NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Trial
Open accessAbstract
Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28‐day, double‐blind, placebo‐controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000‐000)
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Written from the paper’s full text.
TL;DR
In a 28-day phase 2 trial of 45 patients with primary biliary cholangitis and inadequate response to ursodiol, NGM282 significantly reduced alkaline phosphatase versus placebo at both 0.3 mg and 3 mg. NGM282 also lowered transaminases and immunoglobulins, with gastrointestinal adverse events more frequent but no worsening of pruritus.
Key findings
- At day 28, ALP decreased by least-squares mean –51.0 IU/L (SE 15.4) with NGM282 0.3 mg and –66.0 IU/L (SE 16.0) with NGM282 3 mg, versus +3.3 IU/L (SE 14.8) with placebo; least-squares mean differences were –54.3 IU/L (95% CI –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% CI –120.5 to –18.3; P = 0.0030), respectively.
- At least 15% reduction in ALP was achieved by 50% (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) receiving NGM282 3 mg, compared with 7% (1 of 15) receiving placebo.
- NGM282 significantly reduced ALT (LS mean difference –17.1 IU/L, P = 0.002 for 0.3 mg; –17.5 IU/L, P = 0.003 for 3 mg) and AST (–12.7 IU/L, P = 0.003 for 0.3 mg; –12.2 IU/L, P = 0.007 for 3 mg). C4 decreased in the 3-mg group (LS mean –14.9 ng/mL, P < 0.0001), IgM decreased in the 3-mg group (–46.2 mg/dL, P = 0.01), and IgG decreased in the 0.3-mg group (–107.1 mg/dL, P = 0.02).
- Most adverse events were grade 1–2; gastrointestinal disorders were more frequent with NGM282, and no worsening of pruritus was observed with NGM282 treatment.
Methods
- Multicenter, international, randomized, double-blind, placebo-controlled phase 2 trial conducted at 22 sites in Australia and the United States; 45 patients aged 18–75 with PBC and inadequate response to ursodiol were randomized 1:1:1 to daily subcutaneous NGM282 0.3 mg (n = 14), NGM282 3 mg (n = 16), or placebo (n = 15) for 28 days.
- The primary endpoint was absolute change in ALP from baseline to day 28; secondary endpoints included ALT, AST, GGT, bilirubin, C4, bile acids, pruritus, fatigue, and quality of life, with exploratory lipid, immunoglobulin, and vitamin D assessments.
- Efficacy was analyzed in 42 patients using ANCOVA with treatment group as a fixed factor and baseline value as a covariate; categorical endpoints used chi-square or Fisher’s exact test; safety was analyzed descriptively in all 45 randomized patients.
Limitations
- The paper states that treatment duration was short (28 days), analyses were limited to surrogate biomarkers and symptoms, the sample size was smaller than some later-stage phase 2 studies, liver biopsies/fibrosis assessment were not performed, and the study population was entirely Caucasian.
- The text makes evident that the trial was not designed to assess clinical outcomes such as hepatic decompensation, death, or liver transplantation, and that durability of biochemical response remains unknown.
- The text also notes that NGM282 did not significantly change the proportion of patients achieving ALP normalization or ALP less than 1.67× ULN, and 3 patients in the 3-mg group were excluded from the efficacy analysis.
Model-written summary. Check it against the paper before relying on it.
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- Findingown data
In patients with primary biliary cholangitis, NGM282 0.3 mg decreased ALT levels from baseline to day 28 compared with placebo (LS mean difference −17.1 IU/L, P = 0.002).
“Significant decreases in ALT levels from baseline to day 28 were observed in both NGM282 groups (LS mean difference −17.1 IU/L for 0.3‐mg group, P = 0.002; −17.5 IU/L for 3‐mg group, P = 0.003) (Fig. 2C and Table 3).”
Quote in the paperSubstantial claim - Findingown data
In patients with primary biliary cholangitis, NGM282 3 mg decreased ALT levels from baseline to day 28 compared with placebo (LS mean difference −17.5 IU/L, P = 0.003).
“Significant decreases in ALT levels from baseline to day 28 were observed in both NGM282 groups (LS mean difference −17.1 IU/L for 0.3‐mg group, P = 0.002; −17.5 IU/L for 3‐mg group, P = 0.003) (Fig. 2C and Table 3).”
Quote in the paperSubstantial claim - Findingown data
Forty-six percent (6 of 13) of patients receiving NGM282 3 mg achieved at least a 15% reduction in alkaline phosphatase from baseline, compared with 7% (1 of 15) of patients receiving placebo.
“Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3 mg achieved at least a 15% reduction in ALP from baseline, compared with 7% (1 of 15) of patients receiving placebo.”
Quote in the paperSubstantial claim - Findingown data
Gastrointestinal disorders were more frequent in the NGM282 treatment groups.
“Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups.”
Quote in the paperNot a substantial claim - Findingown data
The absolute change in C4 levels from baseline was greater in the NGM282 3-mg group (LS mean −14.9 ng/mL, P < 0.0001) than in the 0.3-mg group (−3.4 ng/mL) or the placebo group (2.8 ng/mL).
“The absolute change in C4 levels from baseline was greater in the 3‐mg group (LS mean −14.9 ng/mL, P < 0.0001) than in the 0.3‐mg group (−3.4 ng/mL) or the placebo group (2.8 ng/mL) (Fig. 3A).”
Quote in the paperSubstantial claim
- Findingown data
Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg achieved at least a 15% reduction in alkaline phosphatase from baseline, compared with 7% (1 of 15) of patients receiving placebo.
“Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3 mg achieved at least a 15% reduction in ALP from baseline, compared with 7% (1 of 15) of patients receiving placebo.”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences between the NGM282 groups and the placebo group with respect to levels of bilirubin or albumin, body weight, or international normalized ratio.
