West Coast Editor

An FDA glitch over rodent toxicity data has stalled for as long as two years the start of Phase III trials with Ligand Pharmaceuticals Inc.'s naveglitazar, formerly known as LY519818, for Type 2 diabetes.

Ligand's stock (NASDAQ:LGND) took the news in stride, closing Friday at $14.16, up 35 cents.

Company officials could not be reached, but Peter Hirth, CEO of Berkeley, Calif.-based Plexxikon Inc. - with an early stage lead product in the same general class as the Ligand drug - said the FDA rule "levels the playing field" in a competitive space.

"There is not one big [pharmaceutical] company I know of that doesn't work on this," he told BioWorld Today.

Discovered through a collaboration with Eli Lilly and Co., of Indianapolis, the Ligand drug is a peroxisome proliferator-activated receptor (PPAR) gamma-dominant, alpha gamma dual agonist. PPARs are a sub-family of intracellular receptors that regulate fat and sugar metabolism.

The FDA said any PPAR trials scheduled to last longer than six months are not allowed to start until two-year rodent toxicity studies are finished and submitted to the agency for consideration. For naveglitazar, that means a delay of 18 months to 24 months. Ligand said data are expected to be available for evaluation next year.

At a recent Drug Information Association meeting and in letters to PPAR drug developers, the FDA said rodent data reviewed by the agency for a number of PPAR agonists (gamma, alpha or dual agonists) - but not including naveglitazar - came up with unsafe carcinogenicity findings, and the six-month rule has been devised to alleviate the agency's concerns.

The cancer effect remains mysterious, Hirth noted, and does not happen with every PPAR, which is why Plexxikon takes a broader, "pan-PPAR" approach. PPAR drugs already on the market include London-based GlaxoSmithKline's Avandia (rosiglitazone) to control blood sugar in Type 2 diabetes and Lilly's Actos (pioglitazone) for the same indication.

"These are clearly efficacious compounds," Hirth said.

The Ligand-Lilly collaboration that yielded naveglitazar dates back to 1997 and first included Targretin (bexarotene), but that compound was later dropped from the deal in favor of PPARs. Ligand has progressed Targretin alone, with the product gaining approval in December 1999, and Ligand recently learned the Centers for Medicare and Medicaid Services will provide reimbursement for Targretin for patients with cutaneous T-cell lymphoma. (See BioWorld Today, Oct. 21, 1997; Feb. 17, 1999; and April 15, 2002.)

Oral naveglitazar seems to work. A Phase II six-arm parallel study in 151 patients with Type 2 diabetes yielded positive results, Ligand said. Four doses, in a dose-dependent fashion, provided a statistically significant reduction in the primary endpoint variable: fasting serum glucose from baseline. Other outcomes proved encouraging, and full data are to be presented at an upcoming scientific meeting, San Diego-based Ligand said.

Meanwhile, in the race for new PPARs, companies such as Ligand that are further along in their research and gearing up for larger trials, must wait to start enrolling until they get the rodent data the FDA wants - while earlier-stage firms such as Plexxikon benefit from the handicap, since they can conduct the studies required by regulators while they are preparing for clinical trials.

Earlier this year, Plexxikon Inc. raised $15 million in venture financing to complete a Series B extension round, saying it would use the funds to accelerate its pan-PPAR agonist PLX204, still in toxicology studies. (See BioWorld Today, May 27, 2004.)

"We're planning to file an [investigational new drug application] in the fall and we'd like to start our Phase I trials before the end of the year," Hirth said.

Separately, Ligand said TAP Pharmaceutical Inc. chose another selective androgen receptor modulator (SARM) as a second clinical candidate, triggering a $1 million milestone payment. The drug will be developed for major androgen-related diseases such as hypogonadism, osteoporosis, male hormone replacement, frailty and male and female sexual dysfunction. Ligand's potential $44 million SARMs deal with TAP, of Lake Forest, Ill., was signed several years ago. (See BioWorld Today, June 27, 2001.)