Teduglutide

How Teduglutide works

Teduglutide is an analog of glucagon-like peptide-2 with a single amino acid substitution that makes it resistant to degradation by dipeptidyl peptidase-4, giving it a longer duration of action than native GLP-2. It binds GLP-2 receptors on intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Receptor activation causes local release of mediators including insulin-like growth factor-1, nitric oxide and keratinocyte growth factor. In a small open-label dose-ranging study in adults with short bowel syndrome, higher doses increased gastrointestinal fluid absorption and increased villus height and crypt depth; that pharmacodynamic finding comes from a very small uncontrolled study, not from a controlled efficacy trial.

What research has looked at

• In the pivotal 24-week phase 3 STEPS trial, 63 percent of treated adults (27 of 43) met the primary responder definition of at least a 20 percent reduction in weekly parenteral support volume at both week 20 and week 24, compared with 30 percent on placebo (13 of 43).
• Across the whole teduglutide arm in STEPS, mean weekly parenteral nutrition and intravenous fluid volume fell by 4.4 litres per week from a baseline of 12.9 litres, versus a fall of 2.3 litres per week on placebo from a baseline of 13.2 litres (p<0.001). The placebo-adjusted difference is therefore about 2.1 litres per week. The 4.4 litre figure is the whole-arm mean, not a responder-only result.
• An earlier 24-week placebo-controlled phase 3 trial tested two doses against a graded response score primary endpoint. The lower dose separated from placebo, but the higher dose did not (8 of 32 versus 1 of 16, p=0.16). The expected dose-response was not observed, and the approved dose is the lower of the two tested.
• Open-label extension studies reported that reductions in parenteral support were maintained or deepened with longer treatment, and a minority of patients achieved enteral autonomy and came off parenteral support entirely. These extensions had no control arm and enrolled patients who had already tolerated and responded to treatment, so they cannot be read as a controlled estimate of effect.
• Approval was based on reduction in parenteral support requirement. Effects on survival, long-term catheter-related complications and mortality were not established endpoints.

Evidence level: Approved labeling. Official prescribing information exists, based on clinical trials in people. These are areas studied or reported, not promised effects.

Reported side effects and risks

• Acceleration of neoplastic growth is the label's leading warning. In adults, colonoscopy AND upper gastrointestinal endoscopy with removal of polyps must be performed within 6 months before starting; a follow-up colonoscopy and upper gastrointestinal endoscopy (or alternate imaging) is recommended at the end of 1 year, then no less often than every 5 years. In pediatric patients, fecal occult blood testing is performed annually, colonoscopy or sigmoidoscopy is recommended after 1 year and every 5 years thereafter, and upper gastrointestinal endoscopy or alternate imaging should be considered during treatment.
• In patients at increased risk for malignancy, the label states the drug should be used only if benefits outweigh the risks. Teduglutide is discontinued if active gastrointestinal malignancy develops, which the label defines as gastrointestinal tract, hepatobiliary or pancreatic. For active non-gastrointestinal malignancy, continuation is a benefit-risk decision.
• Intestinal obstruction, including stomal obstruction, has been reported; the label directs temporary discontinuation pending clinical evaluation, and it may become permanent.
• Biliary and pancreatic disease, including cholecystitis, cholangitis, cholelithiasis and pancreatitis. The label directs bilirubin, alkaline phosphatase, lipase and amylase within 6 months before starting and at least every 6 months during treatment, with imaging and reassessment of continued treatment if clinically meaningful changes occur.
• Fluid overload, including cases described as congestive heart failure. If it occurs, the label directs adjusting parenteral support and reassessing continued treatment. Separately, on discontinuation, patients must be monitored for fluid and electrolyte imbalance as absorption returns toward baseline.
• Increased absorption of concomitant oral medications, which matters for drugs with a narrow therapeutic index; the label names benzodiazepines and notes a postmarketing case of deterioration in mental status progressing to coma in the first week. Dose reduction of the concomitant drug may be required.
• Reactions reported in at least 10 percent of patients are abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection site reactions, vomiting, fluid overload and hypersensitivity. Several sit close to placebo in the controlled studies; abdominal distension and upper respiratory tract infection separate more clearly. The label carries no boxed warning and states Contraindications as None.

Sources

1. PubMed research on Teduglutide · NIH · National Library of Medicine
2. DrugBank record for Teduglutide · DrugBank
3. Active clinical trials for Teduglutide · U.S. National Library of Medicine

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Teduglutide FAQ