The Discovery of Linaclotide (OLD)
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.
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