“There were no significant differences between the NGM282 groups and the placebo group with respect to levels of bilirubin or albumin, body weight, or international normalized ratio (Table 3).”
Quote in the paperNot a substantial claim - Findingown data
A higher incidence of diarrhea/loose stools was observed in the NGM282 0.3-mg and 3-mg groups than in the placebo group.
“A higher incidence of diarrhea/loose stools was observed in the NGM282 0.3‐mg and 3‐mg groups than in the placebo group.”
Quote in the paperNot a substantial claim - Findingown data
Serum IgM levels decreased from baseline in the NGM282 3-mg group compared with placebo (LS mean difference −46.2 mg/dL, P = 0.01).
“As compared with the placebo treatment, the IgM levels decreased from baseline in the NGM282 0.3‐mg (LS mean difference −32.5 mg/dL, P = 0.06) and 3‐mg groups (−46.2 mg/dL, P = 0.01).”
Quote in the paperNot a substantial claim - Findingown data
No significant changes in HDL-C or TGs were detected in NGM282-treated patients.
“No significant changes in HDL‐C or TGs were detected in NGM282‐treated patients (Supporting Fig. S2).”
Quote in the paperNot a substantial claim - Findingown data
In patients with primary biliary cholangitis, NGM282 3 mg decreased AST levels from baseline to day 28 compared with placebo (LS mean difference −12.2 IU/L, P = 0.007).
“There were similar decreases in AST levels from baseline to day 28 in both NGM282 groups (LS mean difference −12.7 IU/L for 0.3‐mg group, P = 0.003; −12.2 IU/L for 3‐mg group, P = 0.007) (Fig. 2D).”
Quote in the paperSubstantial claim - Findingown data
At day 28, alkaline phosphatase was significantly reduced with NGM282 0.3 mg versus placebo (least-squares mean difference -54.3 IU/L, 95% confidence interval -104.2 to -4.5; P = 0.0149).
“At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively.”
Quote in the paperSubstantial claim - Findingown data
ALP levels decreased in a significant, progressive, dose-dependent manner from baseline to day 28 in both the 0.3-mg and 3-mg NGM282 treatment groups.
“ALP levels decreased in a significant, progressive, dose‐dependent manner from baseline to day 28 in both the 0.3‐mg and 3‐mg NGM282 treatment groups.”
Quote in the paperSubstantial claim - Findingown data
At day 28, alkaline phosphatase was significantly reduced with NGM282 3 mg versus placebo (least-squares mean difference -69.3 IU/L, 95% confidence interval -120.5 to -18.3; P = 0.0030).
“At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively.”
Quote in the paperSubstantial claim - Findingown data
NGM282 treatment for 28 days was associated with dose-dependent decreases in C4 levels in both NGM282 groups.
“NGM282 treatment for 28 days was associated with dose‐dependent decreases in C4 levels in both NGM282 groups, findings that are consistent with suppression of de novo bile acid synthesis through the classical pathway.”
Quote in the paperSubstantial claim - Findingown data
No worsening of pruritus was observed with NGM282 treatment.
“No worsening of pruritus was observed with NGM282 treatment.”
Quote in the paperNot a substantial claim - Findingown data
NGM282 0.3 mg decreased total cholesterol (TC) versus placebo by −1.5 mg/dL.
“A dose‐dependent decrease in TC of −1.5 mg/dL and −19.7 mg/dL (P = 0.02) was observed in NGM282 0.3‐mg and 3‐mg groups versus placebo (Table 3).”
Quote in the paperNot a substantial claim - Findingown data
Greater reductions in alkaline phosphatase concentration were achieved in patients with more severe cholestasis at baseline (alkaline phosphatase ≥275 IU/L or gamma-glutamyl transpeptidase ≥150 IU/L).
“Subgroup analyses revealed that greater reductions in ALP concentration (percent and absolute) were achieved in patients with more severe cholestasis at baseline, as evidenced by responses in patients with baseline levels of ALP greater than or equal to 275 IU/L or GGT greater than or equal to 150 IU/L (Supporting Table S3).”
Quote in the paperNot a substantial claim - Findingown data
There was good agreement between the VAS and 5-D itch methods in measuring categorical change from baseline in pruritus severity (k = 0.56, P < 0.0001).
“Overall, there was good agreement between the VAS and 5‐D itch methods in measuring categorical change from baseline in pruritus severity (k = 0.56, P < 0.0001).”
Quote in the paperNot a substantial claim - Findingown data
NGM282 did not result in any significant worsening in symptoms or quality of life as measured by the PBC-40 questionnaire on day 28.
“NGM282 did not result in any significant worsening in symptoms as measured by the PBC‐40 questionnaire on day 28 (Table 3 and Supporting Table S6). Overall, there were no significant changes in quality of life, as assessed by the PBC‐40 questionnaire, among patients who were treated with NGM282.”
Quote in the paperNot a substantial claim - Findingown data
Serum IgM levels decreased from baseline in the NGM282 0.3-mg group compared with placebo (LS mean difference −32.5 mg/dL, P = 0.06).
“As compared with the placebo treatment, the IgM levels decreased from baseline in the NGM282 0.3‐mg (LS mean difference −32.5 mg/dL, P = 0.06) and 3‐mg groups (−46.2 mg/dL, P = 0.01).”
Quote in the paperNot a substantial claim - Findingown data
Levels of gamma-glutamyl transpeptidase decreased in both NGM282 groups.
“Levels of GGT, a second marker of cholestasis in addition to ALP, were also decreased in both NGM282 groups (Fig. 2B and Table 3).”
Quote in the paperNot a substantial claim - Findingown data
Changes from baseline in the 5-D itch and VAS scores for pruritus showed no significant differences when comparing NGM282 groups with the placebo group.
