International Liver Congress 2016

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.

Expanding HIV preexposure prophylaxis to cover people who inject drugs would reduce their disease burden by averting an estimated 26,700 new HIV infections every year, and would also benefit the health of the entire population, according to a cost-effectiveness analysis published online April 25 in Annals of Internal Medicine.

However, such a program would be very expensive, chiefly because of the high current cost of combination tenofovir-emtricitabine therapy, which is approximately $10,000 per patient per year. The overall expense would be higher than is generally considered cost-effective, both in absolute terms and in the cost per quality-adjusted life year (QALY) gained, said Cora L. Bernard of the department of management science and engineering, Stanford (Calif.) University, and her associates.

©grandeduc/Thinkstock

The investigators used a computer model to analyze the cost-effectiveness of a program offering this segment of the population daily oral tenofovir-emtricitabine plus HIV screening, assessment of adverse effects every 3 months, and antiretroviral treatment (ART) if HIV developed. It assumed that 25% of this group would follow such a program. The model incorporated the results of recent clinical trials along with epidemiologic and economic data such as the incidence of the infection in the approximately 0.56% of the U.S. adult population who use injectable drugs, the effectiveness of prevention programs in such populations, and the costs of treatment according to HIV stage and ART status. The model projected relative benefits and costs over the next 20 years.

Preexposure prophylaxis would prevent an estimated 26,700 new HIV infections among people who use injectable drugs each year, gaining 173,000 QALYs. However, the overall cost over the course of 20 years would be $44 billion, which is the equivalent of spending 10% of the total federal budget for domestic HIV-AIDS on just this small segment of the population. The cost per QALY would be $253,000, well above the generally accepted threshold for cost-effectiveness, the investigators said (Ann Intern Med. 2016 April 25. doi: 10.736/M15-2634).

If the eventual release of a generic version of tenofovir-emtricitabine reduced the price of treatment by 65%, this type of preexposure prophylaxis would cost a projected $100,000 per QALY gained. However, “cost-effectiveness is only one of many considerations for policymakers, who must also evaluate the ethical dimensions of [a national] HIV-prevention program for a population with generally low access to health services,” Ms. Bernard and her associates said.

The National Institute on Drug Abuse, Stanford University, the National Science Foundation, the U.S. Department of Veterans Affairs, and the National Institute on Aging funded the study. Ms. Bernard and her associates reported having no relevant disclosures.

Expanding HIV preexposure prophylaxis to cover people who inject drugs would reduce their disease burden by averting an estimated 26,700 new HIV infections every year, and would also benefit the health of the entire population, according to a cost-effectiveness analysis published online April 25 in Annals of Internal Medicine.

However, such a program would be very expensive, chiefly because of the high current cost of combination tenofovir-emtricitabine therapy, which is approximately $10,000 per patient per year. The overall expense would be higher than is generally considered cost-effective, both in absolute terms and in the cost per quality-adjusted life year (QALY) gained, said Cora L. Bernard of the department of management science and engineering, Stanford (Calif.) University, and her associates.

©grandeduc/Thinkstock

The investigators used a computer model to analyze the cost-effectiveness of a program offering this segment of the population daily oral tenofovir-emtricitabine plus HIV screening, assessment of adverse effects every 3 months, and antiretroviral treatment (ART) if HIV developed. It assumed that 25% of this group would follow such a program. The model incorporated the results of recent clinical trials along with epidemiologic and economic data such as the incidence of the infection in the approximately 0.56% of the U.S. adult population who use injectable drugs, the effectiveness of prevention programs in such populations, and the costs of treatment according to HIV stage and ART status. The model projected relative benefits and costs over the next 20 years.

Preexposure prophylaxis would prevent an estimated 26,700 new HIV infections among people who use injectable drugs each year, gaining 173,000 QALYs. However, the overall cost over the course of 20 years would be $44 billion, which is the equivalent of spending 10% of the total federal budget for domestic HIV-AIDS on just this small segment of the population. The cost per QALY would be $253,000, well above the generally accepted threshold for cost-effectiveness, the investigators said (Ann Intern Med. 2016 April 25. doi: 10.736/M15-2634).

If the eventual release of a generic version of tenofovir-emtricitabine reduced the price of treatment by 65%, this type of preexposure prophylaxis would cost a projected $100,000 per QALY gained. However, “cost-effectiveness is only one of many considerations for policymakers, who must also evaluate the ethical dimensions of [a national] HIV-prevention program for a population with generally low access to health services,” Ms. Bernard and her associates said.

