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Summary
Background Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, Published Online
inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment March 5, 2018
http://dx.doi.org/10.1016/
exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety
S0140-6736(18)30474-4
and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis.
See Online/Comment
http://dx.doi.org/10.1016/
Methods In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18–75 years S0140-6736(18)30425-2
with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research Radcliffe Department of
network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA. Medicine, University of Oxford,
Key eligibility criteria included a non-alcoholic fatty liver disease activity score of 4 or higher, stage 1–3 fibrosis, and at Oxford, UK
(Prof S A Harrison MD); Division
least 8% liver fat content. Patients were randomly assigned (1:1:1) via a web-based system and stratified by diabetic of Gastroenterology and
status to receive either 3 mg or 6 mg subcutaneous NGM282 or placebo. The primary endpoint was the absolute Hepatology, Northwestern
change from baseline to week 12 in liver fat content. Responders were patients who achieved a 5% or larger reduction University, Chicago, IL, USA
(Prof M E Rinella MD); Duke
in absolute liver fat content as measured by MRI-proton density fat fraction. Efficacy analysis was by intention to treat.
University, Durham, NC, USA
This trial is registered with ClinicalTrials.gov, number NCT02443116. (Prof M F Abdelmalek MD);
Clinical Research and
Findings Between July 14, 2015, and Aug 30, 2016, 166 patients were screened across 18 sites in Australia and the USA. Education, Texas Digestive
Disease Consultants, Dallas, TX,
82 patients were randomly assigned to receive 3 mg NGM282 (n=27), 6 mg NGM282 (n=28), or placebo (n=27). At
USA (J F Trotter MD); Division of
12 weeks, 20 (74%) patients in the 3 mg dose group and 22 (79%) in the 6 mg dose group achieved at least a Gastroenterology and
5% reduction in absolute liver fat content from baseline (relative risk 10·0 [95% CI 2∙6–38∙7] vs 11∙4 [3∙0–43∙8], Hepatology, Brooke Army
respectively; p<0·0001 for both comparisons) versus two (7%) in the placebo group. Overall, 76 (93%) of 82 patients Medical Center, San Antonio,
TX, USA (A H Paredes MD);
experienced at least one adverse event, most of which were grade 1 (55 [67%]), and only five (6%) were grade 3 or
Gastroenterology Consultants
worse. The most commonly (≥10%) reported adverse events were injection site reactions (28 [34%]), diarrhoea of San Antonio, Live Oak, TX,
(27 [33%]), abdominal pain (15 [18%]), and nausea (14 [17%]). These adverse events were reported more frequently in USA (H L Arnold MD);
the NGM282 groups compared with the placebo group. No life-threatening events or patient deaths occurred during Hepatology, South Denver
Gastroenterology, Englewood,
the study.
CO, USA (M Kugelmas MD);
Department of Radiology,
Interpretation NGM282 produced rapid and significant reductions in liver fat content with an acceptable safety profile Duke University Medical
in patients with non-alcoholic steatohepatitis. Further study of NGM282 is warranted in this patient population. Center, Durham, NC, USA
(M R Bashir MD); Summit
Analytical, Denver, CO, USA
Funding NGM Biopharmaceuticals. (M J Jaros PhD); NGM
Biopharmaceuticals, Inc,
Introduction coexisting obesity, type 2 diabetes, insulin resistance, San Francisco, CA, USA
(L Ling PhD, S J Rossi PharmD,
Non-alcoholic fatty liver disease encompasses a spectrum hypertension, or dyslipidaemia.1 A M DePaoli MD); and
of chronic hepatic diseases ranging from simple steatosis Although the mechanism underlying the development Non-Alcoholic Fatty Liver
(fatty liver) to the more aggressive non-alcoholic and progression from simple steatosis to non-alcoholic Disease Research Center,
steatohepatitis. Non-alcoholic steatohepatitis involves a steatohepatitis and cirrhosis is poorly understood, insulin Division of Gastroenterology
and Epidemiology, University
fatty liver with inflammation and hepatocellular in resistance, lipotoxicity, cytokines, oxidative stress, and of California San Diego,
jury (with or without fibrosis).1 The prevalence of other inflammatory mediators are believed to promote San Francisco, CA, USA
non-alcoholic fatty liver disease is increasing, with the development of non-alcoholic steatohepatitis and its (Prof R Loomba MD)
estimates ranging from 20% to 40% of adults in countries extrahepatic complications.4 Excess lipotoxic metabolites Correspondence to:
adopting a western diet with the disease, 10–20% of in the liver are believed to provide the primary insult Dr Stephen A Harrison, Pinnacle
Clinical Research Group, Live Oak,
whom progress to non-alcoholic steatohepatitis.1 Patients in the pathogenesis of non-alcoholic steatohepatitis, TX 78233, USA
with non-alcoholic steatohepatitis are at increased risk of but evidence supporting a role for bile acids in the sharrison@pinnacleresearch.
