Editor

Peter Hirth, CEO of Plexxikon Inc., doesn't mind crowing about the fact that, when the FDA issued an edict regarding PPAR drug development this summer, he was one of the few industry figures with enough gumption to talk about what it meant. (See BioWorld Financial Watch, July 19, 2004.)

The rule said clinical trials of drugs in the class targeting PPARs, or peroxisome proliferator-activated receptors, expected to last more than six months could not begin until two-year rodent toxicity studies are finished and submitted to the FDA.

There was trouble with the rodents. Findings reviewed by the agency for a number of PPAR agonists - including gamma, alpha or dual agonists - showed indications of cancer. To fix heart disease or diabetes and cause tumors is not to fix much.

Plexxikon's work was in early stages and not affected by the FDA's decree, maybe putting Hirth at extra liberty to talk about the matter. Less fortunate was Ligand Pharmaceu-ticals Inc., which had naveglitazar (formerly known as LY519818, partnered with Eli Lilly and Co.) poised for Phase III trials in Type II diabetes. The compound is being held up for 18 to 24 months while the rodent tests are done.

Although many scientists were skeptical about the notion that all PPARs might pose a cancer risk, the FDA episode cast something of a pall over the entire research landscape - and existing PPARs aren't danger-free, noted Hirth late last month.

GlaxoSmithKline plc's Avandia (rosiglitazone) to control blood sugar in Type II diabetes and Actos (pioglitazone) for the same indication from Lilly "have dramatically improved safety [profiles] but still are not that safe," Hirth told BioWorld Financial Watch. "They still have issues with edema and can have cardiac toxicity, and increase in body weight."

Hirth spoke on the occasion of a whopping potential $372 million deal with Wyeth, which apparently was undaunted by the FDA's professed jitters and put pen to paper with Plexxikon in an agreement using PPARs to go after diabetes and other metabolic disorders.

Alpha PPARs have been on the market the longest, followed by gammas and the more recently identified deltas. Gammas have not been without problems, the first two getting banished from sale because of liver toxicity.

If it's not certain that all PPARs bring side-effect trouble, it's fairly certain that using them together can be tricky, he said.

"When you combine them, many times you have things that all of a sudden interact and you get a worsening of the safety profile," he said. "We thought it would be a great idea to combine all these activities into one compound, so you're only dealing with one type of toxicity." The challenge, though, is that "these three receptors are actually not that similar."

Plexxikon uses co-crystallography and computational methods to "define from the get-go a target profile that we want to have," and came up with PLX204, which modulates the function of three related targets - PPAR alpha, delta and gamma - to regulate levels of glucose, triglycerides, free fatty acids, HDL (the "good cholesterol"), as well as energy expenditure, in a once-daily pill. Potentially, at least.

Kathleen Glaub, president and chief financial officer, explained that in co-crystallography, "we crystallize the protein together with a potential compound that we think might be good. Then we shoot an X-ray beam through it and see how the compound binds to the active site of the protein target."

In the deal, Wyeth is paying more than $22 million, including an up-front license fee and multiyear research funding, and milestones that could total almost $350 million as drugs are developed and commercialized, plus royalties.

Wyeth also will provide a loan to fund Plexxikon's share of clinical efforts.

"This is a very complicated story," Hirth said, referring to attempts to gain the varied benefits from PPARs at once. "It's kind of like a balloon. When you punch in one side, it comes out somewhere else."

And the field for diabetes is competitive, inside and outside of PPARs, as most industry observers understand. Bristol-Myers Squibb Co. and Merck & Co. Inc. in April entered a potential $375 million deal focused on muraglitazar, the dual PPAR agonist from BMS.

Other potential therapies with differing mechanisms of action are coming down the pike, including exenatide, based on a protein that comes from the saliva of the Gila monster. Last week, Lilly, Amylin Pharmaceuticals Inc., and Alkermes Inc. said they will start in the first quarter of 2005 a Phase II multidose study of exenatide long-acting release in Type II diabetes using a once-a-week dosing regimen.

And there's always insulin. In September, Nektar Ther-apeutics Inc. said data reported at the European Association for the Study of Diabetes meeting in Munich, Germany, showed that Exubera, an inhaled form, was effective and well tolerated in controlling blood glucose levels over a two-year period in Type II diabetics. The findings were reported by Pfizer Inc. and Sanofi-Aventis. Nektar develops and provides the inhalers and the powdered insulin for Exubera.

Plexxikon, for its part, will be using its technology to take aim at plenty of other indications. The method has proved solid not only for Plexxikon, but in the company's kinase target collaboration with Genentech Inc.

"They came to us with a target and in five months we came to them with a lead candidate," Hirth said. "We will be applying that method to three of the most important protein families, all of which are incredibly rich in targets." Aside from PPARs, Plexxikon will focus on kinases and phosphodiesterase (inhibitors of which yielded Viagra from Pfizer).

"By next year we'll have three candidates in three clinical trials," Hirth said, noting the investigational new drug application for the drug with Wyeth is coming soon. "Our next one is in inflammatory disease. We actually prevent the production of inflammatory cytokines. You pick your entry indication - usually it's rheumatoid arthritis because the trials are less complicated than, say, multiple sclerosis or inflammatory bowel disease, but eventually these indications are typically all explored."

The possibilities are wide and they can be investigated quickly. "Some people cannot believe the things we do," Hirth said.