“Changes from baseline in the 5‐D itch and VAS scores for pruritus showed no significant differences when comparing NGM282 groups with the placebo group (Table 3 and Supporting Table S5).”
Quote in the paperSubstantial claim - Findingown data
No significant changes in serum vitamin D levels were observed in NGM282-treated patients.
“Despite inhibition of the classical pathway of de novo bile acid synthesis, no significant changes in serum vitamin D levels, an indicator of fat‐soluble vitamin absorption, were observed in NGM282‐treated patients (Supporting Table S4).”
Quote in the paperNot a substantial claim - Findingown data
In patients with primary biliary cholangitis, NGM282 0.3 mg decreased AST levels from baseline to day 28 compared with placebo (LS mean difference −12.7 IU/L, P = 0.003).
“There were similar decreases in AST levels from baseline to day 28 in both NGM282 groups (LS mean difference −12.7 IU/L for 0.3‐mg group, P = 0.003; −12.2 IU/L for 3‐mg group, P = 0.007) (Fig. 2D).”
Quote in the paperSubstantial claim - Findingown data
Among glycine-conjugated and taurine-conjugated primary and secondary bile acids, only GCA was significantly reduced in the NGM282 3-mg group compared with the placebo group.
“Among glycine‐conjugated and taurine‐conjugated primary bile acids (glycocholic acid [GCA], trichloroacetic acid [TCA], glycochenodeoxycholic acid [GCDCA], and taurochenodeoxycholic acid [TCDCA]) and secondary bile acids (glycodeoxycholic acid [GDCA], taurodeoxycholic acid [TLCA], glycolithocholic acid [GLCA], and taurolithocholic acid [TLCA]), only GCA was significantly reduced in the NGM282 3‐mg”
Quote in the paperNot a substantial claim - Findingown data
NGM282 treatment significantly decreased GGT levels.
“Significant decreases in the levels of ALT, AST, and GGT were also observed in patients treated with NGM282.”
Quote in the paperSubstantial claim - Findingown data
Almost half of the patients in the NGM282 groups, as compared with 7% of those in the placebo group, achieved at least a 15% reduction in ALP from baseline.
“Almost half of the patients in the NGM282 groups, as compared with 7% of those in the placebo group, achieved at least a 15% reduction in ALP from baseline.”
Quote in the paperSubstantial claim - Findingown data
NGM282 3 mg decreased total cholesterol (TC) versus placebo by −19.7 mg/dL (P = 0.02).
“A dose‐dependent decrease in TC of −1.5 mg/dL and −19.7 mg/dL (P = 0.02) was observed in NGM282 0.3‐mg and 3‐mg groups versus placebo (Table 3).”
Quote in the paperNot a substantial claim - Findingown data
Serum IgG levels decreased in patients treated with NGM282 3 mg compared with placebo (LS mean difference −77.1 mg/dL, P = 0.10).
“Levels of IgG also decreased in patients treated with 0.3 mg (LS mean difference −107.1 mg/dL, P = 0.02) and 3 mg (−77.1 mg/dL, P = 0.10) of NGM282.”
Quote in the paperNot a substantial claim - Findingown data
Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity.
“Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups.”
Quote in the paperSubstantial claim - Findingown data
NGM282 treatment did not result in a significant change in the proportions of patients achieving ALP normalization or less than 1.67× ULN.
“Although patients in the NGM282 group experienced reductions in ALP levels, NGM282 treatment did not result in a significant change in the proportions of patients achieving ALP normalization or less than 1.67× ULN.”
Quote in the paperSubstantial claim - Findingown data
Serum IgG levels decreased in patients treated with NGM282 0.3 mg compared with placebo (LS mean difference −107.1 mg/dL, P = 0.02).
“Levels of IgG also decreased in patients treated with 0.3 mg (LS mean difference −107.1 mg/dL, P = 0.02) and 3 mg (−77.1 mg/dL, P = 0.10) of NGM282.”
Quote in the paperNot a substantial claim - Findingnone given
There was no worsening of pruritus, either in incidence or severity, in response to NGM282 treatment.
“There was no worsening of pruritus, either in incidence or severity, in response to NGM282 treatment.”
Quote in the paperSubstantial claim - Premisecitation
Administration of fibroblast growth factor 19 protects mice against liver injury in models of intrahepatic and extrahepatic cholestasis.
“Administration of FGF19 has been shown to protect mice against liver injury in models of intrahepatic and extrahepatic cholestasis.12, 13”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology 2012; 142: 355‐ 365,e351‐e354. 22057115 source
Not checked in the free run.
- cites [13] Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6: 247ra100. 25080475
Not checked in the free run.
- Premisecitation
NGM282 differs from fibroblast growth factor 19 in the amino terminus, a key region involved in receptor interactions and signaling modulation.
“NGM282 (also referred to as M70) differs from FGF19 in the amino terminus, a key region of the protein involved in receptor interactions and signaling modulation.15”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014; 74: 3306‐ 3316. 24728076 source
Not checked in the free run.
- Interpretationreasoning
There remains a significant need for additional therapeutic options for patients with primary biliary cholangitis.
“Thus, there remains a significant need for additional therapeutic options for patients with PBC.”
Quote in the paperSubstantial claim - Premisecitation
Only 40% to 60% of patients with primary biliary cholangitis respond adequately to ursodiol.
“but only 40% to 60% of patients respond adequately to ursodiol.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet 2011; 377: 1600‐ 1609. 21529926 source
Not checked in the free run.
- Premisecitation
Fibroblast growth factor 19 acts directly on the liver to suppress expression of CYP7A1, the rate-limiting enzyme in the classic pathway of bile acid synthesis.
“FGF19 acts directly on the liver to suppress expression of CYP7A1, the gene‐encoding cholesterol 7α‐hydroxylase, the enzyme that catalyzes the first and rate‐limiting step in the classic pathway of bile acid synthesis.11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Russell DW. Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res 2009; 50: S120‐ S125. 18815433 PMC2674696 source
Not checked in the free run.
