Teduglutide 1.25mg powder and solvent for solution for injection vials

Abstract Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6–59 months and hospitalised with SAM (using WHO definitions: WLZ <−3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum ( n = 25), (ii) N-acetyl glucosamine ( n = 24), (iii) subcutaneous teduglutide ( n = 26), (iv) budesonide ( n = 25) or (v) standard care only ( n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α 1 -antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size −0.89 (90% CI: −1.69,−0.10) P = 0.07), while colostrum (−0.58 (−1.4, 0.23) P = 0.24), N-acetyl glucosamine (−0.20 (−1.01, 0.60) P = 0.67), and budesonide (−0.50 (−1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.

Abstract licence: CC BY

OBJECTIVES: Patients with short bowel syndrome-associated intestinal failure (SBS-IF) require long-term parenteral nutrition and/or intravenous fluids (PN/IV) to maintain fluid or nutritional balance. We report the long-term safety, efficacy, and predictors of response in pediatric patients with SBS-IF receiving teduglutide over 96 weeks. METHODS: This was a pooled, post hoc analysis of two open-label, long-term extension (LTE) studies (NCT02949362 and NCT02954458) in children with SBS-IF. Endpoints included treatment-emergent adverse events (TEAEs) and clinical response (≥20% reduction in PN/IV volume from baseline). A multivariable linear regression identified predictors of teduglutide response; the dependent variable was mean change in PN/IV volume at each visit over 96 weeks. RESULTS: Overall, 85 patients were analyzed; 78 patients received teduglutide in the parent and/or LTE studies (any teduglutide [TED] group), while seven patients did not receive teduglutide in either the parent or LTE studies. Most TEAEs were moderate or severe in intensity in both groups. By week 96, 82.1% of patients from the any TED group achieved a clinical response, with a mean fluid decrease of 30.1 mL/kg/day and an energy decrease of 21.6 kcal/kg/day. Colon-in-continuity, non-White race, older age at baseline, longer duration of teduglutide exposure, and increasing length of remaining small intestine were significantly associated with a reduction in mean PN/IV volume requirements. CONCLUSIONS: In pediatric patients with SBS-IF, teduglutide treatment resulted in long-term reductions in PN/IV requirements. The degree of PN/IV volume reduction depended on the duration of teduglutide exposure, underlying bowel anatomy, and demographics.

Abstract licence: CC BY-NC

Abstract Introduction Crohn’s disease (CD) with short bowel syndrome (SBS) can present as chronic intestinal failure (CIF) often requiring nutritional support. Teduglutide is a treatment option for these patients. We investigated clinical outcomes of CD-CIF patients with SBS treated with teduglutide. Methods Adults with CD-CIF and SBS who received teduglutide were identified at a tertiary care academic center between 2012 and 2023. Data was collected retrospectively. Primary outcome measured was reduction in parenteral support (PS) by ≥20% volume, with PS defined as utilization of parenteral nutrition (PN) or intravenous fluids (IVF). Several secondary outcomes included immunosuppressive medication changes, subjective symptom improvement, and stool output. Results We identified 32 patients with CD-CIF and SBS receiving teduglutide. Comparing clinical outcomes before and after teduglutide, 26 of 32 patients achieved the primary outcome of ≥20% PS reduction. A decrease was seen in patients requiring PN + IVF, with corresponding increases in patients requiring PN only and IVF only. Among all 3 groups, a total of 23 patients received PN prior to teduglutide, which decreased to 14 following teduglutide. Weekly PN volume reduced from 7.00 to 3.55 L and weekly frequency decreased from 7.00 to 3.00 instances (P < .01). Reductions in weekly volume and frequency were observed among all patients receiving IVF support (25 vs 15). Secondary outcomes showed improvement in patient reported subjective symptoms (84.4%), stool output (90.6%), patients meeting criteria for diarrhea/high ostomy output (27 vs 14), and use of unique antidiarrheal medications (3.0 vs 2.0). Conclusions This retrospective case series demonstrated improved clinical outcomes in patients with CD-CIF and SBS treated with teduglutide resulting in decreased PS requirements, antidiarrheal medications requirement, and stool output without significant effects on immunosuppressive therapy.

Abstract licence: CC BY

Background: Teduglutide, the first glucagon-like peptide 2 analogue, has been demonstrated to facilitate the absorption of gut nutrient and lessen the need for parenteral assistance in patients with Short Bowel Syndrome (SBS). However, its adverse drug events (AEs) are primarily documented in clinical trials, with a deficit in real-world data. This study evaluates the AEs profile of teduglutide based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data. Method: A disproportionality analysis of FAERS data from Quarter 1 (Q1) 2013 to Quarter 3 (Q3) 2023 was conducted to examine the association between teduglutide and adverse events, employing Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) methods. Results: Out of 13,809,302 reports in the FAERS database, 10,114 reports identified teduglutide as the "primary suspect" in AEs identification. During the dosing observation period, the median occurrence of adverse events was 393 days (interquartile range [IQR] 97-996 days). Teduglutide-associated AEs occurred in 27 System Organ Classes (SOC), of which renal and urinary disorders is not mentioned in the specification. Based on the four algorithms, a total of 260 major disproportionality preferred terms (PTs) were filtered out, including previously unreported AEs including weight decreased (n = 805), vascular device infection (n = 683), dehydration (n = 596) and nephrolithiasis (n = 146). Conclusion: Our findings corroborate the AEs listed in the teduglutide prescribing information and additionally unveil new adverse reaction signals such as nephrolithiasis. These discoveries could aid in clinical monitoring and risk identification for teduglutide.

