Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial

Ibironke Oduyebo, Michael Camilleri, Alfred D. Nelson, Disha Khemani, Sara Linker Nord, Irene Busciglio, Duane Burton, Deborah Rhoten, Michael Ryks, Paula Carlson, Leslie Donato, Alan Lueke, Kathline Kim, Stephen J. Rossi, Alan R. Zinsmeister

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objective: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). Methods: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). Statistical analysis: overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008). Results: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). Conclusion: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalAmerican Journal of Gastroenterology
DOIs
StateAccepted/In press - May 2 2018

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Fibroblast Growth Factors
Constipation
Bile Acids and Salts
Gastric Emptying
Placebos
Single Nucleotide Polymorphism
Diarrhea
Fats
Cholangitis
Appetite
Type 2 Diabetes Mellitus
Fasting
Stomach
Alleles
Weights and Measures
Injections
Liver
Therapeutics
Serum
Research

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation : a randomized phase 2 trial. / Oduyebo, Ibironke; Camilleri, Michael; Nelson, Alfred D.; Khemani, Disha; Nord, Sara Linker; Busciglio, Irene; Burton, Duane; Rhoten, Deborah; Ryks, Michael; Carlson, Paula; Donato, Leslie; Lueke, Alan; Kim, Kathline; Rossi, Stephen J.; Zinsmeister, Alan R.

In: American Journal of Gastroenterology, 02.05.2018, p. 1-10.

Research output: Contribution to journalArticle

Oduyebo, I, Camilleri, M, Nelson, AD, Khemani, D, Nord, SL, Busciglio, I, Burton, D, Rhoten, D, Ryks, M, Carlson, P, Donato, L, Lueke, A, Kim, K, Rossi, SJ & Zinsmeister, AR 2018, 'Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial', American Journal of Gastroenterology, pp. 1-10. https://doi.org/10.1038/s41395-018-0042-7
Oduyebo, Ibironke ; Camilleri, Michael ; Nelson, Alfred D. ; Khemani, Disha ; Nord, Sara Linker ; Busciglio, Irene ; Burton, Duane ; Rhoten, Deborah ; Ryks, Michael ; Carlson, Paula ; Donato, Leslie ; Lueke, Alan ; Kim, Kathline ; Rossi, Stephen J. ; Zinsmeister, Alan R. / Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation : a randomized phase 2 trial. In: American Journal of Gastroenterology. 2018 ; pp. 1-10.
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author = "Ibironke Oduyebo and Michael Camilleri and Nelson, {Alfred D.} and Disha Khemani and Nord, {Sara Linker} and Irene Busciglio and Duane Burton and Deborah Rhoten and Michael Ryks and Paula Carlson and Leslie Donato and Alan Lueke and Kathline Kim and Rossi, {Stephen J.} and Zinsmeister, {Alan R.}",
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T2 - a randomized phase 2 trial

AU - Oduyebo, Ibironke

AU - Camilleri, Michael

AU - Nelson, Alfred D.

AU - Khemani, Disha

AU - Nord, Sara Linker

AU - Busciglio, Irene

AU - Burton, Duane

AU - Rhoten, Deborah

AU - Ryks, Michael

AU - Carlson, Paula

AU - Donato, Leslie

AU - Lueke, Alan

AU - Kim, Kathline

AU - Rossi, Stephen J.

AU - Zinsmeister, Alan R.

PY - 2018/5/2

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