West Coast Editor

Elixir Pharmaceuticals Inc. entered a licensing deal with Bristol-Myers Squibb Co. to develop and sell the latter's preclinical growth hormone secretagogue, BMS-604992, and five related compounds.

"We've basically licensed in their entire program," said William Heiden, Cambridge, Mass.-based Elixir's president and CEO, noting that it's the first development deal for research-based Elixir.

In the pact, expected to be made public today, Elixir will pay BMS an up-front license fee comprising undisclosed cash and stock, plus development-based milestone payments and royalties if the drug is approved.

BMS-604992, which privately held Elixir has renamed EX-1314, mimics the body's endogenous growth hormone secretagogue, ghrelin, by binding to its receptor resulting in the release of growth hormone.

Slated to enter the clinic in six months to nine months, the oral drug is a potential therapy for small-for-gestational-age children and for degenerative changes in elderly peoples' cardiovascular, muscular and central nervous systems, as well as other diseases.

More specifically, Heiden said Elixir's strategy is to aim at "beachhead indications" - that is, smaller ones with a quicker development path, such as cancer cachexia (wasting) or HIV lipodystrophy (fat abnormalities).

"As you develop these compounds in small indications, you can capture in human data [evidence of] whether they can be developed for larger, more interesting indications, such as idiopathic short stature," he said. Current therapies for that indication "are injectable peptides, which are very difficult and inconvenient for patients," who are children.

First pinpointed as the peptide hormone that liberates growth hormone from the anterior pituitary and found mainly in epithelial cells in the stomach, ghrelin later was discovered to exert effects on appetite and energy balance. Ghrelin research has been viewed as a prospect for obesity therapies, among others, and research in the field has grown hotter in the past few years.

Before the BMS deal, "we were working on a ghrelin antagonist to treat obesity or Type II diabetes," Heiden said. "This [BMS lead compound], on the other hand, is a ghrelin agonist," the likes of which have been studied over the years by such pharmaceutical giants as Pfizer Inc. and Merck & Co. Inc., he said.

"There was a big chase to develop it for frailty, but that's really hard to measure clinically, and most of the large companies gave up," Heiden said. Lately, though, some have taken their drug candidates off the shelf and begun to study them further.

On the ghrelin agonist front, Heiden acknowledged efforts by Rejuvenon Corp., of The Woodlands, Texas, which last June raised $37 million to push along its Phase I oral ghrelin mimetic RC1291. The compound has proved it can boost appetite in humans and in animal models of wasting disorders. (See BioWorld Today, June 25, 2004.)

Heiden said Roy Smith, the chairman, founder and chief scientific officer of Rejuvenon, was the "grandfather" of the ghrelin program at Merck Research Laboratories and now is developing the ghrelin mimetic for cancer cachexia.

"There's been some controversy around using a pro-growth drug like a ghrelin agonist in a cancer patient," he added, and that's one reason Elixir plans to focus first on HIV lipodystrophy.

Tranzyme Pharma Inc., of Research Triangle Park, N.C., also has been active in ghrelin research. The firm in November reported encouraging preclinical data with its lead agonists at the International Symposium on Growth Hormone Secretagogues in Camogli, Italy.

Two Canadian firms also are gardening in the ghrelin patch. AEterna Zentaris Inc., of Quebec, said last March that it is developing ghrelin antagonist compounds for obesity, plus potential cancer agents. Theratechnologies Inc., of Montreal, is working on unacylated ghrelin for Type II diabetes and related insulin-resistance disorders, as well as ThGRF, described as a stabilized analogue of the growth hormone-releasing factor, for HIV-associated lipodystrophy.

At the end of March, the FDA and Theratechnologies agreed on a Phase III protocol for ThGRF, which is said to "induce the production and secretion of growth hormone in a specific, physiological, controlled and pulsatile fashion." (See BioWorld Today, April 1, 2005.)

Elixir has been watching Rejuvenon closely.

"These are different molecules, so they can't prevent us from getting on the market," Heiden said. Even if Rejuvenon wins FDA clearance for its ghrelin agonist first, "a few months or a year [ahead] is fine with us," he added, since the demand seems likely able to accommodate more than one, and the two products' labels would be different.

In developing a ghrelin antagonist, on the other hand, Elixir seems definitively ahead of the pack. That candidate comes out of the firm's Optimal Aging platform, and Elixir will pursue it first for obesity or diabetes.

"Beyond that, you look at the drug's ability to prevent metabolic diseases, and then to prevent age-related diseases," Heiden said.

Elixir, which began operating in 2000, has focused on genes related to long life. In early 2003, the firm merged with similarly focused Centagenetix Inc., with the new company raising $17 million in the initial closing of a Series B round of financing. Later that year, Elixir closed the second round of its Series B financing, adding $19 million. (See BioWorld Today, Jan. 14, 2003, and Oct. 14, 2003.)

"What came with that is a database of now nearly 3,000 serum and DNA samples of centenarians across the world," Heiden noted.

Since starting operations, Elixir has raised a little more than $50 million, he said, "enough cash to take us into next year, given our current burn rate," but a Series C round is expected in the third quarter to fund the ghrelin agonist project, as well as the ghrelin antagonist program behind it.

"We're also working on the in-licensing of commercialized drugs," Heiden said.

Elixir has been involved in ghrelin research for "about four years," he said, and the investigations have taken scientists down literal and figurative metabolic pathways to probe the ways that, for example, a drug might help affect the long-known link between lowered calorie intake and longevity.

One day, he said, there might be a pill so "you can have your cake and live a long life, too."