cirrhosis and hepatocellular carcinoma, and non- pathogenesis of liver inflammation and fibrosis is com
alcoholic steatohepatitis is projected to be the lead emerging.5 Accumulation of bile acids within hepatocytes
ing indication for liver transplant in 2020.2,3 Further, can cause mitochondrial dysfunction, endoplasmic
most patients with non-alcoholic steatohepatitis have reticulum stress, and immune cell infiltration that can
Research in context
Evidence before this study (AST), and non-invasive serum fibrosis biomarkers
Non-alcoholic fatty liver disease includes a spectrum of (pro-C3 and enhanced liver fibrosis score). The greatest
chronic hepatic diseases, with non-alcoholic steatohepatitis treatment effect was recorded in patients with more severe
being the most aggressive phenotype, leading to an increased disease (high baseline liver fat content and ALT). Decreases in
risk of developing cirrhosis and hepatocellular carcinoma. To liver fat content were strongly correlated with decreases in
identify clinical trials of the treatment of non-alcoholic fatty 7α-hydroxy-4-cholesten-3-one (C4), ALT, AST, and increases
liver disease and non-alcoholic steatohepatitis, we searched in low-density lipoprotein cholesterol (LDL-C). Overall, these
PubMed for English language articles published from data are the most impressive to date among pharmacological
Jan 1, 2007, to Oct 15, 2017, with the search terms, “NAFLD”, agents previously and currently being tested in
“NASH”, “fatty liver”, and “FGF19”. We found no controlled non-alcoholic steatohepatitis. Both doses of NGM282 were
clinical trials investigating an FGF19 analogue in the generally well tolerated with mild adverse events. Significant
treatment of non-alcoholic steatohepatitis, and therefore the decreases in serum C4 concentrations, and the ensuing
current study represents a first-in-class trial in this patient increases in LDL-C were recorded with NGM282, consistent
population. NGM282 is a non-tumorigenic analogue of with potent target engagement and inhibition of CYP7A1.
FGF19 that retains the ability to suppress CYP7A1 without Studies are ongoing to elucidate whether NGM282-related
activating STAT3 signalling. Based on the established increases in LDL-C can be mitigated with concomitant
preclinical biological activity, NGM282 is currently statin use.
being assessed for the treatment of non-alcoholic
Implications of all the available evidence
steatohepatitis.
There is an unmet need in the treatment of non-alcoholic
Added value of this study steatohepatitis, and no Food and Drug
Our findings show that 3 mg and 6 mg doses of NGM282 Administration-approved treatments currently exist. The
produced rapid and sustained improvements in liver fat results of our phase 2 study show the efficacy of NGM282 in
content over 12 weeks as measured by MRI–proton density rapidly decreasing liver fat content and markers of
fat fraction (MRI-PDFF). Hepatic imaging with MRI-PDFF is inflammation and fibrosis, highlighting its therapeutic
highly sensitive to changes in liver fat content compared with potential in non-alcoholic steatohepatitis. Larger clinical trials
histological evaluation. NGM282 also significantly decreased of longer duration are now needed to fully assess the safety
alanine aminotransferase (ALT), aspartate aminotransferase and efficacy of NGM282.
