Ironwood Pharmaceuticals and its partners, Forest Laboratories and Almirall, are in phase III development with linaclotide, an oral peptide that activates GCC receptors in the intestinal tract. The targeted indications are chronic constipation and constipation-predominant irritable bowel syndrome (IBS-C). The companies have reported results for the two pivotal chronic constipation trials and expects to report top-line data for the IBS-C trials in Q4 2010; an NDA filing is scheduled for mid-2011. Results for the chronic constipation trials were statistically robust, but questions remain regarding the clinical relevance. Some uncertainty also remains regarding the outcomes of the IBS-C trials, the impact of new FDA guidance, overhang from FDA's prior experience with IBS therapies (Zelnorm was withdrawn from market and Lotrenox subjected to restricted access), and the implications of linaclotide's unique pharmacology. Finally, this report explores the likelihood of market success, should FDA approve this agent.

Published: August 10, 2010

Number of pages: 34

Authors: Dr. Ellen Brady and Dr. Ilana Fogelman

TABLE OF CONTENTS:
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INTRODUCTION
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DISEASE OVERVIEW
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1. Irritable bowel syndrome
2. Functional (idiopathic) constipation
3. Current treatments
- Anti-depressants
- Tegaserod (Zelnorm, Novartis) – withdrawn
- Lubiprostone (Amitizia, Sucampo and Takeda)
- Alosetron (Lotronex, Prometheus) – available through controlled-distribution program

LINACLOTIDE CLINICAL DATA
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1. Early phase I/II kinetic and pharmacodynamic data
- Study MCP-103-004: Chronic constipation pilot
- Study MCP-103-005 00: IBS-C pilot trial
2. Phase IIb
- Study MCP 103-201: chronic constipation phase IIb trial
- Study MCP 103-202: IBS-C Phase IIb trial
3. Phase III
- Studies MCP 103-303 and LIN MD-01 – phase III chronic constipation
- Studies LIN MD-31 and MCP 103-302 – Phase III IBS-C

CLINICAL AND REGULATORY DISCUSSION
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1. What is the probability that the phase III IBS-C trials will succeed?
2. Are available results clinically relevant?
3. Does the program meet FDA standards?
4. Will there be overhang from FDA’s experience with other IBS therapies?
5. Are there any relevant issues related to linaclotide’s unique mechanism of action?

MARKET ISSUES
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1. Overview
2. Competitive comparison of Amitiza and linaclotide profiles
3. Pipeline products

SUMMARY OPINION
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