Short bowel syndrome - teduglutide
Short bowel syndrome occurs when the functional length of the small intestine is drastically reduced, either by surgical removal or, occasionally, because of a malfunction. As a result, sufferers are unable to absorb fluids or nutrients properly, leading to dehydration and malnutrition.
Short bowel syndrome occurs when the functional length of the small intestine is drastically reduced, either by surgical removal or, occasionally, because of a malfunction. As a result, sufferers are unable to absorb fluids or nutrients properly, leading to dehydration and malnutrition.
Current treatments rely on fluids and nutrients being supplied parenterally, alongside drugs to counteract the diarrhoea and other symptoms the condition causes.
A drug being developed by NPS Pharmaceuticals may help. Teduglutide is an analogue of glucagon-like protein 2, which is important in the regulation of intestinal adaptation, the process by which the remaining small intestine increases its absorptive capacity to make up for the loss of overall intestinal volume. The hormone itself is rapidly metabolised by the enzyme dipeptidyl peptidase IV, and in teduglutide the alanine residue at position 2 has been changed to glycine.1 It retains its activity, but is no longer a substrate for DPP-IV.
An initial trial was carried out in 17 patients with small bowel syndrome resulting from surgery.2 Those with an end jejunostomy were given 0.03, 0.1 or 0.15mg/kg of the drug subcutaneously once or twice a day for 21 days, and those who still had at least 50% colon in continuity 0.1mg/kg for 21 days. It was well tolerated, and common side-effects included headache, swelling in the lower limbs, abdominal pain and swelling in the jejunostomy nipple. After the treatment period, both groups experienced better fluid absorption - up by 22% - increased electrolyte absorption and better nutrient uptake. As a result, a Phase III randomised placebo-controlled trial was started.
The drug also has potential in Crohn's disease, and a randomised, double blind Phase II trial has been carried out in patients with moderate to severe cases of the condition.3 A total of 100 patients were given 0.05, 0.1 or 0.2mg/kg of the drug a day or placebo as a subcutaneous injection for eight weeks. It was well tolerated, and only mild adverse events were seen. Complete remission was seen in 56% of those given the highest dose, compared to a third of those given the placebo.
An open label extension to the study was carried out, in which patients were given 0.1mg/kg of the drug for a further 12 weeks.4 More than half of those who had previously been on the 0.2mg dose were still in remission, compared to just 10% of those who had been given placebo.