- Interpretationown data
Treatment with NGM282 was associated with decreases in levels of IgM and IgG, indicative of potential immune disease-modifying activity.
“Treatment with NGM282 was also associated with decreases in the levels of IgM and IgG, indicative of potential immune disease–modifying activity.”
Quote in the paperSubstantial claim - Interpretationown data
The dose-dependent decreases in C4 levels are consistent with suppression of de novo bile acid synthesis through the classical pathway.
“NGM282 treatment for 28 days was associated with dose‐dependent decreases in C4 levels in both NGM282 groups, findings that are consistent with suppression of de novo bile acid synthesis through the classical pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: A significant component of FXR-mediated biological activity is attributed to the induction of endogenous FGF19.
- Premisecitation
Mice expressing a FGF19 transgene develop hepatocellular carcinomas.
“Given that mice expressing a FGF19 transgene develop hepatocellular carcinomas,14 the potential risk of tumorigenicity in patients treated with FXR agonists may need to be monitored.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160: 2295‐ 2307. 12057932 PMC1850847 source
Not checked in the free run.
- Premisecitation
NGM282 does not activate STAT3, a signaling pathway essential for fibroblast growth factor 19-mediated hepatocarcinogenesis.
“In contrast, NGM282 does not activate STAT3, a signaling pathway essential for FGF19‐mediated hepatocarcinogenesis.16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Zhou M, Yang H, Learned RM, Tian H, Ling L. Non‐cell‐autonomous activation of IL‐6/STAT3 signaling mediates FGF19‐driven hepatocarcinogenesis. Nat Commun 2017; 8: 15433. 28508871 PMC5440856 source
Not checked in the free run.
- Premisecitation
Recent data have revealed the importance of ALP as a surrogate of clinical outcomes in patients with PBC.
“Recent data have revealed the importance of ALP as a surrogate of clinical outcomes in patients with PBC.4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow‐up study. Gastroenterology 2014; 147: 1338‐ 1349,e1335; quiz e1315. 25160979 source
Not checked in the free run.
- Study design and conductown data
Baseline demographics and disease characteristics of the three groups were similar.
“Baseline demographics and disease characteristics of the three groups were similar (Table 1).”
Quote in the paperSubstantial claim - Premisecitation
In NGM282, a 5-amino acid deletion (P24-S28) coupled with substitution of three amino acids (A30S, G31S, H33L) within the amino terminus biases FGFR4 signaling so that NGM282 retains the ability to potently repress CYP7A1 expression through the FGFR4-βKlotho receptor complex.
“In NGM282, a 5‐amino acid deletion (P24‐S28) coupled with substitution of three amino acids at critical positions (A30S, G31S, H33L) within the amino terminus bias FGFR4 signaling so that NGM282 retains the ability to potently repress CYP7A1 expression through the FGFR4‐βKlotho receptor complex.15”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014; 74: 3306‐ 3316. 24728076 source
Not checked in the free run.
- Premisecitation
ALP is considered "reasonably likely" to predict clinical outcome by the Food and Drug Administration for accelerated approval under subpart H/E.
“As a prognostic marker rather than a validated surrogate endpoint, ALP is considered “reasonably likely” to predict clinical outcome by the Food and Drug Administration for accelerated approval under subpart H/E.24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] US Food and Drug Administration. Gastrointestinal Drug Advisory Committee (GIDAC) meeting on obeticholic acid for the treatment of primary biliary cholangitis. April 7, 2016.
Not checked in the free run.
- Interpretationown data
NGM282 was well-tolerated in PBC patients.
“Overall, NGM282 was well‐tolerated in PBC patients.”
Quote in the paperSubstantial claim - Interpretationreasoning
Taken together, these observations indicate that NGM282 represents a potential therapeutic option for the treatment of chronic liver diseases.
“Taken together, these observations indicate that NGM282 represents a potential therapeutic option for the treatment of chronic liver diseases.”
Quote in the paperSubstantial claim - Premisecitation
In a double-blind, placebo-controlled trial in patients with nonalcoholic steatohepatitis, NGM282 produced rapid and significant reductions in liver fat content and serum levels of transaminases.
“In a double‐blind, placebo‐controlled trial in patients with nonalcoholic steatohepatitis, NGM282 produced rapid and significant reductions in liver fat content and serum levels of transaminases.18”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non‐alcoholic steatohepatitis: a multicentre, randomised, double‐blind, placebo‐controlled, phase 2 trial. Lancet 2018; 391: 1174‐ 1185. 29519502 source
Not checked in the free run.
- Interpretationown data
Treatment with NGM282 does not induce or worsen pruritus symptoms in PBC patients.
“These results demonstrate that treatment with NGM282 does not induce or worsen pruritus symptoms in PBC patients.”
Quote in the paperSubstantial claim - Interpretationown data
Direct suppression of hepatic bile acid synthesis may have differential effects on pruritus by altering the amount and composition of bile acids present in blood and tissues.
“Our data suggest that direct suppression of hepatic bile acid synthesis may have differential effects on pruritus by altering the amount and composition of bile acids present in blood and tissues, although further evaluation in trials of longer duration are warranted.”
Quote in the paperSubstantial claim- Rests on an assumption: A significant component of FXR-mediated biological activity is attributed to the induction of endogenous FGF19.
- May combine two claims. 37
- The quote only partly states this claim. 3
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataThere was a dose-dependent decrease in serum concentrations of total bile acids, but it did not reach statistical significance.
“There was a dose‐dependent decrease in serum concentrations of total bile acids, but this did not reach statistical significance (Fig. 3B).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataNGM282 0.3 mg reduced alkaline phosphatase by 15.9% from baseline versus placebo -1.2% (least-squares mean difference -14.7%, 95% confidence interval -25.6% to -3.9%; P = 0.0092).
