Open: 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 D.; Rhoten, Deborah; Ryks, Michael; Carlson, Paula; Donato, Leslie J.; Lueke, Alan; Kim, Kathline; Rossi, Stephen J.; Zinsmeister, Alan R.

doi:10.1038/s41395-018-0042-7

Cited by 31 publications

(26 citation statements)

References 29 publications

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“…Nonetheless, because bile acids stimulate colonic secretion of water and high-amplitude-propagated contractions 23 , 24 , it is hypothesized that a paucity of colonic bile acids may cause constipation. Indeed, the corollary is also true: excess bile acid administered orally 24 or modification of the enterohepatic recycling pathway 25 can exert a laxative effect.…”

Section: Advances In Understanding the Molecular Pathophysiology Of Cmentioning

confidence: 99%

“…In patients with functional constipation, the fibroblast growth factor 19 analog NGM282 accelerated gastric and colonic transit, resulting in an increased number of bowel movements, looser stool form, and increased ease of stool passage 25 . The rationale for this study was the observation that NGM282 induced diarrhea in phase 2 trials relating to type 2 diabetes, primary biliary cholangitis, and non-alcoholic steatohepatitis.…”

Section: Development Of Novel Therapeutic Agents For the Treatment Ofmentioning

confidence: 99%

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Recent advances in understanding and managing chronic constipation

Prichard

Bharucha

2018

F1000Res

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Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.

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Section: Advances In Understanding the Molecular Pathophysiology Of Cmentioning

confidence: 99%

Section: Development Of Novel Therapeutic Agents For the Treatment Ofmentioning

confidence: 99%

Recent advances in understanding and managing chronic constipation

Prichard

Bharucha

2018

F1000Res

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“…FGF19 primarily targets the liver, which expresses both components (FGFR4 and β‐klotho) required for FGF19 signaling . (Pre)clinical studies revealed a myriad of functions of FGF19/Fgf15 including regulation of major metabolic pathways (e.g., energy, carbohydrate and lipid metabolism, bile salt and protein synthesis) and functional processes such as gallbladder relaxation, skeletal muscle mass homeostasis, and GI motility . Considering the beneficial metabolic effects, FGF19 administration is evaluated as treatment of chronic liver diseases .…”

mentioning

confidence: 99%

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients

et al. 2019

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Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum‐derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient‐stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high‐lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient‐stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.

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“…Although there is no evidence for any genetic mutation of FGF19 gene that may be involved in human metabolic diseases, its reduced synthesis and blood levels are suggestive of a causative factor of chronic bile acid diarrhea [80,81] and certain metabolic disorders, such as metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Experimentally, the Fig.…”

Section: Fgf19 Metabolic Axismentioning

confidence: 99%

“…It markedly reduced liver fat content but with significant side effects [70]. In a phase 2 trial in patients with type 2 diabetes and chronic idiopathic constipation, NGM282 significantly improved bowel function by accelerating gastric emptying and colonic transit [81]. Furthermore, NGM282 was further tested in mouse models and human patients with cholestasis and primary biliary cholangitis, showing efficacy in significantly reducing bile acid levels and improving hepatic inflammatory injury and fibrosis [84,88,89].…”

Section: Fgf19 Metabolic Axismentioning

confidence: 99%

The FGF metabolic axis

2019

Front. Med.

112

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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term "FGF Metabolic Axis," which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

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

Abstract: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Cited by 31 publications

References 29 publications

Recent advances in understanding and managing chronic constipation

Recent advances in understanding and managing chronic constipation

Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients

The FGF metabolic axis

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