‘Rich pipeline’ of novel NASH treatments being studied

AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.

AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.

AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.