Liver Disease

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

A version of this article first appeared on Medscape.com.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

A version of this article first appeared on Medscape.com.

Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.

Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.

The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.

In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.

The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
 

More Than One Risk Factor in Play

MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.

It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.

Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.

The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.

Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
 

Single Agents

The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.

“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.

One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.

Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.

A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.

Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”

Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.

A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.

Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
 

Dual and Triple Mechanisms of Action

Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.

“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.

An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.

A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.

“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”

The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.

In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.

Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.

The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said. 

Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.

Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.

Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.

A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.

This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
 

Obstacles and Warnings

Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.

GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.

Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.

Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.

“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.

Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.

“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.

“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.

Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
 

A version of this article first appeared on Medscape.com.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is expected to bring a wave of added healthcare costs to Canada, with projections indicating an increase of almost C$2 billion (Canadian dollars) by 2050, according to a new study.

The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.

K. Ally Memedovich

“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”

Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.

Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).

The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.

The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.

Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.

The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.

Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.

“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is expected to bring a wave of added healthcare costs to Canada, with projections indicating an increase of almost C$2 billion (Canadian dollars) by 2050, according to a new study.

The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.

K. Ally Memedovich

“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”

Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.

Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).

The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.

The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.

Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.

The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.

Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.

“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is expected to bring a wave of added healthcare costs to Canada, with projections indicating an increase of almost C$2 billion (Canadian dollars) by 2050, according to a new study.

The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.

K. Ally Memedovich

“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”

Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.

Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).

The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.

The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.

Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.

The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.

Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.

“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.

Digital pathology assisted by artificial intelligence (AI) has the potential to transform the diagnosis and treatment of fibrotic liver disease in the next few years and to reshape clinical trials, clearing the way for new therapies.

Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.

“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.

“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).

To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
 

Moving Toward Better Diagnoses and Disease Management

The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.

But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.

Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”

In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”

Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view. 

Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”

The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.

“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said. 

Such tools are currently undergoing testing and validation for use in trials and diagnostically.

The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
 

More Effective Clinical Trials

The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.

“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted. 

However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.

That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said. 

The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.

Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.

To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said. 

“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.

The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.

“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”

Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.

This is where AI-assisted pathology comes into play.

“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.

This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
 

What’s Ahead

These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said. 

“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.

Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.

Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.

“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”

Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.

A version of this article appeared on Medscape.com.

Digital pathology assisted by artificial intelligence (AI) has the potential to transform the diagnosis and treatment of fibrotic liver disease in the next few years and to reshape clinical trials, clearing the way for new therapies.

Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.

“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.

“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).

To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
 

Moving Toward Better Diagnoses and Disease Management

The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.

But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.

Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”

In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”

Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view. 

Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”

The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.

“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said. 

Such tools are currently undergoing testing and validation for use in trials and diagnostically.

The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
 

More Effective Clinical Trials

The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.

“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted. 

However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.

That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said. 

The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.

Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.

To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said. 

“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.

The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.

“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”

Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.

This is where AI-assisted pathology comes into play.

“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.

This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
 

What’s Ahead

These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said. 

“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.

Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.

Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.

“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”

Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.

A version of this article appeared on Medscape.com.

Digital pathology assisted by artificial intelligence (AI) has the potential to transform the diagnosis and treatment of fibrotic liver disease in the next few years and to reshape clinical trials, clearing the way for new therapies.

Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.

“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.

“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).

To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
 

Moving Toward Better Diagnoses and Disease Management

The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.

But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.

Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”

In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”

Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view. 

Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”

The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.

“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said. 

Such tools are currently undergoing testing and validation for use in trials and diagnostically.

The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
 

More Effective Clinical Trials

The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.

“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted. 

However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.

That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said. 

The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.

Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.

To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said. 

“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.

The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.

“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”

Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.

This is where AI-assisted pathology comes into play.

“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.

This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
 

What’s Ahead

These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said. 

“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.

Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.

Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.

“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”

Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.

A version of this article appeared on Medscape.com.