ultimately lead to inflammation, cell death, and liver non-alcoholic steatohepatitis. NGM282 (also known
injury. Individuals with non-alcoholic steatohepatitis are as M70) differs from wild-type FGF19 in the amino
reported to have elevated hepatic and circulating terminus, a key region of the protein involved in receptor
concentrations of bile acids, as well as increased interactions and signalling modulation. In NGM282,
concentrations of faecal and urine bile acids.6,7 a 5-aminoacid deletion (P24–S28) coupled with the
Fibroblast growth factor 19 (FGF19), an endocrine substitution of three aminoacids at crucial positions
gastrointestinal hormone, regulates bile acid, carbo- (Ala30Ser, Gly31Ser, and His33Leu) within the amino
hydrate, and energy homoeostasis.8,9 The hormone terminus enable biased FGFR4 signalling so that
controls bile acid metabolism via actions on NGM282 retains the ability to potently repress CYP7A1
CYP7A1, the first and rate-limiting enzyme in the expression.13 Importantly, unlike FGF-19, NGM282
classic pathway of bile acid synthesis from cholesterol. does not activate signal transducer and activator of
FGF19 also exerts insulin-like actions on glycogen transcription 3 (STAT3), a signalling pathway essential
synthesis and gluconeogenesis, thus having the for FGF19-mediated hepatocarcinogenesis.14 Further
potential to regulate multiple pathways involved in more, NGM282 can block hepatocarcinogenesis associ
non-alcoholic steato hepatitis pathogenesis. Notably, ated with human FGF19.13 In animal models of
circulating FGF19 concentration is reduced in patients non-alcoholic steatohepatitis, treatment with NGM282
with non-alcoholic steatohepatitis,10,11 further suggesting resulted in a rapid and robust reduction in concentrations
that dysregulated FGF19 expression might contribute of alanine aminotransferase (ALT) and aspartate amino
to mechanisms governing non-alcoholic steatohepatitis- transferase (AST), as well as a clear improvement in
related progressive liver diseases. However, the thera all histological features associated with non-alcoholic
peutic potential of FGF19 has been hindered by its steatohepatitis, including hepatic steatosis, inflammation,
hepatocarcinogenicity, as shown by findings of studies ballooning degeneration, and fibrosis.15 NGM282 was
in which mice expressing an FGF19 transgene dev safe and well tolerated in healthy volunteers and was
eloped hepatocellular carcinoma.12 associated with reduction in serum concentrations of
NGM282, a non-tumorigenic variant of FGF19, is a 7 α-hydroxy-4-cholesten-3-one (C4), a biomarker of
recombinant protein being studied for treatment of hepatic CYP7A1 activity.16
We aimed to assess the efficacy and safety of NGM282 4 (≥1 point in each component of steatosis, lobular
versus placebo in adult patients with non-alcoholic inflammation, and hepatocellular ballooning); stage 1, 2, or
steatohepatitis using MRI-proton density fat fraction 3 fibrosis; liver fat content 8% or higher as assessed by
(PDFF) to assess changes in liver fat content. MRI-PDFF; and elevated ALT concentrations (≥19 IU/L in
women and ≥30 IU/L in men). These eligibility criteria
Methods were amended on Sept 2, 2015, while blinded from
Study design and participants previous criteria of non-alcoholic fatty liver disease activity
In this multicentre, international, randomised, double- score of 5 or higher and liver fat content of at least 10%,
blind, placebo-controlled, phase 2 trial, patients with which were deemed too restrictive. Exclusion criteria
biopsy-confirmed non-alcoholic steatohepatitis were included clinically significant acute or chronic liver
enrolled across 18 hospitals and gastroenterology and disease unrelated to non-alcoholic steatohepatitis; evi
liver clinics in Australia and the USA. The study protocol dence of drug-induced steatohepatitis; history or presence
and relevant supporting data were approved by local of compensated or decompensated cirrhosis; liver
ethics committees before study initiation. The study was transplantation; any cardiovascular event or evidence of
done in compliance with International Conference active cardiovascular disease within 6 months of screen
on Harmonisation, E6 Good Clinical Practice. Dose ing; and type 1 diabetes (appendix p 3). Patients See Online for appendix
selection was based on phase 1 ascending dose were required to remain on stable regimen of their
studies showing 3 mg as the lowest dose with maximal previous type 2 diabetes and lipid-lowering treatments
C4 reduction (unpublished data). The 12-week treat during the study period. All patients provided written
ment duration was selected based on previous trials informed consent.
