Pfizer's GORD therapy enters the clinic

The trial has been designed to test the safety, tolerability and pharmacokinetics of the drug PF-04548043 (previously called KOS-2187), which Pfizer licensed at the end of December last year from Kosan. The deal involved an upfront payment of $12.5m, with Kosan eligible to receive $250 million if the drug is approved as well as royalties on worldwide sales. This figure includes development milestone payments of up to $72.5m. GORD is a condition that causes the acidic contents of the gastrointestinal (GI) tract to enter into the lower oesophagus which causes burning and severe mucosal damage such as erosions and ulcers in the oesophagus. Left untreated, the condition can lead to a pre-cancerous condition known as Barrett's Oesophagus. While the pathophysiology of the condition is not fully understood, studies have shown that it is not caused by over secretion of stomach acid but rather by a combination of disordered upper GI tract motility and impairment to the oesophageal clearance and protection mechanisms. GORD has been estimated to affect 2 per cent of the adult population in the US and represents a market size of approximately $19bn. In preclinical studies, PF-04548043 has been shown to improve both GI motility and increase the rate of gastric emptying, reducing the exposure of the oesophagus to acidic reflux. The drug is an analogue of the antibiotic erythromycin which has been observed in the clinic to accelerate gastric emptying in diabetic gastroparesis (impaired gastric emptying) and reduce the onset of GORD. Erythromycin is a motilin G-protein coupled receptor agonist that mediates the hormone motilin, which is secreted by the small intestine and stimulates GI motility. However, the antibiotic activity of erythromycin makes it unsuitable for long term use as it will increase antibiotic resistance. Many first generation analogues of erythromycin were found to block the hERG channel in the heart which can lead to an increased risk of dangerous arrhythmias, or irregular heart rhythms. PF-04548043 has been shown in preclinical trials to have a low antibiotic activity as well as an improved safety profile and a high oral bioavailability. In vitro​ studies conducted by Kosan have indicated that the compound is "at least 20-fold more potent as a motilin agonist than erythromycin and has a 10-fold weaker affinity for the hERG channel than erythromycin". ​This mechanism is very different to the current drugs of choice known as protein pump inhibitors (PPIs) such as Santarus' Zegerid (omeprazole). Schering-Plough licensed the rights to make and sell omeprazole at the 20mg dose from Santarus last year in a deal worth up to $80m. Other companies developing treatments for GORD include Addex and Dynogen Pharmaceuticals. Addex​ is developing a selective metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator, ADX10059, which is currently in Phase II. Dynogen is currently investigating DDP733, a serotonin type 3 receptor agonist that is in Phase I trials.