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The Discovery of Linaclotide

When we talk about the art and science of making medicines, we’re referring to an incredibly complex and challenging journey that can take more than a decade. For our first approved medicine, linaclotide, this journey began with our team’s pioneering research on the intestinal enzyme guanylate cyclase-C (GC-C).

GC-C is found mainly on the surface of the intestine and is thought to be a potential target for a variety of gastrointestinal diseases. Our chief scientific officer, Mark Currie, discovered the natural hormones that activate GC-C and brought a unique understanding of its pharmacology to Ironwood. His team began designing GC-C agonists – molecules that activate GC-C – but creating a molecule that selectively hit its target was only half the battle. For patients to one day be able to take the medicine orally, it would also need to survive the harsh acidic environment of the stomach so that it could reach GC-C in the intestine.

The molecule that resulted from this effort was linaclotide.

Ironwood was built on a passion for pharmacology—the study of how molecules interact with and impact the body—so we quickly launched nonclinical studies to evaluate linaclotide in cells and tissues. What we discovered was a novel effect on reducing abdominal pain: in our nonclinical studies, linaclotide decreased the activity of pain-sensing nerves (the clinical relevance of the effect on pain fibers in nonclinical studies has not been established). The studies also demonstrated linaclotide increases the secretion of fluids into the intestine and improves transit through the bowels.

Based on what we learned from these early studies, we quickly prioritized linaclotide for further development and study as a potential treatment for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Our conversations with doctors and patients had revealed an unmet need in this area, particularly in the treatment of IBS-C, for which abdominal pain is a hallmark symptom.

Linaclotide went on to become the first GC-C agonist approved in the U.S., establishing GC-C agonists as a new class of medicines.

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INDICATIONS AND USAGE
LINZESS (linaclotide) is indicated in adults for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC).

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS

LINZESS is contraindicated in patients less than 6 years of age. In nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration. Use of LINZESS should be avoided in patients 6 years to less than 18 years of age. The safety and effectiveness of LINZESS has not been established in patients less than 18 years of age.

Contraindications

• LINZESS is contraindicated in patients less than 6 years of age due to the risk of serious dehydration.

• LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.

Warnings and Precautions

Pediatric Risk

• LINZESS is contraindicated in patients less than 6 years of age. The safety and effectiveness of LINZESS in patients less than 18 years of age have not been established. In neonatal mice, linaclotide increased fluid secretion as a consequence of GC-C agonism resulting in mortality within the first 24 hours due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences.

• Use of LINZESS should be avoided in pediatric patients 6 to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, use of LINZESS should be avoided in pediatric patients 6 years to less than 18 years of age.

Diarrhea

• Diarrhea was the most common adverse reaction in LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar in the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients, and in <1% of 72 mcg LINZESS-treated CIC patients. If severe diarrhea occurs, dosing should be suspended and the patient rehydrated.

Common Adverse Reactions
(incidence ≥2% and greater than placebo)

• In IBS-C clinical trials: diarrhea (20% vs 3% placebo), abdominal pain (7% vs 5%), flatulence (4% vs 2%), headache (4% vs 3%), viral gastroenteritis (3% vs 1%) and abdominal distension (2% vs 1%).

• In CIC trials of a 145 mcg dose: diarrhea (16% vs 5% placebo), abdominal pain (7% vs 6%), flatulence (6% vs 5%), upper respiratory tract infection (5% vs 4%), sinusitis (3% vs 2%) and abdominal distension (3% vs 2%). In a CIC clinical trial of a 72 mcg dose: diarrhea (19% vs 7% placebo) and abdominal distention (2% vs <1%).

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