investigating liver fat content.17,18
Patients were eligible if they met the following inclusion Randomisation and masking
criteria: aged 18–75 years at the time of screening; biopsy- Patients were randomly assigned (1:1:1) via Interactive
confirmed non-alcoholic steatohepatitis diagnosis as Web Response System in randomly permuted blocks
defined by the non-alcoholic steatohepatitis clinical (block size six) to receive 3 mg or 6 mg subcutaneous
research network histological scoring system,19 with a NGM282 or placebo once a day. The placebo was provided
minimum non-alcoholic fatty liver disease activity score of as identical pre-filled syringes in identical containers
84 excluded
18 did not meet histology criteria
18 did not meet MRI criteria
11 withdrew consent or were lost to follow-up
37 did not meet criteria (other)
82 randomly assigned
27 had both baseline and 27 had both baseline and 26 had both baseline and
week 12/EOT MRI week 12/EOT MRI week 12/EOT MRI
of 22 patients per group. As shown by findings of previous Type 2 diabetes 17 (63%) 15 (56%) 17 (61%)
studies, an absolute change in liver fat content of 5% is Hyperlipidaemia 8 (30%) 10 (37%) 15 (54%)
the minimal clinically relevant difference between active Hypertension 21 (78%) 15 (56%) 18 (64%)
treatment and placebo, and correlates with improvements Concomitant medications
in liver histology.17,22,23 Sample size power calculations Antidiabetic
were based on varying common standard deviations to Metformin 14 (52%) 13 (48%) 14 (50%)
achieve an overall (overall F test) significant treatment Insulin 4 (15%) 3 (11%) 5 (18%)
effect of 6% or higher reduction from baseline in liver fat GLP-1 agonists 3 (11%) 3 (11%) 5 (18%)
content with 3 mg or 6 mg NGM282, and a reduction of DPP4 inhibitors 1 (%) 3 (11%) 0
1% or lower in the placebo group (all at a significance SGLT2 inhibitors 3 (11%) 0 2 (7%)
level of 5%). The efficacy population was used to assess Other 4 (15%) 2 (7%) 4 (14%)
efficacy and pharmacodynamic endpoints, and included Antilipidaemic
all randomly assigned and enrolled patients who received Statins 7 (26%) 12 (44%) 14 (50%)
at least one dose (full or partial) of study drug and had a Non-statins 8 (30%) 8 (30%) 8 (29%)
baseline and week 12 or end of treatment MRI-PDFF with Antihypertensives 25 (93%) 21 (78%) 23 (82%)
at least one valid, non-missing post-dose efficacy or Other
pharmacodynamic parameter value. We analysed efficacy Pioglitazone 0 0 1 (4%)
with the intention-to-treat population defined as all Vitamin E 2 (7%) 2 (7%) 0
patients who underwent randomisation. Patients in each Histopathology
treatment group were categorised as either responders or Fibrosis stage
non-responders. The two patients in the NGM282 6 mg 1 11 (41%) 11 (41%) 10 (36%)
group who did not have an end of treatment MRI-PDFF 2 7 (26%) 7 (26%) 12 (43%)
imaging were imputed as non-responders. 3 9 (33%) 9 (33%) 6 (21%)
We compared the absolute change in liver fat content Total NAS activity score 5∙1 (1∙1)* 5∙1 (1∙0) 5∙1 (0∙9)
from baseline to week 12 between treatment groups Hepatocyte ballooning score
using analysis of covariance (ANCOVA), with treatment 0 (none) 0 0 0
group and diabetic status as cofactors and baseline liver
1 (few ballooned cells) 13 (48%) 15 (56%) 21 (75%)
fat content and ALT as a covariate at the 5% level of
2 (many ballooned cells) 13 (48%) 12 (44%) 7 (25%)
significance. Least-squares (LS) means with stand
Steatosis score
ard errors (SE), differences in LS means with SE,
0 (<5%) 0 0 0
95% confidence intervals (CIs), and the corresponding
1 (5–33%) 6 (22%) 6 (22%) 3 (11%)
p values were calculated. Categorical endpoints were
2 (34–66%) 14 (52%) 12 (44%) 15 (54%)
analysed using χ² test or Fisher’s exact test. To adjust for
3 (>66%) 6 (22%) 9 (33%) 10 (36%)
multiple comparisons, the step down Bonferroni method
Lobular inflammation score
was used for analysis between treatment groups.