The National Institute on Drug Abuse, Stanford University, the National Science Foundation, the U.S. Department of Veterans Affairs, and the National Institute on Aging funded the study. Ms. Bernard and her associates reported having no relevant disclosures.

Expanding HIV preexposure prophylaxis to cover people who inject drugs would reduce their disease burden by averting an estimated 26,700 new HIV infections every year, and would also benefit the health of the entire population, according to a cost-effectiveness analysis published online April 25 in Annals of Internal Medicine.

However, such a program would be very expensive, chiefly because of the high current cost of combination tenofovir-emtricitabine therapy, which is approximately $10,000 per patient per year. The overall expense would be higher than is generally considered cost-effective, both in absolute terms and in the cost per quality-adjusted life year (QALY) gained, said Cora L. Bernard of the department of management science and engineering, Stanford (Calif.) University, and her associates.

©grandeduc/Thinkstock

The investigators used a computer model to analyze the cost-effectiveness of a program offering this segment of the population daily oral tenofovir-emtricitabine plus HIV screening, assessment of adverse effects every 3 months, and antiretroviral treatment (ART) if HIV developed. It assumed that 25% of this group would follow such a program. The model incorporated the results of recent clinical trials along with epidemiologic and economic data such as the incidence of the infection in the approximately 0.56% of the U.S. adult population who use injectable drugs, the effectiveness of prevention programs in such populations, and the costs of treatment according to HIV stage and ART status. The model projected relative benefits and costs over the next 20 years.

Preexposure prophylaxis would prevent an estimated 26,700 new HIV infections among people who use injectable drugs each year, gaining 173,000 QALYs. However, the overall cost over the course of 20 years would be $44 billion, which is the equivalent of spending 10% of the total federal budget for domestic HIV-AIDS on just this small segment of the population. The cost per QALY would be $253,000, well above the generally accepted threshold for cost-effectiveness, the investigators said (Ann Intern Med. 2016 April 25. doi: 10.736/M15-2634).

If the eventual release of a generic version of tenofovir-emtricitabine reduced the price of treatment by 65%, this type of preexposure prophylaxis would cost a projected $100,000 per QALY gained. However, “cost-effectiveness is only one of many considerations for policymakers, who must also evaluate the ethical dimensions of [a national] HIV-prevention program for a population with generally low access to health services,” Ms. Bernard and her associates said.

The National Institute on Drug Abuse, Stanford University, the National Science Foundation, the U.S. Department of Veterans Affairs, and the National Institute on Aging funded the study. Ms. Bernard and her associates reported having no relevant disclosures.

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

BARCELONA – Although a new histological scoring system was able to predict mortality from nonalcoholic fatty liver disease (NAFLD), fibrosis remains the key predictor of whether an individual is likely to die decades later.

Patients with severe NAFLD, as determined by having a high steatosis, activity, and fibrosis (SAF) score, were more than twice as likely to die than those with mild-to-moderate disease up to 41 years later.

However, when a sensitivity analysis was performed to adjust for fibrosis stage or exclude patients with stage 3-4 fibrosis, the hazard ratio for mortality was no longer significant.

Sara Freeman/Frontline Medical News

“Severe SAF score was associated with increased mortality, but this largely depended on fibrosis stage,” Dr. Hannes Hagström of the Karolinska Institutet in Stockholm reported at the International Liver Congress.

Although it is known that the more severe the disease the more likely the risk for death, assessing the severity of NAFLD can be challenging for clinicians because it is a continuum of disease, he explained. “NAFLD is the most prevalent liver disease globally with a prevalence of around 25%; it is very heterogeneous and makes prognostication difficult.” This has implications for including people in trials and for determining what the clinical endpoints should be, as well as making it difficult to determine the outlook for individual patients.

There are several histological scoring systems developed over the years trying to help with this issue, including the Brunt score, the NAFLD activity score (NAS), and fibrosis stage.

While the latter has previously been shown to be a robust marker for mortality, the NAS has been criticized, Dr. Hagström noted. This is because the effect of steatosis may be overestimated and because NAS does not measure fibrosis. Thus, there is a need for new means to risk-stratify patients and one relatively new method is the SAF score.

