Staff Writer

Ironwood Pharmaceuticals Inc. and partner Forest Laboratories Inc. reported positive results from two pivotal Phase III trials of its bowel drug candidate linaclotide in chronic constipation.

Both trials met their primary goal of achieving a complete spontaneous bowel movement (CSBMs) in patients with chronic constipation. The 12-week CSBM overall responder rate was 16 percent in the lower dose, 133-mcg linaclotide group and 21.3 percent in the higher 266-mcg linaclotide group.

The studies also met their secondary objectives, which measured bloating, abdominal discomfort and average weekly CSBMs.

Ironwood and Forest currently are enrolling two additional pivotal Phase III trials to assess the safety and efficacy of linaclotide in patients with irritable bowel syndrome (IBS) with constipation, and results are expected in the second half of calendar year 2010.

David Amsellem, an analyst with Piper Jaffray, pointed out in a research note that Forest is not planning to file for regulatory approval for linaclotide until the data from the IBS-C Phase III studies are available. And that may pose a risk.

Amsellem wrote, "We believe the IBS-C studies are riskier than the CC [chronic constipation] studies, given the high incidence of placebo responses typically seen, largely a function of endpoints that assess global IBS symptoms, which encompass pain and bloating." But he said that a setback in IBS-C would not preclude a linaclotide filing and mean approval solely in CC, noting that Amitiza was approved in 2006 for CC and then in 2008 for IBS-C.

Linaclotide is in a crowded field of other bowel drugs being developed by San Carlos, Calif.-based Nektar Therapeutics Inc., Raleigh, N.C.-based Salix Pharmaceuticals Ltd., San Diego-based Tioga Pharmaceuticals Inc. and others.

Robert Hazlett, an analyst at BMO Capital Markets who tracks Forest Labs, told BioWorld Today, "The market is large enough for multiple competitors, and if this drug [linaclotide] is safe enough, it could have decent utilization in chronic constipation and IBS-C."

He issued a research note predicting potential peak sales of $500 million, adding that "upside potential exists if linaclotide's adverse events are benign."

In the Phase III studies, the most common adverse events in linaclotide-treated patients were diarrhea, flatulence and abdominal pain.

Current treatment options for IBS are limited. Lotronex has a restricted label, and Zelnorm has been removed from the market. Although Zelnorm was pulled from the market in 2007, it still may be used in certain emergency situations.

As many as 34 million Americans suffer from symptoms associated with CC, and 8.5 million patients have sought treatment. As many as 11 million people in the U.S. suffer from IBS-C.

Amitiza (lubiprostone), made by Bethesda, Md.-based Sucampo Pharma Americas Inc. and partnered with Osaka, Japan-based Takeda Pharmaceutical Co. Ltd., currently is U.S.-approved to treat IBS in adult women and chronic idiopathic constipation (CIC) in adults. Lubiprostone is in an ongoing Phase III trial in Japan as a potential treatment for CIC.

Cowen & Co. analyst Ian Sanderson issued a research note stating that the linaclotide data "appear superior to Novartis AG' Zelnorm and Johnson & Johnson's prucalopride."

Sanderson said that his firm's clinical consultants set the CSBM data for Zelnorm and prucalopride as the gold standard for chronic constipation efficacy. "Linaclotide's efficacy appears to exceed the standard, and with a mechanism devoid of the [cardiovascular] signals that sidelined Zelnorm and prucalopride," he wrote.

Linaclotide, a first-in-class compound, is an agonist of guanylate cyclase type-C, a receptor found on the lining of the intestine. An issued composition-of-matter patent for linaclotide provides protection to 2025.

Ironwood and Forest entered their 50-50 collaboration in 2007 to co-develop and co-promote linaclotide in the U.S. In April 2009, Ironwood licensed to Almirall the European rights to develop and commercialize linaclotide. (See BioWorld Today, May 5, 2009.)

Published  November 4, 2009