Courtesy of Mark Seward
Combinatorial chemistry and high-throughput screening have been the rage in drug discovery since the late 1990s, but plant and animal sources still hold promise. In particular, venoms have proven to be rich areas for exploitation. Drugs derived from snakes, vampire bats, and Gila monsters are all nearing regulatory review and potentially, approval. But in September, a Food and Drug Administration advisory panel voted against approval of AstraZeneca's Exanta, a cobra venom-derived anticoagulant. These products face the same and possibly higher hurdles as other molecules when it comes to reaching the market.
One of the most successful products derived from venom was the first FDA-approved angiotensin converting enzyme (ACE) inhibitor, captopril. John Vane, a researcher at the Royal College of Surgeons, and a Brazilian fellow in his lab discovered that a peptide in Brazilian viper venom blocked the formation of angiotensin II. That drug went on to become Bristol-Myers Squibb's captopril, which was approved in 1981. In 2002, worldwide sales of ACE inhibitors totaled $7.8 billion (US).
A more recent success is Integrilin, an antiplatelet drug approved in 1998 to treat acute coronary syndrome. Integrilin binds to glycoprotein IIb/IIIa, inhibiting platelet aggregation. It is a synthetic analog of barbourin, which is found in the venom of the Southeastern pygmy rattlesnake. The drug was developed by San Francisco-based COR Therapeutics, which merged with Millennium Pharmaceuticals of Cambridge, Mass. COR screened venoms from 62 snakes to find the right compound, according to COR executive Robert Scarborough.1 The drug is sold by Millennium and Schering-Plough.
Integrilin sales were $305.8 million in 2003, according to Millennium. The company is studying two new uses for the drug: the management of ST-segment elevation myocardial infarction, and the prevention of bleeding and heart attacks during coronary artery bypass surgery.
If approved, Exanta (ximelagatran) could capture an even bigger market – an estimated $3 billion per year by competing with the oral anticoagulant warfarin. Exanta can be given twice daily, and there's no need for the tricky blood level monitoring the older drug requires. Potential uses include post-surgical prevention of venous thrombosis or pulmonary embolism, as well as stroke prevention in patients with atrial fibrillation (which affects two million people in the United States). Only about 35% of patients with atrial fibrillation receive therapy, and many aren't being treated within the correct therapeutic range, says Jonathan Halperin, an AstraZeneca consultant and professor at Mount Sinai Medical Center in New York.
Exanta has European approval for preventing venous thromboembolism in major orthopedic surgery and was launched in Germany in June. However, an FDA advisory panel cited concerns about the drug's efficacy and risks (primarily liver toxicity) and recommended against approval of the drug on Sept. 10. At press time, the company declined to comment on its future plans for the drug.
Other venom-based drugs are at an earlier phase of development. Francis Markland, a biochemistry professor at the University of Southern California (USC) Keck School of Medicine in Los Angeles, has been looking at venom's potential for almost 40 years. His research led to the discovery of fibrolase, a clotbusting compound from the southern copperhead that is now in Phase II studies at Nuvelo in Sunnyvale, Calif. The company was formed through the merger of Hyseq Pharmaceuticals and Variagenics, which closed on Jan. 31, 2003. Nuvelo has created a recombinant form of the protein, alfimeprase, and is testing its ability to restore blood flow in blocked peripheral arteries.
Markland discovered another compound in the copperhead's venom, contortrostatin, which binds to cell-surface proteins called integrins. Blood vessels display integrins as they grow, and Markland believes contortrostatin might be able to block angiogenesis in tumors.
The drug has shown promise in preclinical trials using cultured breast cancer cells and animal models. Markland plans to seek an investigational new drug application from FDA, either through USC or a company he formed, called Pivotal BioSciences, to commercialize contortrostatin. The Los Angeles-based company is still private and has no timetable for going public, says Markland.
