The Pharm Exec Pipeline Report 2007 - Pharmaceutical Executive

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The Pharm Exec Pipeline Report 2007


Pharmaceutical Executive


Ostabolin-C, under development by Zelos in subcutaneous-injectible and oral versions, is a PTH agonist that stimulates bone formation. The drug molecule is a chain of 31 amino acids that resembles the N-terminal region of the parathyroid hormone. Ostabolin will compete directly with Forteo (teripatide)—a similar 34-amino-acid drug, marketed by Lilly—which is widely used despite a black-box warning for bone cancer.

Restoring Muscle Mass
SARMs: Testosterone's Benefits, Without the Negatives



Selective androgen receptor modulators, which bond selectively to testosterone receptors, give new hope to victims of cachexia, or muscle wasting. People who lose muscle mass in bouts with cancer or AIDS, as well as burn victims and patients who wither after surgery, can reap most of the anabolic benefits of testosterone from SARMs without suffering the androgenic side effects.

"SARMs make it possible to produce some hormone effects and avoid others," said Hosam Kamel, MD, professor of medicine at the University of Arkansas Medical School, in Little Rock. "In other words, male patients build muscle tissue without prostate enlargement, while women experience no secondary sexual characteristics, such as hair growth."

In the past six weeks, both GTx and Pharmacopeia have made SARM-related deals with Big Pharma. Pharmacopeia licensed SARM compounds from Bristol-Myers Squibb in an unusual barter deal. The smaller company provides three years of chemistry services in lieu of an up-front payment, but pays cash milestones thereafter. Merck made a $40 million initial investment in GTx's SARM research program, which contains as many as 250 compounds, according to the Wolters Kluwers R&D Insight database. Merck will also buy GTx common stock at a 40 percent premium and may make milestone payments of more than $400 million for successful compounds, according to news reports.

Cancer: Five New Approaches

Ipilimumab/Ticilimumab



These monoclonal antibodies both target CTL4-A, a receptor found on the surface of T-cells that serves as a "brake" on T-cell activity. The drugs, which are being developed first for malignant melanoma, aim to block CTL4-A and release additional T-cells to fight cancer. Both were licensed from Medarex, which in turn licensed the technology from the University of California–Berkeley.

Malignant melanoma is among the fastest-growing cancer markets in the developing world, but it remains relatively small. Lehman Brothers estimates peak world sales of the Pfizer drug at $500 million in 2015, while the BMS compound is expected to double that worldwide in the same year, according to the Wolters Kluwer R&D Insight database.

Zactima

The v-and-e at the beginning of "vandetanib" refers to the drug's rare property of targeting both vascular endothelial growth factor, VEGF, the angiogenic mechanism that has been proven to shrink tumors, and epidermal growth factor, EGF.

"It is rare to have one drug block both types of receptors, since they are from different families and not structurally similar," says John Heymach, MD, assistant professor of oncology at the MD Anderson Cancer Center at the University of Texas in Houston. "The dual activity should be synergistic in non-small cell lung cancer, where both receptors play a role in the disease." The drug is also active against RET receptors, which play an important role in the growth of thyroid tumors, Heymach said.

Apomab/Mapatumumab

These are cell-killing drugs under development for a variety of cancers. The antibodies mimic the agonistic activity of a natural protein called TRAIL (tumor necrosis factor–related apoptosis-inducing ligand). They target TRAIL receptors on the surface of many tumors, where they trigger apoptosis, or cell death.

"Time will tell what indications they will work best for," says John Heymach. "But this is an important class of drugs." Further up the pipeline are TRAIL agonists from Amgen and MedImmune in Phase I as well as preclinical research programs at three other companies.

Romidepsin/Panobistat

Here are two among several dozen histone deacetylase (HDAC) inhibitors in development to target isoenzymes that control some aspects of DNA transcriptional activity and gene expression. Most drugs in this class are in preclinical or Phase I trials, although Merck launched Zolina (vorinostat), an HDAC inhibitor approved for T-cell lymphoma in 2006.

"The drugs are not in wide use yet," said Bruce Chabner, clinical director of the Massachusetts General Hospital Cancer Center. "But if you find they are active in lymphomas, that's 60,000 new patients a year. Some target a broad range of HDAC isoenzymes, and some are more specific." Chabner believes this class of drugs shows promise in lymphoid diseases, B-cell malignancies, and perhaps solid tumors.

Axitinib/Recentin/Motesanib/Pazopanib

These four compounds lead a parade of potent, small-molecule inhibitors of vascular endothelial growth factor (VEGF), which can be taken as pills rather than injections. All have been in trials for a variety of indications, but their eventual value to oncologists may have little to do with each drug's value as a monotherapy. Expect oncologists looking for combination therapies to exploit the fact that each of these compounds targets a different combination of VEGF receptors, not to mention a range of different targets. "The VEGF mechanism crosses different tumor types," said John Heymach. "All of them need blood vessels."

Ron Feemster is based in New York City. He can be reached at ronfeemster@gmail.com.


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