San Diego’s Polaris Moves to Late-Stage Test of Drug for Liver Cancer and Other “Arginine-Dependant” Tumors

Xconomy San Diego — 

Bor-Wen Wu says he had the North Star in mind in 2006 when he founded San Diego’s Polaris Group, a small holding company with a promising lead drug candidate for treating liver cancer, malignant melanoma, and other related cancers. As an explorer in science, Wu says, “I need a North Star to tell me where to go.”

Yet the path Wu has followed has been anything but a sure and constant course. In his quest to develop the drug ADI-PEG 20, Wu has formed eight companies since 2002 that are affiliated with Polaris; raised more than $60 million from individual investors in Taiwan; and battled to retain control of ADI-PEG after paying millions to acquire a predecessor company, Phoenix Pharmacologics of Lexington, KY.

Despite a sometimes-circuitous path, though, Wu has kept the Polaris Group focused on a distant goal. The FDA recently approved the company’s plans for a late-stage clinical trial of ADI-PEG 20, an enzyme also known as pegylated arginine deiminase. ADI-PEG 20 is incredibly effective in breaking down arginine, an amino acid that is critical to the growth of hepatocellular carcinoma—the primary type of liver cancer.

Among cancer drugs in Phase 3 trials, Wu boasts, “We’re not the first in class. We’re the only one in the class. There’s nothing in the rear-view mirror.”

A study published last year in the British Journal of Cancer estimates there are 500,000 new cases of hepatocellular cancer diagnosed worldwide annually, with a five-year survival rate of less than 10 percent in the United States and Europe. Polaris, which contends the liver cancer is far more prevalent in Asia, estimates that worldwide deaths from hepatocellular carcinoma is closer to 700,000 people a year, with more than 330,000, or nearly half, in China.

ADI-PEG 20 represents an especially hot area of cancer research, which has focused on finding ways to starve tumors by depriving them of key nutrients. In the case of liver cancer, Wu says a key genetic mutation that triggers hepatocellular carcinoma coincides with the specific gene that makes arginine in normal cells. The company says the correlation is more than 70 percent in the patients studied so far. As a result, most liver tumor cells are unable to manufacture their own arginine and depend on some other source of arginine to survive and grow.

So liver tumors get arginine from the bloodstream (arginine also is metabolized from food). As silver bullets go, ADI-PEG 20 is ideal because it rapidly breaks down arginine, depriving tumor cells of their external supply of this essential nutrient without affecting nearby healthy cells (which can make their own arginine). ADI-PEG 20 has shown a similar effect on metastatic melanomas—one of the most deadly forms of skin cancer—and on other, so-called arginine-dependant cancers, including certain types of prostate cancer, pancreatic cancer, leukemia, lymphoma, and sarcoma.

Wu told me he first heard about ADI-PEG 20 in 2002, about six months after he had left the San Diego-based operations of Pfizer’s Agouron Pharmaceuticals, where he had worked on nelfinavir mesylate (Viracept), the company’s breakthrough protease inhibitor for treating HIV. (Warner-Lambert had acquired Agouron in 1999 and Pfizer acquired Warner-Lambert in 2000.)

“I was a biochemist lab rat, and I just wanted to be left alone,” Wu says. “I was at Agouron for 14 years and left without knowing what to do.”

Wu says he first read about ADI-PEG 20 in work published by Steven A. Curley, who specializes in gastrointestinal tumor surgery at the M.D. Anderson Cancer Center in Houston, TX. That work led him to Mike A. Clark, a biology professor at the University of Kentucky and the founder and CEO of Kentucky’s Phoenix Pharmacologics.

In the meantime, Wu’s search for a new career had led him in 2002 to start DesigneRx Pharmaceuticals, the first in a tangle of affiliated companies. He founded DesigneRx with the idea of operating a pilot facility in Vacaville, CA, that would use good clinical manufacturing practices to make biologics. He founded TDW Pharmaceuticals in Taiwan the following year to develop treatments for cancer and gout, and eventually made DesigneRx a TDW subidiary.

Wu says he initially in-licensed ADI-PEG 20 at DesigneRx as part of his plan to develop the drug for use in Taiwan and China, where the incidence of liver cancer is many times higher than in the United States.

But in 2004, he acquired Phoenix altogether (at an undisclosed price), and says he has raised at least $60 million from investors in Taiwan. “I never even tried to talk to any VCs in the United States,” Wu says. “When I met with people in Taiwan, the first question I asked was the liver cancer question—if they had any relatives who had died of liver cancer. They weren’t biotech people, but they are smart business people.”

He founded the Polaris Group and Polaris Pharmaceuticals in 2006, and eventually combined their operations with TDW and DesigneRx .

Wu says that one of the main reasons he acquired Phoenix was to see if he could improve upon the compound. He visited with cancer researchers at MD Anderson and elsewhere, hired a contract research organization to audit the results of research that Phoenix had conducted, and carried out his own mid-stage studies of ADI-PEG 20 in terminal cases of liver cancer and melanoma.

After that, Wu says Polaris worked to win an orphan drug designation for ADI-PEG 20, and spent nearly two years designing a Phase 3 clinical trial, which won FDA approval last month as a special protocol assessment, or SPA. The company says the SPA process allows the FDA and drug developers to reach an agreement on the study size and design before starting a Phase 3 trial, and will serve as the primary basis for an efficacy claim in a new drug marketing application.

The global trial, which is expected to cost $25 million, will enroll 600 terminal liver cancer patients who have failed prior systemic chemotherapy in a randomized, placebo-controlled test of ADI-PEG 20 at medical centers in the United States, United Kingdom, Italy, Taiwan, and China. The principal investigator is Ghassan Abou-Alfa, of the Memorial Sloan-Kettering Cancer Center in New York.

The company’s success in developing ADI-PEG 20, however, also led to a legal dispute several years ago with Enzon Pharmaceuticals of Piscataway, NJ, which Wu says was eventually settled. Enzon had tried unsuccessfully to develop the compound in the 1990s when Clark, the Phoenix Technologies founder, was Enzon’s vice president of research, according to Wu. Enzon sued Phoenix Technologies after Clark resumed work on the compound, and Wu says he inherited the case when he acquired Phoenix Technologies in 2004.

If that was a sign that the stakes have grown high, the stakes are even higher now.

Wu says the only drug currently approved for late-stage liver cancer is sorafenib (Nexavar), which had global sales of $934 million last year as a therapy for both liver cancer and renal cell carcinoma. U.S. regulators approved the drug in 2007, after Bayer showed that it adds just two to three months to the lives of most patients with late-stage liver cancer.

Wu says studies already conducted by Polaris shows that ADI-PEG 20 adds three to seven months to the lives of its late-stage cancer patients. He believes that can be extended even more, though, by treating patients diagnosed at a much earlier stage, when the tumor mass is smaller “and it’s easier to starve [tumor cells] to death.” He also says using ADI-PEG 20 in combination with chemotherapy would boost the drug’s potency even more. Cancer cells often can counter the effects of chemotherapy by repairing the damage done at the cellular level.

“With ADI,” Wu says, “cancer cells cannot make the enzymes and proteins needed to repair cell damage. This gives us a hope that maybe we can cure the cancer in certain cases.”

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