0 (none) 0 0 0
Normalisation was defined as patients with an MRI-PDFF
1 (<2) 10 (37%) 12 (44%) 12 (43%)
value of 5% or lower at end of treatment. We analysed
2 (2-4) 14 (52%) 14 (52%) 16 (57%)
secondary and exploratory endpoints with the same
methods as for the primary outcome. For continuous 3 (>4) 2 (7%) 1 (4%) 0
outcomes measured repeatedly over weeks, all values (Table 1 continues on next page)
were summarised at each timepoint and comparisons to
Response (%)
alkaline phosphatase among the treatment groups –8
(table 3, figure 3C). Of note, despite rebound, 40 –10
concentrations of ALT and AST remained significantly –9·7
reduced at week 16 follow-up, 4 weeks after cessation of –13 p<0·0001
–11·9
treatment (appendix). Reductions in C4 concentrations 20
7 –14 p=0·112
from baseline to week 12 were significant for both
p<0·0001
NGM282 groups (p<0∙0001); these changes were also 0 –16
Placebo (n=27) 3 mg (n=27) 6 mg (n=28) Placebo 3 mg 6 mg
significant when compared with the placebo group
(p<0∙0001 for both comparisons; table 3, figure 3D). C D
More than 65% of participants were at or below the limit –0
–3
of quantification for the C4 assay (0·9 ng/mL) as soon as 40%
–10
week 1 of NGM282 treatment. Despite significant
Absolute to relative change in LFC (%)
Change from Change from Change from LS mean difference, 3 mg p value LS mean difference, 6 mg p value
baseline to week baseline to week 12, baseline to week NGM282 group vs placebo NGM282 group vs placebo
12, placebo group 3 mg NGM282 12, 6 mg NGM282 group group
(n=27) group (n=27) group (n=28)
Liver fat content by MRI-PDFF
Liver fat content (%) −0∙1 (3∙03) −9∙6 (6∙92) −12∙5 (7∙94) −8·8 (1∙4; −11∙6 to −6∙1) <0·0001 −11∙1 (1∙4; −13∙9 to −8∙3) <0∙0001
Baseline 8–15% −0∙22 (3∙3) −5∙43 (3∙2) −6∙28 (4∙1) ∙∙ ∙∙ ∙∙ ∙∙
Baseline >15–20% 0∙62 (2∙5) −11∙5 (3∙0) −12 (2∙4) ∙∙ ∙∙ ∙∙ ∙∙
Baseline >20% −0∙3 (3∙3) −12∙9 (8∙8) −18∙9 (6∙3) ∙∙ ∙∙ ∙∙ ∙∙
ALT
Overall ALT (IU/L) −2∙2 (21∙1) −35∙0 (44∙6) −32∙1 (35∙3) −35·1 (6∙0; −47∙1 to −23∙1) <0·0001 −36∙5 (6∙1; −48∙7 to −24∙2) <0∙0001
Baseline ALT >60 (IU/L) −9∙5 (22∙6) −63∙1 (58∙6) −54∙5 (42∙4) ∙∙ ∙∙ ∙∙ ∙∙
Baseline ALT 40-60 (IU/L) 0 (18∙9) −24∙4 (7∙3) −21∙5 (17∙2) ∙∙ ∙∙ ∙∙ ∙∙
