The PharmExec 2005 Pipeline Report - Pharmaceutical Executive


The PharmExec 2005 Pipeline Report
Dry? Not quite. Instead of 1990s-style blockbusters, pharma's new molecules are niche drugs, cancer treatments and—at last—innovative mechanisms for troublesome targets.

Pharmaceutical Executive

TMC 207 by Johnson & Johnson

PA-824 by Chiron/Novartis


After 40 years, TB therapy is changing. To replace harsh drugs that pose toxicity, compliance, and drug-resistance problems, the Global Alliance for TB is pushing new shorter courses of therapy, including repurposing Bayer's moxifloxacin and BMS' gatifloxacin, neither of which have been tried in long-course antibiotic treatments.

TMC 207, a diarylquinalone, undermines the energy sources of myobactyerium tuberculosis by attacking ATPase, an enzyme that assembles ATP energy molecules. The Global Alliance for TB licensed PA 824 from Chiron/Novartis. A nitroimidazole, PA 824 resembles imidazoles that attack anaerobic bacteria. Further up the pipe are OPC 67683 (Otsuka), another nitroimidazole, and LL-3858 (Lupin).


A Look Into the Future of Oncology

Judah Folkman, MD
Judah Folkman, MD, a cancer researcher at Children's Hospital of Harvard University, is the godfather of anti-angiogenic agents. While he is delighted with the success of recently approved drugs like Genentech's Avastin and Tarceva, which inhibit one or two angiogenic growth factors, he envisions a future where drugs—and the companies that make them—will work together to combat a broad range of similar proteins.

"Vascular endothelial growth factor [VEGF] is made by 60 percent of human cancers," Folkman says. "Attacking that is great. But that's when the tumors start. Years later the tumors keep on making VEGF, and they also add redundant angiogenic factors. So the first thing they do is add FGF and HGF [fibroblast and hepatocyte growth factors]. In breast cancer you can have up to six angiogenic proteins coming out of one tumor."

To battle tumors generating a wide range of angiogenic proteins, oncologists will combine angiogenesis inhibitors, Folkman predicts. Avastin is already being used with Tarceva, he points out, and with low-dose chemotherapy. If new angiogenesis inhibitors are to be combined with one another, the companies that make them will have to agree on targets, compounds, and anti-angiogenic cocktails.

Folkman sees a new crop of broad-spectrum angiogenesis inhibitors, like Endostatin and Caplostatin, replacing the combination therapies. Here, Folkman offers his off-the-cuff picks, in no particular order, for the most significant new anti-angiogenic drugs.

Endostatin, a natural protein manufactured in Folkman's lab at Children's Hospital in the late 1990s. The drug was copied and improved by Chinese scientists, and approved by FDA in China for lung cancer. Big advantage: It is non-toxic, with virtually no side effects, Folkman says. Phase II trials were suspended in the United States, although patients who took the drug remained in remission for more than three years.

Caplostatin, by Children's Hospital, is Folkman's pick as the broadest anti-angiogenic agent so far. It inhibits capillary growth. However, it has not yet been manufactured for clinical trials.

ABT 510, by Abbott, mimics the anti-angiogenic activity of a naturally occurring protein, thrombospondin-1. The compound is currently in Phase II studies for lung cancer, lymphoma, renal cancer, sarcoma, and solid tumors, with a target launch date of 2008.

Lucentis, by Genentech, is a cousin of Avastin that has restored vision for age-related macular degeneration patients. (See separate profile.)

Sutent, by Pfizer, is the first major oncology launch from the world's largest pharma company. Folkman projects Sutent as a combination therapy with Avastin. (See separate profile.)


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