West Coast Editor
Upcoming drugs targeting vascular endothelial growth factor (VEGF), as well as Genentech Inc.'s approved Avastin, being developed for indications beyond colorectal cancer - face a higher standard in oncology treatment, said William Li, president and co-founder of the Angiogenesis Foundation.
"We're seeing this bar being raised very rapidly," Li said during a roundtable conference call hosted by Jennifer Chao, analyst with DeutscheBank Securities in New York.
"When the Saltz regimen was all the rage," he said, 14 months to 15 months of survival was the accepted standard. "Suddenly with Avastin you've raised the bar to 20 months."
The cancer standard of care is a "moving target" in itself, he said. The Saltz regimen, (5-FU, leucovorin and irinotecan) has lost ground since a paper was published a year ago in the Journal of Clinical Oncology. That paper described how the FOLFOX-4 regimen (which replaces irinotecan with oxaliplatin) led to survival of 19.6 months in patients with untreated metastatic colorectal cancer - very comparable to Saltz plus Avastin (bevacizumab).
"Irinotecan is regarded by oncologists to have some markedly limiting side effects," Li noted, such as intolerance to the drug itself and severe diarrhea.
"Avastin remains a milestone for modern oncology, in fact, modern medicine," he added, and cautioned that to compare the Genentech compound with other VEGF drugs nearing the market is "almost like comparing apples and oranges," given the shifting environment of oncology therapy.
One such treatment is PTK787, from Novartis AG, of Basel, Switzerland, and Schering AG, of Berlin. The drug is in Phase III trials against colorectal cancer in combination with first- and second-line chemotherapy.
VEGF is "actually a family of at least five different molecules [VEGF-A, B, C, D and E]," Li said. VEGF-A apparently is the most important molecule in colorectal cancer, and Avastin neutralizes all four isoforms of VEGF-A. "Avastin binds to the ligand or protein of VEGF-A only," he said.
The Novartis/Schering compound is a small molecule that penetrates the cell membrane, neutralizing every receptor known to VEGF. Another "very important capability of PTK to think about is that while Avastin blocks only VEGF-A isoforms, PTK also blocks platelet derived growth factor and C-KIT" - potentially making it even more useful. C-kit is a protein on the surfaces of certain cells that binds to stem cell factor.
"PTK is asking, really, the next-generation question, Can you take 19 months as the baseline and add PTK and get more survival?'" Li said. "In theory, one would expect that." The drug "could raise the bar to 25 months," he said. "That's what we're waiting to find out. I think it's realistic [to think] this study can hit that."
Data are due late this year or early next, at which point the side-effect profile will become more clear. But in Phase I/II trials, 1,250 mg of the oral drug yielded satisfying results. PTK787 was "very well tolerated at most doses, and at the very high doses they were looking for dose-limited toxicities," Li said.
VEGF is normally expressed in small amounts in the kidney, where it maintains the filtration system and up-regulates nitric oxide, contributing to regulation of blood pressure.
"There's a little bit of a side effect that hits VEGF in the kidney," Li said, but the resulting hypertension is medically managed. PTK787 might be used "in tandem or in sequence" with Avastin if approved, he said, likening the former to "kind of a Gleevec" with comprehensive VEGF blocking at the receptor level. Gleevec (imatinab) is Novartis' compound for chronic myeloid leukemia.
Li has been "working in angiogenesis for almost 20 years now," starting in the laboratory of pioneer Judah Folkman in the mid-1980s, and he helped create the Angiogenesis Foundation in 1994. The group does not provide medical care, but serves "as a sort of air-traffic control in terms of maintaining intelligence and understanding what is going on in the field.
His organization is tracking 74 distinct anti-angiogenesis compounds in clinical trials, Li said. Of the 74, seven are in Phase III. "We estimate there are more than 200 agents in total," he added, with 100-plus still in preclinical study.
PTK787 is the most promising of those 74, Li said, followed by SU11248, the oral tyrosine kinase inhibitor developed by Sugen Inc., a unit of Pharmacia Corp. (now part of New York-based Pfizer Inc.), and the matrix metalloproteinase inhibitor BAY12-9566 from Bayer AG, of Leverkusen, Germany.
There are "at least 30 different angiogenic growth factors that can be made by tumors," Li pointed out. "Healthy tissues also make them. When we think about targets like VEGF, we need to remember it's not the only target."