Macrocycle Milestone for Ironwood Pharma
Ironwood Pharmaceuticals and Forest Laboratories last week announced submission of an NDA for linaclotide, a peptide macrocycle for treatment of irritable bowel syndrome (IBS). This is the first new drug application for Ironwood, a 13-year old Cambridge, MA company, and it could validate other companies’ strategies for large-ring drugs (covered recently by Carmen Drahl in C&EN). There’s an enormous potential market for this drug; by Ironwood’s count, a combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these conditions. So, how does linaclotide help IBS sufferers, um . . . go?
This 14-amino acid peptide ring, taken orally, arrives at the intestinal lumen, where, according to Ironwood patent literature, it docks with a receptor enzyme called guanylate cyclase C (GC-C). The extracellular domain (part that sticks out of the cell membrane), upon binding, initiates the intracellular domain (inside the cell) to begin production of guanosine-3’, 5’-cyclic monophosphate (cGMP), a signaling molecule that induces changes in the intestinal wall. In short, cGMP prompts the intestinal surface to release chloride and bicarbonate ions into the intestinal tract, which decreases sodium uptake and increases fluid secretion (Note: interestingly, this is similar to the body’s response upon E.coli infection; a bacterial toxin called ST-peptide causes traveller’s diarrhea). In Ironwood’s own words, these physiological changes “accelerate intestinal transit,” which helps to move solid waste and decrease overall pain by acting on local nerve responses.
Update (3:20PM, 8/17/11) – Changed “nearly 45 million people in the US alone suffer from IBS, yet few drugs are approved for this condition” to “combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these conditions.”