National Editor

With positive Phase I data in hand regarding the pharmacokinetics of its Transported Prodrug version of gabapentin, XenoPort Inc. raised $37 million in a private equity financing for the next step - experiments (already under way) with a sustained-release formulation of the compound, and Phase II trials, due later this year.

"The lead program will certainly use the lion's share [of the cash]," said William Harris, senior vice president and chief financial officer of privately held XenoPort, which has a pair of other prodrugs in preclinical stages.

Santa Clara, Calif.-based XenoPort's Engineered Drug Transport approach deploys medicinal chemistry to devise therapeutic compounds that engage the body's own cellular transport systems to boost the drugs' pharmacokinetic performance. The idea is to modify off-patent drugs, creating new patentable Transported Prodrugs with improved medicinal properties.

"Our technology is [designed] to proactively exploit active transport mechanisms expressed throughout your GI tract and responsible for digestion of nutrients in your diet," Harris said.

The technology exploits two such mechanisms: solute carrier transporters, which are cell-membrane proteins that engage molecules on one surface of the membrane, move the molecules across the membrane and release them on the opposite side; and transcytosis, whereby a molecule or particle engages a receptor on one surface of a cell, inducing the cell to engulf or endocytose the material into vesicles, which then are carried across the cell and let go on the other side.

It's about beating not only toxicity issues but also the often drug-foiling foursome of poor absorption, distribution, metabolism and excretion, known as ADME to the scientists who are constantly trying to find new methods of improving them.

Gabapentin, approved in the U.S. as adjunctive therapy for partial seizures and for management of post-herpetic neuralgia, is sold by New York-based Pfizer Inc. as Neurontin, but is "used extensively off label for neuropathic pain," Harris said. Since the drug's approval in 1994, Neurontin has been prescribed to almost 10 million patients.

The problem, he said, is that gabapentin (also known as 1-[aminomethyl] cyclohexaneacetic acid) is not dose proportional.

"As you increase dose, you do not increase exposure to the patients, so there's a ceiling on the level of drug you can get in the blood," Harris told BioWorld Today. "We believe we can go beyond that."

Data disclosed in January from the Phase I trial indicated success with the Transported Prodrug version, a new chemical structure called XP13512, and XenoPort has a Phase I trial study in progress with a sustained-release formulation. Gabapentin ordinarily is dosed three to four times a day. Data are expected around the end of the first quarter, Harris said, and Phase II trials likely will begin later in 2004.

Preclinical work has been done with two other compounds for which XenoPort also intends to develop oral Transported Prodrugs. One is baclofen for spasticity, sold as Lioresal by Novartis AG, of Basel, Switzerland. The other is propofol, an intravenous anesthetic sold as Diprivan by London-based AstraZeneca plc. Propofol has been shown at lower doses to relieve intractable migraines, as well as nausea and vomiting, Harris said.

"Our goal is to file an [investigational new drug application] by the end of the year, but we haven't said which of the two programs it will be," he said.

Gabapentin is unpartnered, but XenoPort entered a deal about a year ago with ALZA Corp., a unit of New Brunswick, N.J.-based Johnson & Johnson, to improve delivery of three undisclosed, existing drugs. (See BioWorld Today, Jan. 8, 2003.)

The financing was led by Granite Global Ventures of Menlo Park, Calif. Other new investors include AIG SunAmerica Ventures, of Los Angeles, and WestRiver Capital, of Seattle.

Previous investors also taking part include Alejandro Zaffaroni, a well-known biotechnology figure who has founded companies that include Symyx Technologies Inc. (located, like XenoPort, in Santa Clara), ALZA Corp. and Affymetrix Inc.; Arch Venture Partners, of Chicago; CMEA Ventures, of San Francisco; Frazier & Co., of Seattle; HBM BioVentures AG, of Zurich, Switzerland; Lilly BioVentures, of Indianapolis; Lombard Odier & Cie, of Geneva; Lotus BioScience Ventures, of Hong Kong; Novartis BioVentures Ltd., of Basel, Switzerland; OrbiMed Advisors, of New York; The Invus Group, of New York; and Venrock Associates, of Menlo Park, Calif.

Montgomery & Co. LLC, of Santa Monica, Calif., assisted XenoPort with some of the financing and participated in the round.

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