MRI‐Proton Density Fat Fraction Treatment Response Criteria in Nonalcoholic Steatohepatitis

Loomba, Rohit

doi:10.1002/hep.31624

Cited by 28 publications

(29 citation statements)

References 11 publications

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“…The primary efficacy end point was change in liver fat by MRI-PDFF imaging at 12 weeks. 22,23 TVB-2640 treatment resulted in significant relative and absolute reductions of liver fat compared to placebo in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 93%

“…Secondary outcomes included MRI-PDFF responder criteria assessment as defined by a relative reduction in MRI-PDFF of 30% given its association with histologic response. [21][22][23]…”

Section: Discussionmentioning

confidence: 99%

“…In other studies, NASH patients who achieved an MRI-PDFF response (relative reduction of 30% liver fat), after 12-24 weeks of treatment have been shown later to have improved liver histology on repeat liver biopsy, and this response has emerged as a strong and important indicator of NASH histologic improvement. 21,23,26 Patients with an MRI-PDFF response have a 7-fold increase in the improvement of NAFLD Activity Score by 2 or more points, a 5-fold increase in the rate of NASH resolution and improved fibrosis compared to those who do not achieve a response. 21,27 These rates of histologic improvement are likely even higher in subjects who achieve a 50% reduction of liver fat by MRI-PDFF.…”

Section: Discussionmentioning

confidence: 99%

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TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

Loomba

Mohseni²,

Lucas³

et al. 2021

Gastroenterology

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123

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BACKGROUND & AIMS: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States. METHODS: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with 8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography 2.5 kPa or liver biopsy were eligible. Ninetynine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment. RESULTS: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n ¼ 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P ¼ .053), and 28.1% in the 50-mg cohort (n ¼ 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P ¼ .001). Eleven percent of patients in the placebo group achieved a 30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups. CONCLUSIONS: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.

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Section: Resultsmentioning

confidence: 93%

“…Secondary outcomes included MRI-PDFF responder criteria assessment as defined by a relative reduction in MRI-PDFF of 30% given its association with histologic response. [21][22][23]…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

Loomba

Mohseni²,

Lucas³

et al. 2021

Gastroenterology

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123

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“…114 The ability of MRI-PDFF to track change in liver steatosis has been evaluated as a secondary endpoint in clinical trials with paired liver biopsies. [172][173][174][175] These preliminary studies have shown that changes in MRI-PDFF values correlate well with changes in steatosis on liver biopsy. In addition, it has been suggested that MRI-PDFF could be more sensitive than liver biopsy to detect small changes in liver steatosis.…”

Section: Evaluation Of Treatment Response In Therapeutic Trialsmentioning

confidence: 84%

EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update

Berzigotti¹,

Tsochatzis²,

Boursier³

et al. 2021

Journal of Hepatology

899

615

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“…Meaningful responses are being classified as those demonstrating either (i) a resolution of steatohepatitis as defined by a ballooning score of 0 and an inflammation score of 0-1 and no worsening of liver fibrosis, (ii) improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis, or (iii) both resolution of steatohepatitis and improvement in fibrosis (8), often expressed as a two-point change in the NAFLD activity score (NAS) with no worsening in fibrosis. Analysis of a trial of ezetimibe in NASH showed that PDFF could distinguish histological responders from non-responders (32), which was later characterized as a relative reduction of~30% liver fat corresponding to a two-point change in NAS (33,34). Equally, data on the ability of cT1 to measure changes in fibroinflammatory disease have recently been published (30,31).…”

Section: Introductionmentioning

confidence: 99%

Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis

Dennis¹,

Kelly²,

Fernandes³

et al. 2021

Front. Endocrinol.

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IntroductionLate stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. The well-reported limitations with biopsy, such as associated risks and sampling error, coupled with patient preference, are driving investigation into non-invasive alternatives. MRI-derived biomarkers proton density fat fraction (PDFF) and iron-corrected T1 mapping (cT1) are gaining traction as emerging alternatives to biopsy for NASH. Our aim was to explore the correlations between cT1 and PDFF (from LiverMultiScan®), with the histological components on the NAFLD-NASH spectrum in a large cohort of cross-sectional data, in order to calibrate the measurement to histology, and to infer what might constitute a clinically meaningful change when related to the FDA’s criteria.Materials and MethodsIn a retrospective analysis of data combined from three previously published observational NASH studies, in which adult participants who underwent liver biopsy on suspicion of NAFLD or NASH and had an MRI scan measuring cT1 and PDFF (LiverMultiScan®, Perspectum Ltd, UK), associations between imaging biomarkers and histology were tested using Spearman’s rank correlation coefficient (rs), and further exploration of the relationships between the imaging variables and histology were performed using linear regression.ResultsN = 264 patients with mean age of 54 (SD:9.9), 39% female, and 69% with BMI ≥ 30kg.m−2 were included in the analysis. cT1 and PDFF both correlated with all features of the NAFLD activity score (NAS). cT1 was also positively correlated with Kleiner-Brunt fibrosis. Partial correlations, adjusting for steatosis, revealed cT1 correlated with inflammation and fibrosis, whereas PDFF did not, and both were still associated with the NAS, but correlation was weaker with PDFF than cT1. An estimated difference of 88 ms in cT1, or 21% relative difference in PDFF was related to a two-point difference in overall NAS.ConclusionThe correlations between cT1 and PDFF with the histopathological hallmarks of NASH demonstrate the potential utility of both cT1 and PDFF as non-invasive biomarkers to detect a pharmacodynamic change in NASH, with cT1 showing superiority for detecting changes in inflammation and fibrosis, rather than liver fat alone.

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MRI‐Proton Density Fat Fraction Treatment Response Criteria in Nonalcoholic Steatohepatitis

Cited by 28 publications

References 11 publications

TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update

Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis

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