“Percentage change in ALP levels indicates a significant decrease in both the 0.3 mg (−15.9%) and 3 mg (−19.0%) groups, compared with the placebo group (−1.2%) (Supporting Fig. S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataResponse to NGM282 was rapid, with a significant decrease in alkaline phosphatase concentrations in both NGM282 groups on day 7, sustained throughout the duration of treatment.
“Response to NGM282 was rapid, with a significant decrease in ALP concentrations in both NGM282 groups on day 7, and was sustained throughout the duration of treatment (Fig. 2A and Supporting Fig. S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAlmost all adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the NGM282 and placebo groups for all organ classes and symptoms, with the exception of gastrointestinal disorders.
“Almost all adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the NGM282 and placebo groups for all organ classes and symptoms, with the exception of gastrointestinal disorders (Table 4).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataNGM282 3 mg reduced alkaline phosphatase by 19.0% from baseline versus placebo -1.2% (least-squares mean difference -17.9%, 95% confidence interval -29.0% to -6.7%; P = 0.0025).
“Percentage change in ALP levels indicates a significant decrease in both the 0.3 mg (−15.9%) and 3 mg (−19.0%) groups, compared with the placebo group (−1.2%) (Supporting Fig. S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere were no deaths or potentially life-threatening adverse events reported during the study.
“There were no deaths or potentially life‐threatening adverse events reported during the study.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataNGM282 significantly reduced serum concentrations of transaminases and immunoglobulins compared with placebo.
“NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLDL-C levels in the NGM282 3-mg group showed a trend toward improvement (−13.1 mg/dL), not significant (P = 0.07).
“LDL‐C levels in the NGM282 3‐mg group showed a trend toward improvement (−13.1 mg/dL), albeit not significant (P = 0.07).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMeasures of vital signs were similar among the three groups and there were no abnormal clinically significant electrocardiogram results for any of the patients.
“Measures of the vital signs were similar among the three groups and there were no abnormal clinically significant electrocardiogram results for any of the patients.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMost treatment-related adverse events were gastrointestinal and mild in severity.
“Most treatment‐related adverse events were gastrointestinal and mild in severity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNew therapies such as peroxisome proliferator-activated receptor agonists reduce alkaline phosphatase levels but are associated with elevated transaminase concentrations or creatinine levels in patients with primary biliary cholangitis.
“New therapies, such as agonists of peroxisome proliferator‐activated receptors, reduce ALP levels but are associated with elevated transaminase concentrations or creatinine levels.9”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, et al. Seladelpar (MBX‐8025), a selective PPAR‐delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double‐blind, randomised, placebo‐controlled, phase 2, proof‐of‐concept study. Lancet Gastroenterol Hepatol 2017; 2: 716‐ 726. 28818518 source
Not checked in the free run.
May combine two claims.
PremisecitationNGM282 is a nontumorigenic analogue of fibroblast growth factor 19 being evaluated for the treatment of primary biliary cholangitis.
“NGM282 is a nontumorigenic analogue of FGF19 being evaluated for the treatment of PBC.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014; 74: 3306‐ 3316. 24728076 source
Not checked in the free run.
- cites [16] Zhou M, Yang H, Learned RM, Tian H, Ling L. Non‐cell‐autonomous activation of IL‐6/STAT3 signaling mediates FGF19‐driven hepatocarcinogenesis. Nat Commun 2017; 8: 15433. 28508871 PMC5440856 source
Not checked in the free run.
May combine two claims.
PremisecitationReduction in alkaline phosphatase levels has been validated as a surrogate marker of slower disease progression and improved transplant-free overall survival in patients with primary biliary cholangitis.
“Reduction in ALP levels has been validated as a surrogate marker of slower disease progression as well as improved transplant‐free overall survival.4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow‐up study. Gastroenterology 2014; 147: 1338‐ 1349,e1335; quiz e1315. 25160979 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationFibroblast growth factor 19 is an endocrine hormone induced in the gut by activation of the farnesoid X receptor.
“FGF19 is an endocrine hormone that is induced in the gut by activation of FXR.10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR‐FGF15/19 pathway. Dig Dis 2015; 33: 327‐ 331. 26045265 PMC4465534 source
Not checked in the free run.
May combine two claims.
PremisecitationHigher alkaline phosphatase levels correlate with disease progression and are associated with higher risk of liver transplantation or death in patients with primary biliary cholangitis.
“Higher levels of ALP correlate with disease progression, and are associated with higher risk of liver transplantation or death.4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow‐up study. Gastroenterology 2014; 147: 1338‐ 1349,e1335; quiz e1315. 25160979 source
Not checked in the free run.
May combine two claims.
PremisecitationEctopic overexpression of fibroblast growth factor 19 in mice results in development of hepatocellular carcinoma, limiting the therapeutic potential of fibroblast growth factor 19.
“However, the therapeutic potential of FGF19 is limited by concerns about tumorigenicity, as ectopic overexpression of FGF19 in mice results in the development of hepatocellular carcinoma.14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002; 160: 2295‐ 2307. 12057932 PMC1850847 source
Not checked in the free run.
May combine two claims.
PremisecitationTreatment with obeticholic acid, alone or in combination with ursodiol, reduces alkaline phosphatase levels but is associated with worsening pruritus and increased serious adverse events in patients with primary biliary cholangitis.
“Treatment with OCA, alone or in combination with ursodiol, resulted in a reduction in ALP levels, but was associated with worsening pruritus and increased serious adverse events.8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo‐controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375: 631‐ 643. 27532829 source
Not checked in the free run.
May combine two claims.
Study design and conductreasoningA sample of 12 patients per group would provide 90% power to detect a significant difference between the study drug group and the placebo group, and allowing for a 15% drop-out rate, 15 subjects per group (total 45) were needed.