Compared with endoscopy, the Baveno VI criteria present a noninvasive and cost-effective method to detect high-risk varices in patients with Child-Pugh A cirrhosis, according to new research.

Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.

“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.

Andrew McConnell/EASL

“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Baveno VI Criteria Analysis

On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm³ and a liver stiffness measurement < 20 kPa. 

In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm³ and a liver stiffness < 25 kPa.

Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.

Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.

As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.

In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.

For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.

In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.

The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
 

Baveno VI Considerations

Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.

“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.

Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.

“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.

Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.

Waikato Hospital

A version of this article first appeared on Medscape.com.

Compared with endoscopy, the Baveno VI criteria present a noninvasive and cost-effective method to detect high-risk varices in patients with Child-Pugh A cirrhosis, according to new research.

Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.

“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.

Andrew McConnell/EASL

“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Baveno VI Criteria Analysis

On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm³ and a liver stiffness measurement < 20 kPa. 

In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm³ and a liver stiffness < 25 kPa.

Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.

Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.

As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.

In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.

For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.

In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.

The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
 

Baveno VI Considerations

Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.

“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.

Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.

“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.

Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.

Waikato Hospital

A version of this article first appeared on Medscape.com.

Compared with endoscopy, the Baveno VI criteria present a noninvasive and cost-effective method to detect high-risk varices in patients with Child-Pugh A cirrhosis, according to new research.

Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.

“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.

Andrew McConnell/EASL

“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Baveno VI Criteria Analysis

On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm³ and a liver stiffness measurement < 20 kPa. 

In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm³ and a liver stiffness < 25 kPa.

Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.

Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.

As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.

In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.

For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.

In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.

The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
 

Baveno VI Considerations

Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.

“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.

Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.

“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.

Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.

Waikato Hospital

A version of this article first appeared on Medscape.com.

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

A version of this article first appeared on Medscape.com.

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

A version of this article first appeared on Medscape.com.

Alcohol-associated liver disease (ALD) is a significant global health concern, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.

ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.

“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.

Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
 

As Women Consume More Alcohol, ALD Follows

Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.

Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.

Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.

Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.

Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”

Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.

Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
 

Certain Ethnic, Racial Minorities Have Higher Rates of ALD

In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.

A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.

Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.

ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.

The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.

As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.

Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.

Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.

“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
 

ALD Rates High in Young Adults, but the Tide May Be Changing

Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.

In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.

ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.

From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”

Younger adults may be more susceptible to ALD due to the way they drink.

In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.

Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).

“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”

Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.

“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
 

A version of this article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) granted accelerated approval for Livdelzi (seladelpar, Gilead Sciences, Inc.) for primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as monotherapy in those who can’t tolerate UDCA. 

Livdelzi, a selective agonist of peroxisome proliferator–activated receptor delta, is not recommended in adults who have or develop decompensated cirrhosis.

PBC is a rare, chronic, autoimmune disease of the bile ducts that affects roughly 130,000 Americans, primarily women, and can cause liver damage and possible liver failure if untreated. The disease currently has no cure.

The FDA approved Livdelzi based largely on results of the phase 3 RESPONSE study, in which the drug significantly improved liver biomarkers of disease activity and bothersome symptoms of pruritus in adults with PBC.

The primary endpoint of the trial was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level, at 12 months.

After 12 months, 62% of patients taking Livdelzi met the primary endpoint vs 20% of patients taking placebo.

In addition, significantly more patients taking Livdelzi than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the Livdelzi group vs 4.3% in the placebo group.

At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the Livdelzi group compared with 6.5% and 11.4%, respectively, in the placebo group.

A key secondary endpoint was change in patient-reported pruritus.

At baseline, 38.3% of patients in the Livdelzi group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score ≥ 4 out of 10.

Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with Livdelzi than with placebo (change from baseline, -3.2 vs -1.7 points). These improvements were sustained through 12 months.

Improvements on the 5-D Itch Scale in both the moderate- to severe-pruritis population and the overall population also favored Livdelzi over placebo for itch relief, which had a positive impact on sleep.

