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Magic Molecules
Pipeline Report


Pharmaceutical Executive


Rituxan has a few built-in marketing advantages too, Gibbons adds. "Even if it doesn't work better than existing drugs, it works differently and so may find support for being used in tandem with them. Also, people with autoimmune diseases tend to have an elevated risk of lymphoma to which Remicade and other similar drugs may possibly contribute. Even if this is not the case, however, Rituxan stands out because it is a treatment for lymphoma and so almost certainly won't worsen this risk, and may even possibly improve it—although that has not been tested."




SB 480848from GlaxoSmithKline

SB 480848 has not yet entered Phase III and is still at least four years from approval. But Mara Goldstein nominated it because it is a lipoprotein-associated phospholipase A2 (LpPLA2) inhibitor, and elevated levels of inflammatory markers such as LpPLA2 "have been shown to indicate an increased risk of coronary artery disease," she says. In fact, they appear to do a better job of predicting stroke than cholesterol does. LpPLA2is now thought to play a critical role in transforming LDL cholesterol into plaque and triggering the inflammation that eventually produces clots. Attacking this enzyme may hinder the development of atherosclerosis.




Sutent [SU 11248]from Pfizer

Sutent combats cancer in two ways at once. An orally administered angiogenesis inhibitor, it also acts as a multi-targeted tyrosine kinase inhibitor for solid tumors. Thus, it seems capable of not only preventing tumors from increasing their blood supply but also interfering with several of the kinase pathways essential for their survival. According to Mara Goldstein, "Data released this year show an increase in objective response rates and time to progression in patients with renal cell carcinoma or gastrointestinal stromal tumors (GIST)." What's more, Kelly says, the drug's "been shown to be effective with cases that Novartis' Gleevec [imatinib] can't handle."




Thymitaq [nolatrexed]Eximias Pharmaceutical

Thymitaq is a novel thymidilate synthetase inhibitor that, Samet says, "does not require facilitated uptake into cells." What's more, its MOA, inhibition of DNA synthesis, "makes it potentially applicable to a wide range of tumors," and "its unique molecular structure may reduce the resistance many cytotoxic chemotherapeutics face."

Thymitaq is one of two drugs in Phase III trials for hepatocellular carcinoma (HCC), a disease closely associated with hepatitis C, which infects 4 million Americans annually. Studies show that it increases survival time in nonresectable HCC patients by up to144 percent. "Orphan disease status for this condition would provide a quick path to market," says Samet.




UK 427857from Pfizer

Gibbons says people who are HIV- positive but don't develop AIDS have a version of the CCR-5 receptor that works to their advantage. UK 427857 "blocks those receptors so HIV can't use them to affect T-cells, stopping or slowing the progress of AIDS." Drugs with a similar method of action (MOA) are in development, including a preclinical compound from Sangamo BioSciences. But with UK 427857 moving to Phase III this quarter, it may become the first to advance that far.




Velcade [bortezomib]rom Millennium/Johnson & Johnson (Ortho Biotech)

Velcade, recently approved for the treatment of multiple myeloma, has a "unique MOA that is potentially applicable to a wide variety of cancers," says Samet. It works by blocking proteasomes, which he describes as "the garbage dump of cells," to induce apoptosis (cell death). One problem: "The potential for fatal overdose is significant. Proteasome activity is an intracellular pathway tightly connected to protein function and viability. Nonspecific proteasome inhibition has no antidote, unlike other cytotoxic antimetabolites." Samet believes the extent to which Velcade's therapeutic index can remain high will play a big part in its success as an anticancer agent. It is currently in late-stage development for lung, prostate, renal, and colorectal tumors.

SOURCE: The R&D Insight (RDI) database, generously provided by the Adis division of Wolters Kluwer Health. NOTE: Data were not available for all products. Adis ratings assess therapeutic impact. A score of 80–100 means "potential major advance"; 60–79, "important benefits compared to existing therapies and some modest benefits"; and 45–59, "equivalent efficacy." Probability of success—defined as obtaining the anticipated approvals—and global peak sales were extracted from RDI but generated by Lehman Bros.


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