Among the army of acronyms that marches across the pages of biomedical research reports is PPAR, standing for "perixosome proliferator-activated receptor," which entered the limelight earlier this month as a result of a ruling from an outfit known by yet another acronym: the FDA.
Drugs - mostly in the glitazone family - targeting PPARs have been kicking around for a while. Two marketed ones are GlaxoSmithKline plc's Avandia (rosiglitazone) to control blood sugar in Type II diabetes and Eli Lilly and Co.'s Actos (pioglitazone) for the same indication. Others, not glitazones, are in the works.
A major challenge in developing a diabetes drug is to find one that boosts insulin sensitivity, but doesn't make the body create more fat cells, thus worsening the obesity that often accompanies, aggravates and might have created the disease. PPARs seem like just the ticket, keeping fat and sugar metabolism in line. The problem with them, however, could be worse than fat. It could be cancer.
At a recent Drug Information Association meeting and in letters to PPAR drug developers, the FDA said rodent data related to a number of PPAR agonists (gamma, alpha or dual agonists) yielded carcinogenicity findings that reached an unsafe level. As a result, the agency declared that any PPAR trials that would last longer than six months in duration would not be allowed to begin until two-year rodent toxicity studies were completed and handed over to the FDA for consideration.
That's not much of a problem for companies with early stage research in the area, such as Plexxikon Inc., but it turns out to be quite a delaying factor for the likes of Ligand Pharmaceuticals Inc., which had naveglitazar, formerly known as LY519818, nearly ready for Phase III trials in Type II diabetes.
Naveglitazar - a gamma-dominant, alpha-gamma dual agonist partnered with Lilly that came out of a research collaboration between Lilly and Ligand - was not among the unspecified number of PPAR agonists cited by the FDA as worrisome, but it fell under the rule just the same. Ligand said Phase III trials would be pushed back 18 months to 24 months, while the rodent data are gathered.
With a respected product for cutaneous T-cell lymphoma, Targretin (bexarotene, which once was part of the same research deal with Lilly), already on the market, Ligand hardly was sent reeling by the unfortunate news on the PPAR drug. But the FDA's edict has wide ramifications, noted Peter Hirth, CEO of Plexxikon, who said he could think of no major pharmaceutical firm that isn't doing some work in the PPAR space. 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.
The cancer effect, Hirth told BioWorld Financial Watch, is a riddle.
"It's sometimes difficult to know whether these cancer events were because of the chemical nature of the compound or because of a mechanism-based effect," he said. "That hasn't really been separated out."
The trouble "might have to do with the chemical nature, in part," he said. "If I read the literature correctly, several [PPARs] have been shown to have some effects on the bladder, but not consistently, so it may have to do with the pharmacology and distribution" in the body.
"Remember, most of them have been in the glitazone family," he said. "We think a pan-PPAR' would be a better way to go than what has been tried so far. Our approach from the get-go has been to develop several [at a time]."
Plexxikon plans to file an investigational new drug application in the fall and hopes to start Phase I trials before the end of the year, which gives the company plenty of time to finish and submit the rodent data that the FDA now requires.
"We knew it was coming," Hirth said of the agency's decree, which "affects those [companies such as Ligand] who have advanced programs and were delaying this study. You know, typically in the drug discovery business, you do these cancer studies that everybody has to do as late as possible, so you have them when you're ready to file your NDA. It's a very expensive, time-consuming study, and you want to do it as late as possible."
He said that if a company is managing its budget correctly and hasn't seen anything that suggests a drug isn't safe, a cancer study wouldn't be done until near NDA time.
Hirth called diabetes "a big issue for our health care system. It's a patient population that is growing and growing, and some of this [PPAR work] could benefit pre-diabetics. If you can manage, delay or even prevent the disease, you'd have a major contribution."
Among those other than Plexxikon in the initial stages of shooting for the prize is the Swiss firm CareX SA, which in April raised €25 million for its work. Even with PPARs' potential, regulators on both sides of the ocean have reason for expressing caution, Hirth said.
"PPARs activate a series of genes, and that might have some effect [on the variance in the cancer effect]," he said. "Nobody really knows for sure. That's why the FDA takes the position of being rather safe than sorry."