Editor

SAN FRANCISCO - The differing priorities of the FDA, the public and would-be litigators in drug development's much-discussed risk-benefit ratio became one of the topics during a panel talk at the Biotechnology Industry Organization's InvestorForum conference at the Palace Hotel here.

Jason Kantor, analyst with RBC Capital Markets, was blunt.

"The FDA's primary goal is to judge the safety of a drug, and as long as it meets minimum efficacy standards, they're willing to approve it," he said. "The public wants to be able to eat fast food, drink coffee, and be as fat as they want and still be healthy, so they want drugs that work. The lawyers want drugs that aren't safe because that's where they make their money."

Kantor's remarks came during a session called "Cardiovascular Disease: Not for the Faint-Hearted." The same descriptor might be attached to drug research in general, as George Schreiner, president of research and development at Scios Inc., noted a "shift toward safety and less emphasis on efficacy" in the climate that took hold after the withdrawals earlier this year of Merck & Co. Inc.'s COX-2 painkiller Vioxx (rofecoxib) due to heart concerns and Tysabri (natalizumab), the planned blockbuster for multiple sclerosis from Biogen Idec Inc., also because of safety worries.

Biotechnology might be the realm of pioneers, but "one of the reasons why big companies sometimes feel more comfortable developing a sixth-generation ACE inhibitor" is that the risks with a known mechanism of action are well defined, said Schreiner, who moderated the panel.

"In the absence of all the other tools that a large pharmaceutical company has, including marketing prowess, biotech companies have to get it right," he said. "They can't compensate for deficiencies in the data or deficiencies in understanding. They can try to for a while, but sooner or later the science will catch up with them."

Schreiner's firm developed Natrecor (nesiritide) for acute congestive heart failure in patients who have dyspnea at rest or with minimal activity. The drug was approved more than four years ago, and Scios was bought by Johnson & Johnson for $2.4 billion in cash in 2003.

Lately, Natrecor has run into some potential difficulty of its own. The U.S. Attorney's office in Boston has subpoenaed documents related to the drug's sales and marketing. Earlier in the year, Natrecor's label was changed to include additional data on mortality, though the FDA acknowledged that such conclusions are difficult. The revision followed the publication of studies on risks related to death and worsened renal function.

Scios recently convened a panel of cardiologists and heart failure clinicians that suggested the company conduct more trials. The FDA, for its part, remains confident that the drug is safe and effective when used as recommended to treat patients indicated in its label. Meanwhile, J&J has acquired European rights to the drug from GlaxoSmithKline plc. Janssen-Cilag, also a J&J company, will market the product in Europe as Noratak.

The Vioxx and Tysabri episodes undoubtedly cast a pall over regulatory procedures while causing some to doubt the honesty of drug makers, though Schreiner said "a lot of people talk about the Vioxx effect exclusively with respect to whether or not Merck was obscuring cardiovascular complications. Much more harm was done to the whole field by the advertising to the consumer that suggested that when you take this medicine, an elderly couple can hold hands and skip through a field of flowers. [That sort of campaign] really changed a lot of advertising around COX-2 [and] fed the illusion that you could have a new mechanism with powerful effects for good and possibly for bad, but in fact there were no downsides to this - you could live a happy, fulfilled life, and live forever."

Fady Malik, director of cardiovascular programs at Cytokinetics Inc., said COX-2s themselves represented the cautious, incremental steps taken by big pharma. The drugs were "designed to solve a specific problem, but in terms of their efficacy, it's not clear that they have any large benefit over existing agents."

Schreiner pointed that most biotechnology investors, "aren't interested in an incremental approach, or they would invest in Pfizer. They want to invest in something they think is going to be a definitive advance. This is an area where investors have a much bigger impact on the direction of a research program than they would by investing in a very large pharmaceutical company."

Some might place bets on the likes of Arginox Pharmaceuticals Inc., which in June started patient enrollment in a pivotal Phase III trial of its lead candidate, tilarginine acetate, an injected small-molecule inhibitor of nitric oxide, for cardiogenic shock.

CS afflicts as many as 100,000 heart attack victims who reach the hospital alive in the U.S. every year - a major cause of death in that segment - and Arginox's drug works by interrupting the circulatory shutdown that can lead to death.

The company, Schreiner said, is "at the other end of the spectrum" from other cardiovascular firms, from whom regulators typically required large, long trials that cost a great deal.

"In classic biotech fashion," he said, Arginox is "focusing on a problem that no one else will touch, which is patients who are at the end of their cardiovascular lifespan, who present to the emergency room in cardiogenic shock, that have a mortality, depending upon who's counting, of 55 percent to 90 percent."

Called TRIUMPH, the trial will enroll 658 patients at more than 120 sites in the U.S., Canada and Europe, with subjects getting either tilarginine acetate as a bolus and as five-hour infusion, or a placebo. Enrollment is expected to finish by the end of the third quarter of next year. TRIUMPH follows a Phase II dose-ranging study that proved the drug was well tolerated in the full cohort of patients tested, including those more than 75 years old.

Kenneth Drazan, founder, acting chairman and CEO of Arginox, noted that "regulatory authorities are focused on clear events, which in this case means death, and they're interested in concentrating those events in two distinct trials so they can be certain there wasn't a chance" outcome from the first study."

Studied in the Phase III as an orphan patient population meant FDA officials "were sympathetic to our needs and that also we could likely scavenge all the world's resources to conduct this single pivotal trial," he said. No such study has been conducted before, "nor are cardiologists necessarily prepared for clinical research in the acutely dying patient," Drazan added. "There's no less challenge in identifying competent investigators and getting the sites to pay attention. Many sites in the U.S. are conducting more than 30 trials, and usually [have only] one coordinator for that cardiovascular research group."

Still, the effort makes for a promising business opportunity, Drazan said, thanks to the "handshake agreement with regulatory authorities" for the relatively small, short trials. He expects the time from the filing of the investigational new drug application to the finish of the Phase III trial will be "under four years, and I think that will be unique."

The two-day BIO conference ended Thursday.