West Coast Editor

Microbia Inc.'s potential $330 million deal - $70 million up front as a licensing fee - with Forest Laboratories Inc. for the Phase IIb gastrointestinal drug linaclotide could let the pair jump into the $500 million-plus market gap left earlier this year when Novartis AG pulled its compound for constipative irritable bowel syndrome, Zelnorm, off the shelves due to safety concerns.

Peter Hecht, CEO of Cambridge, Mass.-based Microbia, said $125 million of the $330 million would come as "near-term" payments (including the license fee), but he could not be more specific.

"We've been after this opportunity for three or four years," he added, noting that the "enthusiasm Novartis received for Zelnorm was a good indication of how big the unmet patient need is."

Microbia and Forest will split U.S. development and marketing costs as well as any profits, and Microbia stands to get royalties from sales in Mexico and Canada, where Forest holds exclusive rights to the compound, an agonist of the guanylate cyclase type-C receptor found on the lining of the intestine. The full partnership was the most important part of the deal for Microbia, Hecht said.

"We presented our Phase IIa data in chronic constipation last fall at one of the GI meetings, and immediately following that, every pharmaceutical company that had significant U.S. primary care capability got very interested and came at us," Hecht said.

Microbia officials "had very extensive discussions with many of them," he added, and "quite a lot of semifinalists for the deal" emerged - some with even better near-term offers and overall cash packages.

Linaclotide, a 14-amino-acid peptide in capsule form, is undergoing Phase IIb tests in two indications, chronic constipation and constipation-predominant IBS, with a total of about 700 patients expected to enroll in the pair of trials - 400 in IBS and 300 in chronic constipation. Microbia expects to present data from the trials in the first half of next year, and Phase III studies would begin in the second half.

About one in six adults in developed countries suffers from IBS, the most common disorder diagnosed by gastroenterologists, and the constipative type makes up 30 percent to 40 percent of all cases. The market for chronic constipation is even larger. As many as 26 million people deal with the problem in the U.S., and Microbia's composition-of-matter patent application for linaclotide is pending.

Other companies are marching ahead in constipative IBS, including Bethesda, Md.-based Sucampo Pharmaceuticals Inc., which said Monday the FDA accepted its supplemental new drug application for lubiprostone, a chloride channel activator already cleared as Amitiza for chronic idiopathic constipation - the only such prescription drug approved by the FDA. Phase III trials are testing the compound in opioid-induced bowel dysfunction.

Ryuji Ueno, chairman and CEO of Sucampo, said Phase III trials with Amitiza in CIC included a group of IBS patients who made up about 20 percent of the whole, and they showed "very significant improvements."

Constipative IBS is looking good to other firms as well, especially after Basel, Switzerland-based Novartis withdrew Zelnorm (tegaserod) because of possible cardiovascular side effects - though, under a restricted access program, the drug is available "if you can find a physician who will prescribe it to you," Hecht said.

Brad Fackler, vice president of commercial operations for Sucampo, said access to Zelnorm is "very limited. The critical thing is all of the responsibility and accountability [for prescribing Zelnorm] falls to the doctor." In constipative IBS, the market is "wide open, at this point," he said.

Among other players is Theravance Inc., of South San Francisco, whose TD-5108, like Zelnorm, targets the 5-HT4 receptor but with potentially more specificity. TD-5108 has yielded positive Phase II results in chronic constipation, but partner GlaxoSmithKline plc, of London, skipped a licensing option earlier this month. (See BioWorld Today, Sept. 10, 2007.)

The other two types of IBS are diarrhea predominant and alternating, and Raleigh, N.C.-based Salix Pharmaceuticals Inc. this month reported top-line Phase IIb results with the antibiotic rifaximin in the treatment of diarrheic IBS. The firm expects to meet with the FDA later this year and begin Phase III trials in the first quarter of 2008. Rifaximin already is sold as Xifaxan in 200-mg tablets for the treatment of travelers' diarrhea caused by noninvasive E. coli. (See BioWorld Today, Sept. 6, 2007.)

In June, Pharmos Corp., of Iselin, N.J., started a Phase IIb trial with dextofisopam in diarrheic and alternating IBS, enrolling 480 patients. The primary endpoint of "adequate overall relief" of IBS symptoms was met in a Phase IIa study (p=0.033). Dextofisopam, an enantiomer of racemic tofisopam, already is marketed in 15 countries outside of the U.S.

With Phase II-stage linaclotide, Microbia and Forest have "a long way to go," Hecht conceded, but the drug's edge apparently lies in its mechanism of action. "Because the receptor part is exposed into the GI lumen, we didn't need exposure outside of the gut," he said. "That was done on purpose when we were designing the compound." Safety results have proved encouraging.

"We've seen no nausea signal, and really the only safety signal we've seen is an extension of the intended pharmacology," Hecht said. Some patients on higher doses of linaclotide had occasional loose or watery stools, but those resolved quickly.