“On the basis of a two‐sided test of equality of binomial proportions at an alpha level of 5%, we calculated that a sample of 12 patients per group would provide the trial with 90% power to detect a significant difference between the study drug group and the placebo group, in agreement with previous studies.22, 23”
- Also stated in: § Statistical Analysis · hedged
“Allowing for a 15% drop‐out rate per treatment group, it was estimated that 15 subjects were needed to be allocated to each treatment group, requiring a total sample size of 45 for the study.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22] Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148: 751‐ 761,e758. 25500425 source
Not checked in the free run.
- cites [23] Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018; 67: 1890‐ 1902. 29023915 PMC5947631 source
Not checked in the free run.
- Also stated in: § Statistical Analysis · hedged
May combine two claims.
PremisecitationIn animal models of cholestasis and cholangiopathy, NGM282 inhibited bile acid synthesis, reduced excess hepatic bile acid accumulation, and protected mice from liver injury induced by intrahepatic or extrahepatic cholestasis without carcinogenesis.
“In animal models of cholestasis and cholangiopathy, NGM282 inhibited bile acid synthesis, reduced excess hepatic bile acid accumulation, and protected mice from liver injury induced by intrahepatic or extrahepatic cholestasis without carcinogenesis.13, 17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6: 247ra100. 25080475
Not checked in the free run.
- cites [17] Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2‐deficient mice. Hepatology 2016; 63: 914‐ 929. 26418580 PMC5063176
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationFGF19 expression is induced in response to FXR activation in the ileum.
“FGF19 expression is induced in response to FXR activation in the ileum.10”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR‐FGF15/19 pathway. Dig Dis 2015; 33: 327‐ 331. 26045265 PMC4465534 source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn this double-blind, randomized, placebo-controlled phase 2 trial, treatment with NGM282 reduced ALP levels, as well as markers of cholestasis, hepatocellular injury, immunity and inflammation, in patients with PBC who had inadequate response to ursodiol.
“In this double‐blind, randomized, placebo‐controlled phase 2 trial, treatment with NGM282, an engineered analogue of FGF19, reduced ALP levels, as well as markers of cholestasis, hepatocellular injury, immunity and inflammation, in patients with PBC who had inadequate response to ursodiol.”
Quote in the paperSubstantial claim- Rests on an assumption: Patients with PBC who have inadequate response to ursodiol are more difficult to treat and at greatest risk for adverse outcomes.
May combine two claims.
Interpretationown dataResults from this study demonstrate that an FGF19 analogue can safely modulate disease activity in patients with PBC.
“Results from this study demonstrate that an FGF19 analogue can safely modulate disease activity in patients with PBC.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenInvestigators, patients, sponsor, clinical site staff, and medical monitor remained blinded throughout the study period.
“Investigators, patients, sponsor, clinical site staff, and medical monitor remained blinded throughout the study period.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationElevated levels of ALP are prognostic of worse clinical outcomes in PBC, with lower levels of ALP associated with longer transplant-free survival and improved overall survival.
“Elevated levels of ALP are prognostic of worse clinical outcomes in PBC, with lower levels of ALP associated with longer transplant‐free survival and improved overall survival.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow‐up study. Gastroenterology 2014; 147: 1338‐ 1349,e1335; quiz e1315. 25160979 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataThe trial was a multicenter, randomized, double-blind, placebo-controlled study.
“This trial was a multicenter evaluation of NGM282 in a randomized, double‐blind, placebo‐controlled study.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe study protocol was approved by institutional review boards and national ethics and regulatory agencies and was conducted in accordance with the International Conference on Harmonization E6 Good Clinical Practice Guidelines and the Declaration of Helsinki.
“The study protocol was approved by institutional review boards and national ethics and regulatory agencies and was conducted in accordance with the International Conference on Harmonization E6 Good Clinical Practice Guidelines and the Declaration of Helsinki.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataPatients were randomized 1:1:1 using an interactive voice/web response system to once-daily subcutaneous NGM282 doses of 0.3 mg, NGM282 3 mg, or placebo for 28 days.
“Patients were randomized 1:1:1 using an interactive voice/web response system to once‐daily subcutaneous NGM282 doses of 0.3 mg, NGM282 3 mg, or placebo for 28 days.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn healthy human subjects, NGM282 reduced serum concentration of 7α-hydroxy-4-cholesten-3-one (C4), a surrogate marker for enzymatic activity of CYP7A1, and was found to be safe and well tolerated.
“In healthy human subjects, NGM282 reduced serum concentration of 7α‐hydroxy‐4‐cholesten‐3‐one (C4), a surrogate marker for enzymatic activity of CYP7A1, and was found to be safe and well tolerated.13”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6: 247ra100. 25080475
Not checked in the free run.
May combine two claims.
Interpretationown dataNGM282 was generally safe and well tolerated.
“NGM282 was generally safe and well tolerated.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationALP-lowering is regarded as an important treatment strategy and the primary efficacy outcome for clinical trials in PBC.
“Despite the fact that meta‐analyses of randomized clinical trials of a number of drug classes have not shown consistent improvement in ALP and lower risk of liver complications or death in PBC patients,25, 26, 27, 28 ALP‐lowering is regarded as an important treatment strategy and the primary efficacy outcome for clinical trials in PBC.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [25] Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012; 12: CD000551. 23235576 PMC7045744
Not checked in the free run.
- cites [26] Prince M, Christensen E, Gluud C. Glucocorticosteroids for primary biliary cirrhosis. Cochrane Database Syst Rev 2005: CD003778. 15846681 PMC8729220
Not checked in the free run.
- cites [27] Giljaca V, Poropat G, Stimac D, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev 2010: CD004385. 20464729 PMC13500184
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThis trial was registered with ClinicalTrials.gov (NCT02026401).
