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VIDEO: FXR agonists provide multiple hepatic improvements in NASH

BOSTON — In this exclusive video from The Liver Meeting 2019, Arun Sanyal, MD, professor of medicine at Virginia Commonwealth University, highlights new data on emerging therapeutics for nonalcoholic steatohepatitis presented at the meeting.

“This year at the meeting, several important studies were presented, which reflect significant advances in the treatment of NASH,” Sanyal told Healio Gastroenterology and Liver Disease. He then discussed outcomes from studies of Ocaliva (obeticholic acid, Intercept) and tropifexor (Novartis).

In the phase 3 REGENERATE trial of obeticholic acid, an FXR agonist that has shown antifibrotic and anti-inflammatory effects, Sanyal and colleagues observed dose-dependent reductions in alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase among patients with fibrosis stage 1 to stage 3.

The data showed greater liver stiffness reductions in patients treated with 10 mg (–0.56 vs 1.11; P = .0187) or 25 mg obeticholic acid (–1.3 vs. 1.11; P = .0008), as measured by transient elastography compared with placebo.

“In addition, several noninvasive markers were shown to improve concomitantly with the use of obeticholic acid and demonstrated superior sensitivity to change than routine histology, which provides us an opportunity to further explore the use of these markers as response markers to assess the course of patients on treatment,” he said.

Regarding tropifexor, another FXR agonist, interim results from the third part of an adaptive-design trial showed improvement in liver enzymes and hepatic steatosis with no significant signal for hepatotoxicity and modest change in both LDL and HDL cholesterol at 12 weeks.

“These data are compatible with the mechanism of action of this molecule, which is through the activation of the FXR pathway and has a signature quite similar to other reported FXRs,” Sanyal said. “Importantly, very few patients had to discontinue treatment because of side effects, giving us hope that this pathway can be further leveraged particularly ... to develop combination therapies for NASH.”

Reference:

Anstee QM, et al. Abstract 1715. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Lucas KJ, et al. Abstract LO4. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Sanyal AJ, et al. Abstract 0034. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Disclosure: Sanyal reports he has an advisory committee or review panel role with Axcella Health; is a stock shareholder with Akarna, Durect, Exhalenz, Galmed, Genfit, Indalo, Sanyal Biotechnology and Tiziana; has received grant or research support from Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Cirius Therapeutics, Cumberland, Echosens, Galectin, Gilead, Intercept, Malinckrodt, Merck, Novartis, Salix and Sequana; and is a consultant for 89Bio, Afimmune, Albireo, Allergan, AMRA Medical, Ardelyx, AstraZeneca, BASF, Birdrock, Boehringer Ingelheim, Chemomab, Cirius, Conatus, Echosens, Elsevier, ENYO Pharma, Fractyl, General Electric, Gilead, Hemoshear, IFMO, Immuron, Innovate, Intercept, Janssen, Lilly, Lipocine, Malinckrodt, NGM Bio, Nimbus, Nitto Denko, Novartis, NorthSea Therapeutics, Novo Nordisk, OWL, Perspectum, Pfizer, Poxel, RedX, Salix, Sanofi, Second Genome, Servier, Sundise, Takeda, Terns, Teva, Uptodate and Zydus.

BOSTON — In this exclusive video from The Liver Meeting 2019, Arun Sanyal, MD, professor of medicine at Virginia Commonwealth University, highlights new data on emerging therapeutics for nonalcoholic steatohepatitis presented at the meeting.

“This year at the meeting, several important studies were presented, which reflect significant advances in the treatment of NASH,” Sanyal told Healio Gastroenterology and Liver Disease. He then discussed outcomes from studies of Ocaliva (obeticholic acid, Intercept) and tropifexor (Novartis).

In the phase 3 REGENERATE trial of obeticholic acid, an FXR agonist that has shown antifibrotic and anti-inflammatory effects, Sanyal and colleagues observed dose-dependent reductions in alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase among patients with fibrosis stage 1 to stage 3.

The data showed greater liver stiffness reductions in patients treated with 10 mg (–0.56 vs 1.11; P = .0187) or 25 mg obeticholic acid (–1.3 vs. 1.11; P = .0008), as measured by transient elastography compared with placebo.

“In addition, several noninvasive markers were shown to improve concomitantly with the use of obeticholic acid and demonstrated superior sensitivity to change than routine histology, which provides us an opportunity to further explore the use of these markers as response markers to assess the course of patients on treatment,” he said.

Regarding tropifexor, another FXR agonist, interim results from the third part of an adaptive-design trial showed improvement in liver enzymes and hepatic steatosis with no significant signal for hepatotoxicity and modest change in both LDL and HDL cholesterol at 12 weeks.

“These data are compatible with the mechanism of action of this molecule, which is through the activation of the FXR pathway and has a signature quite similar to other reported FXRs,” Sanyal said. “Importantly, very few patients had to discontinue treatment because of side effects, giving us hope that this pathway can be further leveraged particularly ... to develop combination therapies for NASH.”

Reference:

Anstee QM, et al. Abstract 1715. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Lucas KJ, et al. Abstract LO4. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Sanyal AJ, et al. Abstract 0034. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.

Disclosure: Sanyal reports he has an advisory committee or review panel role with Axcella Health; is a stock shareholder with Akarna, Durect, Exhalenz, Galmed, Genfit, Indalo, Sanyal Biotechnology and Tiziana; has received grant or research support from Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Cirius Therapeutics, Cumberland, Echosens, Galectin, Gilead, Intercept, Malinckrodt, Merck, Novartis, Salix and Sequana; and is a consultant for 89Bio, Afimmune, Albireo, Allergan, AMRA Medical, Ardelyx, AstraZeneca, BASF, Birdrock, Boehringer Ingelheim, Chemomab, Cirius, Conatus, Echosens, Elsevier, ENYO Pharma, Fractyl, General Electric, Gilead, Hemoshear, IFMO, Immuron, Innovate, Intercept, Janssen, Lilly, Lipocine, Malinckrodt, NGM Bio, Nimbus, Nitto Denko, Novartis, NorthSea Therapeutics, Novo Nordisk, OWL, Perspectum, Pfizer, Poxel, RedX, Salix, Sanofi, Second Genome, Servier, Sundise, Takeda, Terns, Teva, Uptodate and Zydus.

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