Baseline ALT <40 (IU/L) 12∙7 (22∙0) −6∙8 (12∙5) −9∙1 (8∙6) ∙∙ ∙∙ ∙∙ ∙∙
7α-hydroxy-4-cholesten-3-one (C4)
C4 (ng/mL) 11∙7 (32∙4) −48∙5 (57∙1) −25∙9 (26∙2) −43·2 (7∙4; −58∙0 to −28∙4) <0·0001 −39∙3 (7∙2; −53∙6 to −25∙0) <0∙0001
Liver function
AST (IU/L) −0∙6 (23∙9) −17∙9 (20∙8) −17∙0 (21∙2) −20·4 (4∙7; −29∙8 to −11∙0) <0·0001 −22∙5 (5∙0; −32∙4 to −12∙7) <0∙0001
ALP (IU/L) −0∙1 (21∙9) −0∙5 (19∙8) 2∙3 (16∙5) 0·7 (5∙2; −9∙6 to 11∙0) 0·90 1∙7 (5∙1; -8∙4 to 11∙9) 0·74
GGT (IU/L) 0∙3 (32∙7) 10∙3 (62∙3) −3∙3 (53∙3) 11·6 (13∙7; −15∙8 to 40∙0) 0·40 −4∙2 (14∙0; −32∙1 to 23∙7) 0·77
Total bilirubin 0 (0∙1) 0 (0∙2) 0 (0∙2) 0·1 (0; 0 to 0∙2) 0·11 0∙1 (0; 0 to 0∙2) 0·09
Albumin (g/L) 0 (0∙3) 0∙2 (0∙4) 0∙1 (0∙3) 0·2 (0∙1; 0 to 0∙4) 0·08 0∙2 (0∙1; 0 to 0∙3) 0·12
Fibrosis biomarkers
Pro-C3 (ng/mL) −1∙21 (10∙7) −5∙4 (10∙7) −3∙6 (8∙3) −4·0 (2∙2; −8∙3 to 0∙3) 0·07 −4∙6 (2∙1; −8∙9 to −0∙4) 0·0342
Patients with >15% decrease 6/25 (24%) 17/23 (74%) 19/25 (76%) ∙∙ 0·0005 ∙∙ 0·0002
in pro-C3
ELF score 0 (0∙5) −0∙3 (0∙6) −0∙1 (0∙6) −0·3 (−0∙2; 0∙7 to 0) 0·047 −0∙2 (0∙2; −0∙5 to 0∙2) 0·33
Hyaluronic acid (UG/L) 7∙0 (55∙9) −5∙5 (32∙0) 22∙6 (107∙4) −7·5 (21∙4; −50∙5 to 35∙4) 0·73 21∙7 (22∙3; −23 to 66∙3) 0·34
PIIINP (UG/L) 0 (3∙1) −2∙9 (5∙6) −1∙5 (4∙3) −2·5 (1∙3; −5 to 0) 0·052 −2∙2 (1∙3; −4∙8 to 0∙4) 0·10
TIMP-1 (UG/L) 5∙2 (69∙4) −25∙9 (39∙2) −18∙0 (41∙0) −40·7 (14∙2; −69∙1 to −12∙3) 0·006 −35∙1 (14∙8; −64∙8 to −5∙4) 0·021
Lipids
Triglycerides (mmol/L) –0∙1 (0∙8) –0∙4 (1∙3) –0∙5 (0∙8) –0·1 (0∙2; –0∙5 to 0∙2 0·51 –0∙5 (0∙2; –0∙8 to –0∙1) 0·012
Cholesterol (mmol/L) 0 (0∙6) 1∙1 (1∙0) 0∙8 (0∙8) 1·1 (0∙2; 0∙6 to 1∙5) <0·0001 0∙8 (0∙2; 0∙4 to 1∙2) 0·0002
HDL (mmol/L) 0 (0∙2) 0 (0∙3) 0 (0∙3) 0 (0; –0∙1 to 0∙1) 0·74 0 (0; –0∙1 to 0∙2) 0·57
LDL (mmol/L) 0 (0∙5) 1∙2 (1∙0) 1∙0 (0∙8) 1·2 (0∙2; 0∙7 to 1∙6) <0·0001 ∙0 (0∙2; 0∙6 to 1∙5) <0∙0001
Concomitant statin 0∙2 (0∙5) 1∙1 (0∙7) 1∙0 (0∙6) ∙∙ ∙∙ ∙∙ ∙∙
No concomitant statin –0∙1 (0∙5) 1∙2 (1∙3) 1∙0 (0∙9) ∙∙ ∙∙ ∙∙ ∙∙
Metabolic factors
Glucose (mg/dL) −1∙7 (60∙6) 2∙9 (31∙3) 2∙9 (29∙7) −4·1 (8∙6; −21∙3 to 13∙2) 0·64 −0∙1 (8∙8; −17∙6 to 17∙4) 0·99
