Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension

Chalasani, Naga; Abdelmalek, Manal F.; García–Tsao, Guadalupe; Vuppalanchi, Raj; Alkhouri, Naim; Rinella, Mary E.; Noureddin, Mazen; Pyko, Maxmillan; Shiffman, Mitchell L.; Sanyal, Arun J.; Allgood, Adam; Shlevin, Harold; Horton, R. G.; Zomer, Eliezer; Irish, William; Goodman, Zachary; Harrison, Stephen A.; Traber, Peter G.; Balart, Luis A.; Borg, Brian B.; Charlton, Michael; Conjeevaram, Hari S.; Fuchs, Michael; Ghalib, Reem; Gholam, Pierre M.; Marzio, Dina Halegoua-De; Jue, Christopher; Kemmer, Nyingi; Kowdley, Kris V.; Lai, Michelle; Lawitz, Eric; Loomba, Rohit; Paredes, Angelo H.; Rockey, Don C.; Rodríguez, M.A; Rubin, Raymond A.; Ryan, Michael; Scanga, Andrew; Sepe, Thomas; Tetri, Brent A.; Thuluvath, Paul J.; Torres, Dawn M.; Vierling, John M.; Wattacheril, Julia; Weiland, Amanda; Zogg, Donald L.

doi:10.1053/j.gastro.2019.11.296

Cited by 245 publications

(185 citation statements)

References 27 publications

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“…Phase 2: No effect on fibrosis following within 52 weeks of treatment in NASH patients. Significant protective effects on hepatocyte ballooning as well as significant lower HPVG and varices development in a subgroup of patients with NASH cirrhosis [352].…”

Section: Inhibitor Of Galectin-3 Belapectinmentioning

confidence: 92%

“…Belapectin, an inhibitor or galectin-3 has shown potent anti-fibrotic efficacy in mouse and rat models of liver fibrosis [349,350] and was well tolerated in a phase 1 clinical trial [351]. However, just recently published results of a phase 2b placebo-controlled clinical study of belapectin in patients with NASH and liver fibrosis showed no effect on fibrosis following treatment for 52 weeks [352]. Still, considering significant protective effects on hepatocyte ballooning as well as significant lower HPVG and varices development in a subgroup of patients with NASH cirrhosis, a phase 3 clinical study in patients with NASH cirrhosis without varices at baseline timepoint is currently being initiated.…”

Section: Immune Modulationmentioning

confidence: 99%

“…The medication was well tolerated by NASH patients. Most frequently reported mild-moderate adverse events included infections, gastrointestinal, and musculoskeletal, as well as connective tissue disorders [352].…”

Section: Immune Modulationmentioning

confidence: 99%

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Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

747

440

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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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Section: Inhibitor Of Galectin-3 Belapectinmentioning

confidence: 92%

Section: Immune Modulationmentioning

confidence: 99%

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Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

747

440

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“…Moreover, none of the new drugs or small molecules with diverse molecular targets on the pathways of hepatocyte injury, inflammation, and fibrosis can achieve primary efficacy endpoints. [5][6][7][8][9][10] Diverse factors have been postulated to contribute to the low success rate in NAFLD/NASH drug discovery, including lack of robust animal models needed for preclinical studies, insufficient target engagement or target modulation by the novel drugs, absence or insufficient demonstration of a proof-of-concept in early trials, and/or high false discovery rate (FDR) in phase 2 trials. 11 Likewise, it has been hypothesized that, as data on the candidate drugs are not only insufficient but are also not corroborated by genetic inactivation, pharmacological inhibition, antisense oligonucleotides, and/or small interfering RNAs, this poses an additional obstacle to achieve consistent and sustained effects on severe histological outcomes, including improvement in fibrosis scores.…”

Section: Introductionmentioning

confidence: 99%

Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology

Sookoian

Pirola

2020

Clin Mol Hepatol

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Despite more than two decades of extensive research focusing on nonalcoholic fatty liver disease (NAFLD), no approved therapy for steatohepatitis—the severe histological form of the disease—presently exists. More importantly, new drugs and small molecules with diverse molecular targets on the pathways of hepatocyte injury, inflammation, and fibrosis cannot achieve the primary efficacy endpoints. Precision medicine can potentially overcome this issue, as it is founded on extensive knowledge of the druggable genome/proteome. Hence, this review summarizes significant trends and developments in precision medicine with a particular focus on new potential therapeutic discoveries modeled via systems biology approaches. In addition, we computed and simulated the potential utility of the NAFLD polygenic risk score, which could be conceptually very advantageous not only for early disease detection but also for implementing actionable measures. Incomplete knowledge of the druggable NAFLD genome severely impedes the drug discovery process and limits the likelihood of identifying robust and safe drug candidates. Thus, we close this article with some insights into emerging disciplines, such as chemical genetics, that may accelerate accurate identification of the druggable NAFLD genome/proteome.

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“…In animal models of NASH, the compound decreases hepatic steatosis, proinflammatory cytokines and infiltration, fatty acid oxidation, hepatocyte apoptosis, and fibrosis [ 108 ]. In a recent phase 2b trial involving patients with cirrhosis secondary to NASH, belapectin showed a clinical effect in reducing portal pressure [ 109 ]. At the time of writing this article, clinical cardiovascular effects have not been studied, but we postulate that the medication will have positive effects on AF.…”

Section: Potential Therapies Targeting Nafld and Afmentioning

confidence: 99%

Nonalcoholic fatty liver disease and atrial fibrillation: possible pathophysiological links and therapeutic interventions

Haghbin

Gangwani

Ravi

et al. 2020

aog

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Atrial fibrillation (AF) and nonalcoholic fatty liver disease (NAFLD) share common risk factors and appear to have an association. Independently, the incidence and prevalence of both diseases are on the rise. Epidemiological evidence, experimental studies and various randomized clinical trials suggest a link between the 2 entities, delineating cumulative risks and clinical strategies to improve outcomes. Dyslipidemia, insulin resistance, inflammatory milieu, and activation of the renin-angiotensin system are likely common pathophysiological mechanisms linking AF and NAFLD. In this article we review the known pathways and pathophysiology that link the 2 conditions. This review also discusses therapies that target both NAFLD and AF, such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, metformin, and vitamin E. We further discuss other potential medications that have shown effects in NAFLD or AF through anti-inflammatory, antidiabetic, lipid-lowering, or renin-angiotensin system inhibiting effects. Future epidemiological studies are needed to establish a direct causal relationship between NAFLD and AF.

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Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension

Cited by 245 publications

References 27 publications

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology

Nonalcoholic fatty liver disease and atrial fibrillation: possible pathophysiological links and therapeutic interventions

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