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WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
REPORTING FROM DDW 2018