A CURE FROM BLOODLUST
Another animal targeted for drug discovery is the vampire bat, the source of a potential stroke therapy called desmoteplase. The bat's saliva contains three components that increase blood flow from its prey: an anticoagulant, an antiplatelet aggregator, and a compound that prevents constriction at the wound site. Desmoteplase was first isolated in 1995 from the common vampire bat, and was dubbed Draculin by its Venezuelan discoverers. Forest Laboratories in New York City is betting that the drug will pan out and aims to seek FDA approval by 2007, says Forest president Ken Goodman.
Paion of Aachen, Germany, conducted early-stage development of the drug. Forest joined forces with Paion in June 2004, agreeing to take on the regulatory clearance and sales and marketing in the United States and Canada. Desmoteplase can be given up to nine hours after symptom onset, so it may offer an advantage over tissue plasminogen activator (tPA), the standard therapy for ischemic stroke, sold by South San Francisco-based Genentech as Activase. That drug, which had sales of about $185 million in 2003, must be given within three hours, says Goodman.
Goodman says he does not expect a huge market for desmoteplase. Even though stroke occurs in 600,000 to 700,000 people annually, not all will be eligible for the drug. "From a revenue standpoint, it's not an enormous product, but a reasonably decent product," he says.
A MONSTER FIND
Eli Lilly and Co. may have bigger expectations for exenatide, a synthetic version of a hormone found in Gila monster saliva. In the early 1990s, researchers discovered that the one-to-two-foot-long lizard,
John Eng of the Bronx Veterans Affairs Medical Center discovered the hormone, which is similar to the human digestive hormone, glucagon-like peptide-1 (GLP-1), but lasts longer. The company was so intrigued that it located some Gila monster saliva, tested it, and eventually licensed the patent from Eng, says Gregg Stetsko, Amylin's vice president of operations.
Exenatide holds the promise of being a more convenient replacement for insulin, says Stetsko. The drug will be given twice daily, but patients with diabetes won't need to calculate their weight or monitor blood glucose to determine dosage or when to take the drug. In trials, 1,400 patients who failed to control their type 2 diabetes with oral medications were given either exenatide or the oral drugs metformin, sulfonylurea, or both, over 30 weeks. The performance was comparable to insulin in reducing hemoglobin A1C levels, says Stetsko. But those on exenatide had an added advantage: They lost weight, a boon to a patient with diabetes. Exenatide could see marketing daylight as soon as 2005, Lilly applied for FDA approval in late June 2004.
Amylin considers exenatide to be one of its more promising drugs and with a potentially huge market. Of the 13 million people diagnosed with diabetes, 12% take both insulin and oral medications, and 19% take insulin only, according to the American Diabetes Association.
A FECUND FUTURE?
Having come this far, exenatide has been a relative hit for Amylin and Lilly. But neither company is likely to invest heavily in screening animals as sources for the next potential blockbuster, says Stetsko, who added that he thinks this is true for most big drug makers. The growing number of hits "has given some credibility to the approach, but it still has a ways to go before it becomes a routine part of drug development," he says.
Potential hurdles still remain with animal-derived drugs, especially in manufacturing. Many of the compounds are proteins and peptides that are difficult to chemically reproduce or make stable, says Stetsko. Exenatide is chemically synthesized, but other products are produced in bacterial or cell cultures, raising issues of safety and purity. Moreover, a nonsynthetic, animal-derived drug that retains characteristics of its origin can cause allergic reactions. These issues raise the bar even higher for FDA approval, says Stetsko.
However, the field does hold promise, says Irena Melnikova, a senior research analyst with Framingham, Mass.-based Life Science Insights. Safety, particularly of products intended for chronic use, will continue to be a hurdle, she says, but the success rate may start to grow, thanks to better screening capabilities, as well as more cross-over between disciplines aided and abetted by the Internet, which is allowing researchers in disparate fields to view each other's work.
Markland agrees that demonstrating safety of the animal-derived products will be an important task, but no more so than with traditionally sourced compounds. "I think we're scratching the top of the iceberg in terms of what's out there," he says. There's much to be learned, even in the well-studied area of venoms, he adds. "Even if I was working for another 50 or so years, I think there's novel things to be found in venom."