“The availability of a new treatment option that can help reduce [the] intense itching while also improving biomarkers of active liver disease is a milestone for our community,” Carol Roberts, president, The PBCers Organization, said in a news release announcing the approval. 

The most common adverse reactions with Livdelzi were headache, abdominal pain, nausea, abdominal distension, and dizziness.

The company noted that the FDA granted accelerated approval for Livdelzi based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval of Livdelzi for PBC may be contingent on verification and description of clinical benefit in confirmatory trial(s).
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) granted accelerated approval for Livdelzi (seladelpar, Gilead Sciences, Inc.) for primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as monotherapy in those who can’t tolerate UDCA. 

Livdelzi, a selective agonist of peroxisome proliferator–activated receptor delta, is not recommended in adults who have or develop decompensated cirrhosis.

PBC is a rare, chronic, autoimmune disease of the bile ducts that affects roughly 130,000 Americans, primarily women, and can cause liver damage and possible liver failure if untreated. The disease currently has no cure.

The FDA approved Livdelzi based largely on results of the phase 3 RESPONSE study, in which the drug significantly improved liver biomarkers of disease activity and bothersome symptoms of pruritus in adults with PBC.

The primary endpoint of the trial was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level, at 12 months.

After 12 months, 62% of patients taking Livdelzi met the primary endpoint vs 20% of patients taking placebo.

In addition, significantly more patients taking Livdelzi than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the Livdelzi group vs 4.3% in the placebo group.

At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the Livdelzi group compared with 6.5% and 11.4%, respectively, in the placebo group.

A key secondary endpoint was change in patient-reported pruritus.

At baseline, 38.3% of patients in the Livdelzi group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score ≥ 4 out of 10.

Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with Livdelzi than with placebo (change from baseline, -3.2 vs -1.7 points). These improvements were sustained through 12 months.

Improvements on the 5-D Itch Scale in both the moderate- to severe-pruritis population and the overall population also favored Livdelzi over placebo for itch relief, which had a positive impact on sleep.

“The availability of a new treatment option that can help reduce [the] intense itching while also improving biomarkers of active liver disease is a milestone for our community,” Carol Roberts, president, The PBCers Organization, said in a news release announcing the approval. 

The most common adverse reactions with Livdelzi were headache, abdominal pain, nausea, abdominal distension, and dizziness.

The company noted that the FDA granted accelerated approval for Livdelzi based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval of Livdelzi for PBC may be contingent on verification and description of clinical benefit in confirmatory trial(s).
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) granted accelerated approval for Livdelzi (seladelpar, Gilead Sciences, Inc.) for primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as monotherapy in those who can’t tolerate UDCA. 

Livdelzi, a selective agonist of peroxisome proliferator–activated receptor delta, is not recommended in adults who have or develop decompensated cirrhosis.

PBC is a rare, chronic, autoimmune disease of the bile ducts that affects roughly 130,000 Americans, primarily women, and can cause liver damage and possible liver failure if untreated. The disease currently has no cure.

The FDA approved Livdelzi based largely on results of the phase 3 RESPONSE study, in which the drug significantly improved liver biomarkers of disease activity and bothersome symptoms of pruritus in adults with PBC.

The primary endpoint of the trial was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level, at 12 months.

After 12 months, 62% of patients taking Livdelzi met the primary endpoint vs 20% of patients taking placebo.

In addition, significantly more patients taking Livdelzi than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the Livdelzi group vs 4.3% in the placebo group.

At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the Livdelzi group compared with 6.5% and 11.4%, respectively, in the placebo group.

A key secondary endpoint was change in patient-reported pruritus.

At baseline, 38.3% of patients in the Livdelzi group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score ≥ 4 out of 10.

Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with Livdelzi than with placebo (change from baseline, -3.2 vs -1.7 points). These improvements were sustained through 12 months.