“This trial was registered with ClinicalTrials.gov (NCT02026401).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThree patients in the 3-mg NGM282 group were excluded from the efficacy analysis (1 withdrew consent, 1 missed at least 5 doses, 1 discontinued dosing on day 23 and delayed the final lab draw for 3 days).
“Three patients in the 3‐mg NGM282 group were excluded from the efficacy analysis: 1 patient withdrew consent, 1 patient missed at least 5 doses, and 1 patient discontinued dosing on day 23 and delayed the final lab draw for 3 days.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningPatients were stratified according to their pruritus status to ensure equitable distribution across the treatment arms.
“Patients were stratified according to their pruritus status, as defined by the severity assessment in the 5‐D itch questionnaire,19 to ensure equitable distribution across the treatment arms.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFXR is increasingly recognized as a master regulator of bile acid metabolism in human physiology and health, and synthetic activators of FXR have been recently approved or are currently in clinical development for treatment of chronic liver diseases.
“FXR is increasingly recognized as a master regulator of bile acid metabolism in human physiology and health, and synthetic activators of FXR have been recently approved or are currently in clinical development for treatment of chronic liver diseases.29”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Jhaveri MA, Kowdley KV. New developments in the treatment of primary biliary cholangitis—role of obeticholic acid. Ther Clin Risk Manag 2017; 13: 1053‐ 1060. 28860789 PMC5572954
Not checked in the free run.
May combine two claims.
Interpretationown dataNGM282 administered for 28 days resulted in significant improvements in alkaline phosphatase and transaminase levels compared with placebo, with an acceptable safety profile in patients with primary biliary cholangitis.
“Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe efficacy population included all randomized subjects who received at least one dose of drug and had at least one valid, non-missing postdose value for efficacy or pharmacodynamic parameter.
“The efficacy population was used to assess efficacy and pharmacodynamics endpoints and included all randomized subjects who received at least one dose (full or partial) of drug, and had at least one valid, non‐missing postdose value for efficacy or pharmacodynamic parameter.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Study design and conductnone givenThis is the first randomized, placebo-controlled trial to report the effect of an FGF19 analogue in patients with PBC.
“First, this is the first randomized, placebo‐controlled trial to report the effect of an FGF19 analogue in patients with PBC.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPruritus is the most common symptom in patients with PBC, and can be further exacerbated by OCA.
“Pruritus is the most common symptom in patients with PBC, and can be further exacerbated by OCA, a recently approved therapy.8, 22, 23”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [8] Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo‐controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375: 631‐ 643. 27532829 source
Not checked in the free run.
- cites [22] Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148: 751‐ 761,e758. 25500425 source
Not checked in the free run.
- cites [23] Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018; 67: 1890‐ 1902. 29023915 PMC5947631 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationProposed pruritogens include bile acids, lysophosphatidic acid/autotaxin, and modulators of the TGR5 receptor, opioidergic, or serotonergic pathways.
“Although the pathogenesis of pruritus is poorly understood, proposed pruritogens include bile acids, lysophosphatidic acid/autotaxin, and modulators of the TGR5 receptor, opioidergic, or serotonergic pathways.33, 34”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Bolier AR, Peri S, Oude Elferink RP, Beuers U. The challenge of cholestatic pruritus. Acta Gastroenterol Belg 2012; 75: 399‐ 404. 23402082
Not checked in the free run.
- cites [34] Beuers U, Kremer AE, Bolier R, Elferink RP. Pruritus in cholestasis: facts and fiction. Hepatology 2014; 60: 399‐ 407. 24807046 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPatients with PBC typically present with hyperlipidemia, showing elevated levels of TC, HDL-C and LDL-C, which is not associated with increased atherosclerotic diseases in this population.
“Patients with PBC typically present with hyperlipidemia, showing elevated levels of TC, HDL‐C and LDL‐C,31 which is not associated with increased atherosclerotic diseases in this population.32”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [31] Su TC, Hwang JJ, Kao JH. Hypercholesterolemia in primary biliary cirrhosis. N Engl J Med 2007; 357: 1561‐ 1562. 17928612 source
Not checked in the free run.
- cites [32] Allocca M, Crosignani A, Gritti A, Ghilardi G, Gobatti D, Caruso D, et al. Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis. Gut 2006; 55: 1795‐ 1800. 16632556 PMC1856484 source
Not checked in the free run.
May combine two claims.
Interpretationown data28 days of treatment with NGM282, administered subcutaneously in patients with PBC who had inadequate response to ursodiol, resulted in improvement in the serum levels of ALP, ALT, AST, GGT, IgG, IgM, and other biochemical markers of disease.
“In conclusion, 28 days of treatment with NGM282, administered subcutaneously in patients with PBC who had inadequate response to ursodiol, resulted in improvement in the serum levels of ALP, ALT, AST, GGT, IgG, IgM, and other biochemical markers of disease.”
Quote in the paperSubstantial claim- Rests on an assumption: Patients with PBC who have inadequate response to ursodiol are more difficult to treat and at greatest risk for adverse outcomes.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenPruritus and other symptoms of PBC were monitored throughout the trial and detailed records of these data were collected for analysis.
“Third, pruritus and other symptoms of PBC were monitored throughout the trial and detailed records of these data were collected for analysis.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningLiver biopsies are not routinely conducted to assess disease progression in patients with PBC; therefore, assessment of fibrosis was not performed in this trial.
“Liver biopsies are not routinely conducted to assess disease progression in patients with PBC; therefore, assessment of fibrosis was not performed in this trial.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataChanges in GCA levels correlated with changes in pruritus, and consequently, GCA concentration may serve as a marker of pruritus response to treatment.
“Interestingly, changes in GCA levels correlated with changes in pruritus, and consequently, GCA concentration may serve as a marker of pruritus response to treatment.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataTreatment with 3-mg NGM282 significantly reduced levels of TC, primarily due to reductions in LDL-C.