Abstract licence: CC BY

Background: Teduglutide (TED), a glucagon-like peptide 2 analogue licensed for children with short bowel syndrome (SBS), is increasingly used in the attempt to augment intestinal absorption and lower parenteral nutrition (PN) needs. Data from real-life studies on TED efficacy and predictors of response in children with SBS are limited. This study aimed to define pre-treatment and on-treatment predictors of response, in terms of PN reduction and weaning, in TED treated children with SBS. Methods: In this multicenter cohort study, we collected retrospective and prospective data of children with SBS undergoing TED treatment in 7 countries in Europe (Italy, Spain, Croatia, Germany, France, Israel, Portugal). All children with SBS starting TED treatment and not included in clinical trials were eligible. Information on patients' post-surgical anatomy, amount of PN calories and volume required at baseline and at 3, 6 and 12 months after TED start, along with biochemical markers of PN tolerance and complications, were recorded. The main outcome was predicting factors of 1 year response to TED treatment defined as a reduction of ≥20% of PN needs. Findings: Between 01.06.2021 and 31.05.2023, we collected information on 104 children (64 males, 61.5%; 40 females, 38.5%) the median age at enrolment was 6.7 years old (IQR: 3.6-10.4); at 12 months' follow up after TED start 68 children achieved response (cumulative incidence: 70%, 95% CI 61%-79%), whereas complete PN weaning was achieved in 21 children (cumulative incidence: 22%, 95% CI 15%-31%). Multivariable logistic regression analysis showed that predictors of response were longer residual small bowel length (p = 0.027), higher weight Z-score at baseline (p = 0.0061) and normal liver enzymes (p = 0.010). Pre-treatment PN calories <35 kcal/kg/day (p = 0.044) and citrulline ≥14 μmol/L (p = 0.047) predicted complete PN weaning, as well as haemoglobin and citrulline rise in the first 6 months of treatment (p = 0.014 and p = 0.044 respectively). Interpretation: In children with SBS, longer residual small bowel, better nutritional status and absence of liver disease were associated with response to teduglutide. Complete PN weaning was predicted by lower calories needs and higher citrulline at baseline. An increase of haemoglobin and citrulline in the first 6 months of treatment were further predictors of complete PN weaning. Even if limited by the real-life design of the study, these findings may guide a tailored indication for the use of teduglutide in children with short bowel syndrome. Funding: The European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Networking grant.

Abstract licence: CC BY-NC-ND

Intestinal glucocorticoid-refractory (SR) acute (a) graft-versus-host disease (GVHD) causes high non-relapse mortality (NRM) in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Recent preclinical data indicate that acute GVHD causes a loss of intestinal neuroendocrine L-cells leading to reduced levels of glucagon-like peptide-2 (GLP-2). GLP-2 substitution improved GVHD severity and increased Paneth cells and intestinal stem cells in mice. This motivated us to treat patients with refractory intestinal aGHVD using the GLP-2-analogon teduglutide. In this retrospective multicenter survey, 17 patients received teduglutide as salvage-therapy for SR-intestinal aGVHD. The best response (CR or PR) at any time point during and after treatment was 64.7% (11/17) including 41.2% (7/17) CR and 23.5% (4/17) PR. At a median follow-up of 28 weeks after teduglutide 10/17 patients are alive. Most patients experienced an increase of the albumin serum level within 2 months after the first teduglutide dose, including patients who clinically did not respond to teduglutide treatment. No specific teduglutide-related toxicity was observed. Our retrospective analysis suggests that teduglutide is safe and has activity in a fraction of patients with intestinal SR-aGVHD, which needs validation in a prospective trial.

Abstract licence: CC BY

OBJECTIVE: This study aimed to explore the lived experiences and coping strategies of patients with short bowel syndrome (SBS) prescribed teduglutide and weaning off home parenteral nutrition (HPN), and to compare the quality of life (QOL) of these patients to patients with SBS but not prescribed teduglutide. METHODS: A qualitative study was conducted, with patients recruited from a specialist HPN clinic. Participants completed handwritten semi-structured daily diaries for 6 weeks and a validated Home Parenteral Nutrition-Quality of Life (HPN-QOL) paper-based questionnaire as part of what aimed to be a mixed methods cross-tracks study. Participants were age-matched with patients with SBS receiving HPN but not prescribed teduglutide, and these 'controls' also completed the HPN-QOL questionnaire. Data analysis involved qualitative analysis of diary entries using grounded theory methodology and descriptive analysis of HPN-QOL questionnaire responses. RESULTS: Five participants completed the study and were matched with four 'controls'. All participants and 'controls' reported a high QOL with no differences observed between patients prescribed and not prescribed teduglutide. Qualitative analysis revealed that participants engaged in iterative cycles of problem-focused action and emotion-focused coping strategies to manage their condition and wean off parenteral nutrition (PN). Key subthemes included polyphagia and pleomorphism in diet, fatigue-related emotional distress and positive reframing using an objective scientific lens. Decisional regret was absent, participants agreed that treatment with teduglutide was the right choice for them, despite its challenges. Their goal of independence from PN was the main motivating factor. CONCLUSION: This study provides valuable insights into the lived experiences and coping strategies of patients with SBS prescribed teduglutide to wean off PN. The findings underscore the importance of healthcare teams understanding these everyday challenges to facilitate shared decision-making and tailor care plans. Further research is needed to explore the long-term impact of teduglutide on QOL, including the validation of tools to screen for fatigue-related emotional distress and the development of targeted interventions to support patients during the weaning process.

Abstract licence: CC BY-NC