HbA1c (%) −0∙1 (1∙0) −0∙2 (0∙7) −0∙1 (0∙5) −0·2 (0∙2; −0∙5 to 0∙2) 0·37 0 (0∙2; −0∙4 to 0∙3) 0·85
Insulin (pmol/L) –0∙5 (2∙0) –0∙9 (4∙9) 0∙2 (2∙3) 0·2 (0∙8; -1∙4 to 1∙9 ) 0·78 0∙6 (0∙9; -1∙2 to 2∙3) 0·50
HOMA-IR 1∙13 (6∙7) −0∙9 (8∙7) 0∙7 (7∙8) −1·4 (2∙2; −5∙8 to 2∙9) 0·51 −0∙5 (2∙2; −5 to 3∙9) 0·81
Weight (kg) −0∙8 (2∙4) −1∙2 (3∙5) −2∙7 (3∙4) −0·4 (0∙8; −2∙0 to 1∙3) 0·67 −2∙0 (0∙9; −3∙7 to −0∙3) 0·023
BMI (kg/m²) −0∙2 (0∙9) −0∙4 (1∙6) −0∙9 (1∙3) −0·3 (0∙3; −0∙9 to 0∙4) 0·42 −0∙8 (0∙3; −1∙5 to −0∙1) 0·024
Waist circumference (cm) −2∙5 (12∙8) −0∙3 (4∙5) −4∙6 (12∙6) 3·1 (2∙9; −2∙8 to 8∙9) 0·30 −1∙4 (3∙0; −7∙3 to 4∙5) 0·65
Data are mean (SD), SE (95% CI), unless otherwise stated. ALP=alkaline phosphatase. ALT=alanine aminotransferase. AST=aspartate aminotransferase. ELF=enhanced liver fibrosis. GGT=α -glutamyl
transpeptidase. HbA1C=glycated haemoglobin. HDL=high-density lipoprotein. HOMA-IR=homoeostasis model assessment-estimated insulin resistance. LDL=low-density lipoprotein. LS=least squares.
MRI-PDFF=MRI-proton density fat fraction. PIIINP=N-terminal pro-peptide of collagen III. Pro-C3=N-terminal type III collagen pro-peptide. SD=standard deviation∙ SE=standard error. TIMP-1=tissue inhibitor of
metalloproteinase 1.
baseline to week 12 in participants given 3 mg NGM282 metabolic factors including glucose, HbA1c, insulin,
compared with those in the placebo group (table 3). HOMA-IR, or waist circumference (all p>0∙05). Patients
We recorded no significant placebo-adjusted changes in the 6 mg NGM282 group reported significant
from baseline to week 12 for the NGM282 groups in reductions in weight and BMI compared with placebo
A B
Placebo 3 mg 6 mg
80 80
70 70
60 60
50 50
*
AST (IU/L)
ALT (IU/L)
†
40 * † 40 *
* * * * † *
30 * * 30 *
* * *
20 * 20 †
10 End of 10 End of
treatment Follow-up treatment Follow-up
0 0
C D
80 80
60
70
50
50
C4 (ng/mL)
ALP (IU/L)
40
30
20
End of
10 treatment
End of 10 *
* * *
treatment Follow-up
0 0 * * * *
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18
Week Week
Figure 3: Levels of alanine aminotransferase (A), aspartate aminotransferase (B), alkaline phosphatase (C), and 7α-hydroxy-4-cholesten-3-one (D) over time
*p<0·001. †p<0·01.