Improvements on the 5-D Itch Scale in both the moderate- to severe-pruritis population and the overall population also favored Livdelzi over placebo for itch relief, which had a positive impact on sleep.

“The availability of a new treatment option that can help reduce [the] intense itching while also improving biomarkers of active liver disease is a milestone for our community,” Carol Roberts, president, The PBCers Organization, said in a news release announcing the approval. 

The most common adverse reactions with Livdelzi were headache, abdominal pain, nausea, abdominal distension, and dizziness.

The company noted that the FDA granted accelerated approval for Livdelzi based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval of Livdelzi for PBC may be contingent on verification and description of clinical benefit in confirmatory trial(s).
 

A version of this article appeared on Medscape.com.

The combination of the antiviral bulevirtide (Hepcludex) plus pegylated interferon alfa-2a was superior to bulevirtide monotherapy for chronic hepatitis delta (HDV) infection, a multinational phase 2b open-label study in Europe found.

The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.

“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.

“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”

The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.

While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.

HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.

Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.

Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”

The Trial

The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:

• Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
• Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).

All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.

At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.

For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).

At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.

Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”

The combination of the antiviral bulevirtide (Hepcludex) plus pegylated interferon alfa-2a was superior to bulevirtide monotherapy for chronic hepatitis delta (HDV) infection, a multinational phase 2b open-label study in Europe found.

The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.

“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.

“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”

The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.

While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.

HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.

Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.

Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”

The Trial

The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:

• Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
• Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).

All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.

At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.

For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).

At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.

Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”

The combination of the antiviral bulevirtide (Hepcludex) plus pegylated interferon alfa-2a was superior to bulevirtide monotherapy for chronic hepatitis delta (HDV) infection, a multinational phase 2b open-label study in Europe found.

The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.

“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.

“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”

The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.

While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.

HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.

Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.

Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”

The Trial

The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:

• Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
• Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
• Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).

All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.

At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.

For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).

At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.

Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”

MILAN — Liver transplantation improves survival in patients with acute-on-chronic liver failure (ACLF), according to interim clinical outcomes of the large, international CHANCE study.

To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.

University College London Hospitals

“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.

These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.

Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.

If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
 

Organ Allocation Principally Based on MELD Scores

ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.

As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.

MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.

With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.

The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.

Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.

For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.

Secondary endpoints included quality of life and cost of care.

Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).

Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.

“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.

Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.

However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
 

Death or Delisting

Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.

Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.

Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.

“This is likely due to low donation rates in Latin America,” Dr. Jalan said.

Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.

“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”

There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.

Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.

“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”

The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
 

‘The Landscape of Organ Allocation Is Extremely Complex’

Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.

“The landscape of organ allocation is extremely complex,” she added.

The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.

“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”

The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.

However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.

This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.

Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.

A version of this article first appeared on Medscape.com.

MILAN — Liver transplantation improves survival in patients with acute-on-chronic liver failure (ACLF), according to interim clinical outcomes of the large, international CHANCE study.

To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.

University College London Hospitals

“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.

These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.

Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.

If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
 

Organ Allocation Principally Based on MELD Scores

ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.

As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.

MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.

With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.

The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.

Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.

For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.

Secondary endpoints included quality of life and cost of care.

Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).

Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.

“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.

Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.

However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
 

Death or Delisting

Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.

Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.

Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.

“This is likely due to low donation rates in Latin America,” Dr. Jalan said.

Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.

“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”

There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.

Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.

“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”

The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
 

‘The Landscape of Organ Allocation Is Extremely Complex’

Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.

“The landscape of organ allocation is extremely complex,” she added.

The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.

“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”

The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.

However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.

This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.

Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.

A version of this article first appeared on Medscape.com.

MILAN — Liver transplantation improves survival in patients with acute-on-chronic liver failure (ACLF), according to interim clinical outcomes of the large, international CHANCE study.

To date, the results show that 3-month post–liver transplantation mortality rates in patients with ACLF grades 2 and 3 were only 9%, which is not significantly different than that of patients with decompensated cirrhosis, with a mortality of 7%.