“Treatment with 3‐mg NGM282 significantly reduced levels of TC, primarily due to reductions in LDL‐C.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study population consisted entirely of Caucasian patients.
“Finally, the study population consisted entirely of Caucasian patients.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFXR activation alters transcriptome beyond the induction of endogenous FGF19, affecting numerous target genes including bile acid transporters in the liver.
“Furthermore, FXR activation alters transcriptome beyond the induction of endogenous FGF19, affecting numerous target genes including bile acid transporters in the liver.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Zhan L, Liu HX, Fang Y, Kong B, He Y, Zhong XB, et al. Genome‐wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes. PLoS One 2014; 9: e105930. 25198545 PMC4157742
Not checked in the free run.
May combine two claims.
Study design and conductreasoningThe results were collected during a study that involved a short duration of treatment (28 days) with NGM282, and consequently, the corresponding analysis was limited to surrogate biomarkers and symptoms.
“In particular, the results reported here were collected during a study that involved a short duration of treatment (28 days) with NGM282, and consequently, the corresponding analysis was limited to surrogate biomarkers and symptoms.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationOCA, a recently approved therapy for PBC, was associated with reduced levels of HDL-C, with unclear implications on long-term cardiovascular outcome.
“In contrast, OCA, a recently approved therapy for PBC, was associated with reduced levels of HDL‐C, with unclear implications on long‐term cardiovascular outcome.8”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo‐controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375: 631‐ 643. 27532829 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Study design and conductnone givenThe sample size was similar to previous proof-of-concept studies, albeit smaller than some later-stage phase 2 studies.
“The sample size was similar to previous proof‐of‐concept studies, albeit smaller than some later‐stage phase 2 studies.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationNGM282 is a nontumorigenic analogue of FGF19 that retains its metabolic activity.
“In contrast, NGM282 is a nontumorigenic analogue of FGF19 that retains its metabolic activity.13, 15”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014; 6: 247ra100. 25080475
Not checked in the free run.
- cites [15] Zhou M, Wang X, Phung V, Lindhout DA, Mondal K, Hsu JY, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res 2014; 74: 3306‐ 3316. 24728076 source
Not checked in the free run.
The paper relies on this without support.
Patients with PBC who have inadequate response to ursodiol are more difficult to treat and at greatest risk for adverse outcomes.
“Second, this multicenter, international study population included patients with inadequate response to ursodiol, who are more difficult to treat and at greatest risk for adverse outcomes.”
The paper relies on this without support.
A significant component of FXR-mediated biological activity is attributed to the induction of endogenous FGF19.
“A significant component of FXR‐mediated biological activity is attributed to the induction of endogenous FGF19.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In patients with PBC, 28 days of aldafermin/NGM282 slightly improved liver enzymes, with gastrointestinal symptoms (mostly diarrhoea).
“Aldafermin/NGM282: PBC (phase 2)131: 28 days of aldafermin slightly improved liver enzymes. Side effects: gastrointestinal symptoms (mostly diarrhoea).”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [131]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
The 3-mg ALP confidence interval has two upper bounds
MinorThe text reports an upper confidence bound of −18.3 IU/L, while Table 2 gives −18.2 IU/L for the same comparison.
“–69.3 IU/L (95% CI –120.5 to –18.3; P = 0.0030)”
“| LS mean difference (95%CI) | | ‐54.3 (‐104.2 to ‐4.5) | ‐69.3 (‐120.5 to ‐18.2) |”
Claim of no worsening pruritus conflicts with a reported case
MinorThe abstract says no worsening was observed with NGM282, whereas the results report worsening in one NGM282-treated patient by the 5-D itch method.
“No worsening of pruritus was observed with NGM282 treatment.”
“Two patients in the placebo group versus 1 patient in the NGM282 0.3‐mg group and none in the 3‐mg group developed worsening of pruritus during the study by the 5‐D itch method.”
The citation lists haven’t been fetched yet
References 38 · Cited by 125
Research works printed but not linked: 2
- 1994, Ursodiol for the long‐term treatment of primary biliary cirrhosis. The UDCA‐PBC Study Group, N Engl J Med, 330, 1342, 10.1056/NEJM199405123301903 · DOI · Paper page
- 2002, A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice, Am J Pathol, 160, 2295, 10.1016/S0002-9440(10)61177-7 · DOI · Paper page
- Authors
- Mayo, M. J., Wigg, A. J., Leggett, B. A., Arnold, H., Thompson, A. J., Weltman, M., Carey, E. J., Muir, A. J., Ling, L., Rossi, S. J., & DePaoli, A. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Flinders Medical Center,Adelaide,South Australia,Australia
- The University of Queensland (AU)
- Digestive Research Center,San Antonio,Texas
- St Vincent's Hospital Melbourne (AU)
- Nepean Hospital (AU)
- Mayo Clinic in Arizona (US)
- Duke University (US)
- NGM Biopharmaceuticals (United States) (US)
- Corresponding author
- Mayo, Marlyn J.
- ORCID
- Venue
- Hepatology Communications
- Published
- 2018-08-30
- Volume
- 2
- Issue
- 9
- Pages
- 1037-1050
- ISSN
- 2471-254X (ISSN-L)
- PMC
- PMC6128239
- OpenAlex
- W2888935993
- Cited by
- 125
- References
- 38
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 15 · 2023: 12 · 2022: 21 · 2021: 20 · 2020: 15 · 2019: 25 · 2018: 2
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Hepatology Communications (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NGM Biopharmaceuticals
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- primary biliary cirrhosis, alkaline phosphatase, bile acid synthesis, liver fibrosis, transaminases, immunoglobulins, adverse events, drug safety, liver transplantation risk, mortality risk, subcutaneous administration, dose comparison
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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