The SAF score was developed to evaluate the severity of fatty liver lesions, originally in morbidly obese individuals (Hepatology. 2012 Oct;56:1751-9). Using this score, the extent of fatty accumulation in the liver can be assessed, with a score of 0 signifying that steatosis is present in less than 5% of the liver and a score of 3 signifying that more than two-thirds of the liver is affected. NAFLD activity is determined on a scale of 0 to 4 by assessing the degree of ballooning and lobular inflammation. Finally, the score looks at the extent of fibrosis, rating it from 0 (not present) to 4 (cirrhosis).

The aim of the study was to examine the impact of this score on overall mortality in a previously published (Hepatology. 2015 Mar;61:1547-54) cohort of patients with long follow-up, Dr. Hagström explained at the meeting sponsored by the European Association for the Study of the Liver (EASL). Data on 139 patients with biopsy-proven NAFLD were obtained from a historical cohort of patients who had undergone liver biopsy between 1974 and 1994. Their biopsies were reclassified using the SAF score and the presence of nonalcoholic steatohepatitis was also determined using the FLIP algorithm and the NAS score. Data on causes of death were taken from a national Swedish population register. At baseline, 35 patients had mild, 35 had moderate, and 69 had severe NAFLD.

After a median follow-up of 25 years, ranging from 2 to 41 years, 74 patients died. Of these deaths, 45 occurred in patients with severe NAFLD, representing 65% of the severe NAFLD group. Half (n = 18; 51%) of the patients with moderate NAFLD and just under one-third (n = 11; 31%) of those with mild NAFLD had also died. The median time to death was 18 years after liver biopsy.

Dr. Hagström reported that cardiovascular causes were the main cause of mortality, in 21% of patients; extrahepatic malignancy caused 12% of deaths, 7% of deaths were liver related, and 13% were due to other reasons. Patients with severe NAFLD identified by a high SAF score were more than two and a half times more likely to die than those with mild NAFLD, with a hazard ratio of 2.65 (P = .02). Patients with moderate NAFLD were no more likely than those with mild liver disease to die (HR = 1.23; P = .84). Data had been adjusted for gender, body mass index, and for the presence of type 2 diabetes.

HRs for mortality comparing high with low SAF scores after adjusting for fibrosis stage and excluding patients with fibrosis stages 3-4 were a respective 1.85 (P = .18) and 1.94 (P = .15). In a press statement issued by EASL, Dr. Laurent Castera of Hôpital Beaujon in Paris noted that these data were an important step forward for the medical community in being able to identify the patients who are most at risk of death from NAFLD. Dr. Castera, who is the secretary general of EASL, noted that these long-term study data also demonstrated the importance of having sufficient follow-up periods for patients with NAFLD.

In an interview after his presentation Dr. Hagström also emphasized the importance of long-term follow-up of patients.

“The clinical importance of this is that it is most important for clinicians to look at fibrosis stage, and I think to have to follow these patients a little bit more,” he said. “You can’t just do a liver biopsy, say ‘you just have steatosis, you don’t have NASH [nonalcoholic steatohepatitis], [so] you are fine’,” he added. Equally, it is not possible to say that because NASH is not present that patients won’t advance in the future. Patients need to be followed up for a long period of time.

“Fibrosis is the most important thing, both for clinicians and for patients,” Dr. Hagström said.Dr. Hagström has been a consultant to Novo Nordisk. Dr. Castera had no relevant financial disclosures.

BARCELONA – Although a new histological scoring system was able to predict mortality from nonalcoholic fatty liver disease (NAFLD), fibrosis remains the key predictor of whether an individual is likely to die decades later.

Patients with severe NAFLD, as determined by having a high steatosis, activity, and fibrosis (SAF) score, were more than twice as likely to die than those with mild-to-moderate disease up to 41 years later.

However, when a sensitivity analysis was performed to adjust for fibrosis stage or exclude patients with stage 3-4 fibrosis, the hazard ratio for mortality was no longer significant.

Sara Freeman/Frontline Medical News

“Severe SAF score was associated with increased mortality, but this largely depended on fibrosis stage,” Dr. Hannes Hagström of the Karolinska Institutet in Stockholm reported at the International Liver Congress.

Although it is known that the more severe the disease the more likely the risk for death, assessing the severity of NAFLD can be challenging for clinicians because it is a continuum of disease, he explained. “NAFLD is the most prevalent liver disease globally with a prevalence of around 25%; it is very heterogeneous and makes prognostication difficult.” This has implications for including people in trials and for determining what the clinical endpoints should be, as well as making it difficult to determine the outlook for individual patients.