(table 3), but the reductions in liver fat content were pain in 15 (18%), and nausea in 14 (17%; table 4). These
independent of weight loss and BMI. adverse events were reported more frequently in the
Six (22%) of 27 patients in the 3 mg dose group and NGM282 groups than the placebo group. Treatment-
seven (25%) of 28 in the 6 mg dose group tested positive related adverse events occurred in 60 patients; the
for antidrug antibodies; only three patients had titres majority of which were mild (grade 1/2; table 4).
above background (one patient from the NGM282 3 mg Two (7%) patients in the 3 mg dose group had treatment-
cohort had a titre of 1:22, two patients from the 6 mg related grade 3 adverse events (one patient with
cohort had titres of 1:18 and 1:23, respectively). Titres were aggravated abdominal pain, one patient with acute
low in the remaining ten patients (all with a titre of 1:3), pancreatitis) compared with two (7%) in the 6 mg dose
which were considered background levels because a titre group (one patient with nausea or abdominal pain, one
of 1:3 was also detected in two patients in the placebo patient with depression), and one (4%) patient in the
group. Absolute liver fat content changed from 26·9% at placebo group (increased hepatic enzyme). No grade 4
baseline to 14·0% at end of treatment for the patient with treatment-related adverse events were reported in any
a titre of 1:22 in the 3 mg cohort, from 15·0% to 7·0% for treatment group. One patient in the 3 mg dose group
the patient with a titre of 1:18 in the 6 mg cohort, and experienced a serious adverse event (acute pancreatitis),
from 14·0% to 18·0% for the patient with a titre of 1:23 in which was resolved with standard clinical support. This
the 6 mg cohort. The NGM282 levels (Cmin) were singular case of pancreatitis was unlikely to be related to
16·6 ng/mL, 14·3 ng/mL, and 46·9 ng/mL at end of study drug because the patient was on other medications
treatment in these three patients, respectively. None of known to be associated with pancreatitis and the
the antidrug antibodies tested positive for neutralising patient also previously had a cholecystectomy. Study
activity against FGF19. drug withdrawal because of adverse events occurred in
Overall, 76 (93%) of 82 patients reported at least one three (11%) of 27 patients in the 3 mg NGM282 group
adverse event, most of which were grade 1 (55 [67%]), (four events in three patients; aggravated abdominal
and only five (6%) experienced adverse events that were pain, acute pancreatitis and increased lipase, aggravated
grade 3 or worse. The most commonly (≥10%) re nausea) and three (11%) of 28 patients in the 6 mg
ported adverse events were injection site reactions in dose group (three events in three patients; loose
28 (34%) patients, diarrhoea in 27 (33%), abdominal stools, injection site reaction, and depression). No
administration of a statin can mitigate NGM282-related content, as well as markers of liver inflammation and
increases in LDL-C.29 fibrosis. Additionally, both doses were generally well
A strength of this trial was the use of non-invasive tolerated. These results support the further exploration
MRI-PDFF to evaluate changes in liver fat content as of NGM282 for the safe and effective treatment of
opposed to histological evaluation. Subjects enrolled in non-alcoholic steatohepatitis.
this study had both pre- and post-treatment MRI exams, Contributors
and MRI scans were read centrally in a manner similar to SAH, MER, MFA, MK, SJR, AMD, and RL participated in study design.
that described previously.26 MRI-PDFF is highly sensitive SAH, MER, MFA, JFT, AHP, HLA, MK, MRB, RL were responsible for
data collection. SAH, MJJ, LL, SJR participated in data analysis.
to changes in liver fat content, is non-invasive and highly SAH, MER, MFA, JFT, AHP, HLA, MK, MRB, LL, SJR, AMD,
repeatable, provides quantitative estimates of overall liver RL participated in data interpretation. All authors participated in
fat content, and is less vulnerable to sampling error than manuscript review and writing. SAH, LL, SJR were responsible for
liver biopsy alone. Importantly, MRI-PDFF has been preparation of the tables and figures.
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