth Equities Inc., in San Francisco, saw potential use on several fronts, and recited other EGF players in a research note.

AstraZeneca plc, of London, has an EGF tyrosine kinase inhibitor, Iressa (ZD1839), in Phase III trials. New York-based Pfizer Inc. has one called CI-1033 in Phase II studies. Abgenix Inc., of Fremont, Calif., and Immunex Corp., of Seattle, have ABX-EGF, a fully human monoclonal antibody in development against cancers expressing the EGF receptor. The latter two companies offered positive preliminary results from a Phase I trial at ASCO, and have begun a Phase II study in kidney cancer.

YM BioSciences Inc., of Mississauga, Ontario, has TheraCIM, an EGF receptor antibody in Phase I trials, and the Institute of Cancer Research in London has ICR62 in Phase I.

The oncology show stealer in the mainstream media came not from or even out of ASCO, but from Novartis, whose Gleevec (imatinib mesylate) won approval May 10 as an oral therapy for chronic myeloid leukemia in the blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy.

At ASCO, days after winning the FDA's nod, Gleevec came out strong in another indication. The Dana-Farber Cancer Institute said Gleevec helped the majority of patients with the rare and otherwise incurable form of gastrointestinal cancer called gastrointestinal stromal tumor. More than 75 percent of patients had some shrinkage of their tumors and, in more that 50 percent of patients, tumors shrank by at least 50 percent.

Berger said Novartis' drug is "thematically in the same area [as EGF receptor drugs]," Berger said. "It's an elegant way of interfering in nuclear proliferation. EGF is not different, because the signal that it finally fires to, in the nucleus, is a signal transduction pathway."

Gleevec, the name of which was changed from Glivec in the U.S. to avoid confusion with other drugs, is a signal transduction inhibitor, the likes of which are hardly unknown in biotechnology. Three years ago, Sugen Inc. said it had SU101 in Phase III trials against the brain cancer glioblastoma, and touted it as potentially the first signal transduction inhibitor to be approved for cancer.

Pharmacia & Upjohn took over Sugen in 1999 in a $650 million stock swap (and later merged with St. Louis-based Monsanto Co., forming Pharmacia Corp.), and Gleevec beat SU101 to market by a mile. Several miles. Berger said SU101 has "pretty much dropped off the map."

Spokespeople for Pharmacia did not return calls to explain the drug's status. Others, anyway, have taken up the charge, Berger said, and the trend will continue.

"There's nothing really original here," he said. "The promise of molecular biology is that you can understand function, and then interfere in a rational way."

But EGF, he said, shows exceptional promise.

"The EGF pathway allows us to understand the whole chain of events that leads to proliferation, which is cancer," he said. "Anywhere along that line of communication, from the initial binding, or the inhibitor at any point in that chain up to the nucleus" might be profitably investigated, he said, adding that EGF research is a "tremendously bright opening" through which to understand how cells grow.

Whether that leads to new stand-alone drugs, or new treatments to be used with chemotherapy, the harvest may be great. "And we'll learn how to use the drugs we have a lot better, because we know what we're doing," Berger said.

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