There are several histological scoring systems developed over the years trying to help with this issue, including the Brunt score, the NAFLD activity score (NAS), and fibrosis stage.

While the latter has previously been shown to be a robust marker for mortality, the NAS has been criticized, Dr. Hagström noted. This is because the effect of steatosis may be overestimated and because NAS does not measure fibrosis. Thus, there is a need for new means to risk-stratify patients and one relatively new method is the SAF score.

The SAF score was developed to evaluate the severity of fatty liver lesions, originally in morbidly obese individuals (Hepatology. 2012 Oct;56:1751-9). Using this score, the extent of fatty accumulation in the liver can be assessed, with a score of 0 signifying that steatosis is present in less than 5% of the liver and a score of 3 signifying that more than two-thirds of the liver is affected. NAFLD activity is determined on a scale of 0 to 4 by assessing the degree of ballooning and lobular inflammation. Finally, the score looks at the extent of fibrosis, rating it from 0 (not present) to 4 (cirrhosis).

The aim of the study was to examine the impact of this score on overall mortality in a previously published (Hepatology. 2015 Mar;61:1547-54) cohort of patients with long follow-up, Dr. Hagström explained at the meeting sponsored by the European Association for the Study of the Liver (EASL). Data on 139 patients with biopsy-proven NAFLD were obtained from a historical cohort of patients who had undergone liver biopsy between 1974 and 1994. Their biopsies were reclassified using the SAF score and the presence of nonalcoholic steatohepatitis was also determined using the FLIP algorithm and the NAS score. Data on causes of death were taken from a national Swedish population register. At baseline, 35 patients had mild, 35 had moderate, and 69 had severe NAFLD.

After a median follow-up of 25 years, ranging from 2 to 41 years, 74 patients died. Of these deaths, 45 occurred in patients with severe NAFLD, representing 65% of the severe NAFLD group. Half (n = 18; 51%) of the patients with moderate NAFLD and just under one-third (n = 11; 31%) of those with mild NAFLD had also died. The median time to death was 18 years after liver biopsy.

Dr. Hagström reported that cardiovascular causes were the main cause of mortality, in 21% of patients; extrahepatic malignancy caused 12% of deaths, 7% of deaths were liver related, and 13% were due to other reasons. Patients with severe NAFLD identified by a high SAF score were more than two and a half times more likely to die than those with mild NAFLD, with a hazard ratio of 2.65 (P = .02). Patients with moderate NAFLD were no more likely than those with mild liver disease to die (HR = 1.23; P = .84). Data had been adjusted for gender, body mass index, and for the presence of type 2 diabetes.

HRs for mortality comparing high with low SAF scores after adjusting for fibrosis stage and excluding patients with fibrosis stages 3-4 were a respective 1.85 (P = .18) and 1.94 (P = .15). In a press statement issued by EASL, Dr. Laurent Castera of Hôpital Beaujon in Paris noted that these data were an important step forward for the medical community in being able to identify the patients who are most at risk of death from NAFLD. Dr. Castera, who is the secretary general of EASL, noted that these long-term study data also demonstrated the importance of having sufficient follow-up periods for patients with NAFLD.

In an interview after his presentation Dr. Hagström also emphasized the importance of long-term follow-up of patients.

“The clinical importance of this is that it is most important for clinicians to look at fibrosis stage, and I think to have to follow these patients a little bit more,” he said. “You can’t just do a liver biopsy, say ‘you just have steatosis, you don’t have NASH [nonalcoholic steatohepatitis], [so] you are fine’,” he added. Equally, it is not possible to say that because NASH is not present that patients won’t advance in the future. Patients need to be followed up for a long period of time.

“Fibrosis is the most important thing, both for clinicians and for patients,” Dr. Hagström said.Dr. Hagström has been a consultant to Novo Nordisk. Dr. Castera had no relevant financial disclosures.

BARCELONA – Although a new histological scoring system was able to predict mortality from nonalcoholic fatty liver disease (NAFLD), fibrosis remains the key predictor of whether an individual is likely to die decades later.

Patients with severe NAFLD, as determined by having a high steatosis, activity, and fibrosis (SAF) score, were more than twice as likely to die than those with mild-to-moderate disease up to 41 years later.

However, when a sensitivity analysis was performed to adjust for fibrosis stage or exclude patients with stage 3-4 fibrosis, the hazard ratio for mortality was no longer significant.

