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In one of the larger U.S.-led Series B rounds, NeurAxon Inc. raised $32 million for its approach to pain drugs that targets neuronal nitric oxide synthase (nNOS), with the lead candidate - oral NXN-188, which also is an agonist of 5-hydroxytryptamine (5-HT) - set to enter Phase IIa trials for migraine some time this quarter.

The Waltham, Mass.-based firm has enough cash to easily get into 2009, when as many as five trials could be ongoing, possibly even some Phase II studies, said CEO Lawrence Bloch. At that point, NeurAxon would consider a Series C financing, collaboration or initial public offering.

Still at the preclinical stage are an intravenous form of NXN-188 for rescue migraine, along with other oral compounds for chronic tension type headache, migraine prophylaxis and neuropathic pain. There's also a preclinical drug that combines the nNOS enzyme strategy with an opiate.

As a target, nNOS has been appealing, but getting a drug that nails it without hitting either of the two other types - endothelial (eNOS) and inducible (iNOS) - has been tough, and no other researchers have been able to do it, Bloch said.

Endothelial and neuronal NOS are "very closely related, structurally," he said, comparing them to overlapping bull's eyes. "If you hit both of those, you can get blood pressure increases. That's not acceptable in the post-Vioxx world.

"There've been very few dual-mechanism-of-action-by-design small molecules" like NXN-188, although some have been discovered to have dual mechanisms later, Bloch noted. "We're not trying to do a me-too or a knockoff combination of existing drugs."

He credited the company's founding scientific team - which includes John Andrews, Suman Rakhit and Shawn Maddaford, all previously from big pharma firms - for the success so far with the internally done work.

"Now that we've got that [dual-action] validation, we can start parallel processing similar molecules," beginning with the nNOS scaffold and replacing the 5-HT agonism with, for example, an opiate, as in the case of an oral compound in the pipeline for severe pain, Bloch said.

Nitric oxide, once known mainly as an air pollutant found in car exhaust and cigarette smoke, was found in humans through experiments that in 1988 earned the Nobel Prize for three scientists, who discovered that it's closely involved not only in blood pressure but immunity and neurotransmission. Firms such as NicOx SA, of Sophia Antipolis, France, are focused on providing more nitric oxide. "We're trying to do the converse," Bloch said.

Trying for inhibition of iNOS is Kalypsys Inc., of San Diego, which in April started a second Phase I trial with topical KD7040 for neuropathic pain. The company expects to finish the multiple dose trial later this year. The first focus is on postherpetic neuralgia.

In NeurAxon's Series A financing, about $16 million was raised, with approximately $10 million of that amount used between the founding of the company in summer 2004 and the recent finish of the Phase I trial with NXN-188.

NeurAxon, with 13 employees, was established as a spinout of a medicinal chemistry company called MCR Research Inc., of Toronto, and mostly has kept below the radar until now.

"I've always been of the belief that you're better off being conservative with your profile until you have something meaningful to discuss," Bloch said.

Apart from inhibiting nNOS without touching eNOS (as NXN-188 does), developing pain drugs is notoriously tricky, he acknowledged - partly because of trial design and partly because of subjective measures of outcomes, such as patient questionnaires.

"In the pain area, you really need to bring significant clinical benefit to the patient, so you can overcome some of that inherent noise," Bloch said.

Still, companies reported notable successes in the space last week. Frazer, Pa.-based Cephalon Inc., with positive data last week from a third Phase III trial of Fentora in noncancer breakthrough pain, plans to file for approval in that broader indication for the compound later this year. A fentanyl buccal tablet, Fentora won approval in late 2006 for use in opioid-tolerant cancer patients with breakthrough pain. Anesiva Inc., of South San Francisco, won approval of Zingo, a lidocaine product for needle-stick pain in patients ages 3 to 18. (See BioWorld Today, Aug. 17, 2007, and Aug. 20, 2007.)

The quest for better pain drugs continues to draw pharma interest, as shown by the potential $1 billion deal between Research Triangle Park, N.C.-based Icagen Inc. and Pfizer Inc., of New York, to develop sodium ion channel modulators for pain. (See BioWorld Today, Aug. 15, 2007.)

NeurAxon's Series B was led by new investors Delphi Ventures and OrbiMed Advisors LLC. Also participating in the round were BDC Venture Capital, Genesys Capital Partners, H.I.G. Ventures, NeuroVentures Fund, Ventures West Capital Ltd. and CEO Bloch. Deepa Pakianathan, general partner at Delphi, and Samuel Wertheimer, principal of OrbiMed, have been appointed to NeurAxon's board.

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