Sara Freeman/Frontline Medical News

“Severe SAF score was associated with increased mortality, but this largely depended on fibrosis stage,” Dr. Hannes Hagström of the Karolinska Institutet in Stockholm reported at the International Liver Congress.

Although it is known that the more severe the disease the more likely the risk for death, assessing the severity of NAFLD can be challenging for clinicians because it is a continuum of disease, he explained. “NAFLD is the most prevalent liver disease globally with a prevalence of around 25%; it is very heterogeneous and makes prognostication difficult.” This has implications for including people in trials and for determining what the clinical endpoints should be, as well as making it difficult to determine the outlook for individual patients.

There are several histological scoring systems developed over the years trying to help with this issue, including the Brunt score, the NAFLD activity score (NAS), and fibrosis stage.

While the latter has previously been shown to be a robust marker for mortality, the NAS has been criticized, Dr. Hagström noted. This is because the effect of steatosis may be overestimated and because NAS does not measure fibrosis. Thus, there is a need for new means to risk-stratify patients and one relatively new method is the SAF score.

The SAF score was developed to evaluate the severity of fatty liver lesions, originally in morbidly obese individuals (Hepatology. 2012 Oct;56:1751-9). Using this score, the extent of fatty accumulation in the liver can be assessed, with a score of 0 signifying that steatosis is present in less than 5% of the liver and a score of 3 signifying that more than two-thirds of the liver is affected. NAFLD activity is determined on a scale of 0 to 4 by assessing the degree of ballooning and lobular inflammation. Finally, the score looks at the extent of fibrosis, rating it from 0 (not present) to 4 (cirrhosis).

The aim of the study was to examine the impact of this score on overall mortality in a previously published (Hepatology. 2015 Mar;61:1547-54) cohort of patients with long follow-up, Dr. Hagström explained at the meeting sponsored by the European Association for the Study of the Liver (EASL). Data on 139 patients with biopsy-proven NAFLD were obtained from a historical cohort of patients who had undergone liver biopsy between 1974 and 1994. Their biopsies were reclassified using the SAF score and the presence of nonalcoholic steatohepatitis was also determined using the FLIP algorithm and the NAS score. Data on causes of death were taken from a national Swedish population register. At baseline, 35 patients had mild, 35 had moderate, and 69 had severe NAFLD.

After a median follow-up of 25 years, ranging from 2 to 41 years, 74 patients died. Of these deaths, 45 occurred in patients with severe NAFLD, representing 65% of the severe NAFLD group. Half (n = 18; 51%) of the patients with moderate NAFLD and just under one-third (n = 11; 31%) of those with mild NAFLD had also died. The median time to death was 18 years after liver biopsy.

Dr. Hagström reported that cardiovascular causes were the main cause of mortality, in 21% of patients; extrahepatic malignancy caused 12% of deaths, 7% of deaths were liver related, and 13% were due to other reasons. Patients with severe NAFLD identified by a high SAF score were more than two and a half times more likely to die than those with mild NAFLD, with a hazard ratio of 2.65 (P = .02). Patients with moderate NAFLD were no more likely than those with mild liver disease to die (HR = 1.23; P = .84). Data had been adjusted for gender, body mass index, and for the presence of type 2 diabetes.

HRs for mortality comparing high with low SAF scores after adjusting for fibrosis stage and excluding patients with fibrosis stages 3-4 were a respective 1.85 (P = .18) and 1.94 (P = .15). In a press statement issued by EASL, Dr. Laurent Castera of Hôpital Beaujon in Paris noted that these data were an important step forward for the medical community in being able to identify the patients who are most at risk of death from NAFLD. Dr. Castera, who is the secretary general of EASL, noted that these long-term study data also demonstrated the importance of having sufficient follow-up periods for patients with NAFLD.

In an interview after his presentation Dr. Hagström also emphasized the importance of long-term follow-up of patients.

“The clinical importance of this is that it is most important for clinicians to look at fibrosis stage, and I think to have to follow these patients a little bit more,” he said. “You can’t just do a liver biopsy, say ‘you just have steatosis, you don’t have NASH [nonalcoholic steatohepatitis], [so] you are fine’,” he added. Equally, it is not possible to say that because NASH is not present that patients won’t advance in the future. Patients need to be followed up for a long period of time.

“Fibrosis is the most important thing, both for clinicians and for patients,” Dr. Hagström said.Dr. Hagström has been a consultant to Novo Nordisk. Dr. Castera had no relevant financial disclosures.