University College London Hospitals

“Treatment of ACLF is an unmet medical need,” said Rajiv Jalan, MD, professor of hepatology and honorary consultant in hepatology, University College London Hospitals, London, England.

These findings highlight “the inadequacy of current transplant allocation criteria for patients with ACLF 2 and 3,” which is leading to excess mortality on the wait list, he added.

Dr. Jalan presented the interim results at the European Association for the Study of the Liver (EASL) Congress 2024.

If confirmed in the full analysis, these results argue strongly for increasing access to liver transplantation and changing organ allocation for patients with ACLF 2 and 3, he said.
 

Organ Allocation Principally Based on MELD Scores

ACLF, which occurs in patients with cirrhosis and acutely decompensated liver disease admitted to hospital, carries a high, short-term risk for death. The risk for 28-day mortality for ACLF 2 and 3 is between 30% and 90% and characterized by multiorgan failure.

As seen in previous data, even patients on the transplant waiting list with a low Model for End-Stage Liver Disease (MELD) score have a risk for death between 20% and 30% if they are ACLF 2 and 3, Dr. Jalan said.

MELD scores do not consider the risk for death because of failure of extrahepatic organs, he added. Existing worldwide organ allocation systems are principally based on patient MELD scores or its variations; therefore, many patients die on the waiting list.

With this in mind, the CHANCE study aimed to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF 2 or 3 at the time of transplantation with patients with decompensated cirrhosis without ACLF and transplantation-free survival of patients with ACLF 2 or 3 not listed for liver transplantation.

The multicenter observational study comprised 66 liver transplant centers from 21 countries and over 500 investigators. Recruitment was closed after 1000 patients were enrolled.

Patients were aged 54-56 years, 31%-35% were women, 48%-70% had alcohol-related cirrhosis, and 19%-24% had metabolic dysfunction–associated steatohepatitis. MELD scores ranged from 25 to 36.

For the interim results, Dr. Jalan and colleagues assessed mortality on the waiting list and 3-month post–liver transplantation mortality.

Secondary endpoints included quality of life and cost of care.

Of the 823 patients in the study, they were grouped as follows: 376 patients with ACLF 2 or 3 listed for liver transplantation (group 1), 313 patients with ACLF 0 or 1 and MELD score > 20 listed for liver transplantation (group 2), and 134 patients with ACLF 2 or 3 not listed for liver transplantation (group 3).

Overall, patients in group 1 had very severe ACLF; 177 patients with ACLF 3 had three or more organ failures, Dr. Jalan noted.

“It is interesting to note that, in group 3, there is an overrepresentation of alcohol-related cirrhosis, and this might reflect a bias in transplantation,” he added.

Dr. Jalan highlighted geographical points of difference. Patients in the United States were younger, which could be important when interpreting results of post-transplantation outcomes. In Asia, the majority of the patients were men and primarily from India, where living donor transplantation is commonly performed. In Latin America, only 33% of study participants had alcohol-related cirrhosis in contrast to 67% of those in North America.

However, “comorbidities across the world were similar, and MELD scores were also similar,” Dr. Jalan said.
 

Death or Delisting

Between listing and transplantation, 28% of patients in group 1 either died or were delisted, compared with 16% of those in group 2. In group 3, 85% of patients who were not listed for transplantation in the first place died.

Similar to what has been seen in other studies, nearly 50% of patients with ACLF 3 but a MELD score < 25 on the wait list died or were delisted, Dr. Jalan pointed out, suggesting that these patients are disadvantaged under the current system of waiting list priority.

Geographically, deaths on the wait list were significantly higher in Latin America at 40% than in North America, Europe, and Asia at 20%, 18%, and 13%, respectively.

“This is likely due to low donation rates in Latin America,” Dr. Jalan said.

Turning to 3-month post-transplantation mortality, the rates in groups 1 and 2 were 9% and 7%, respectively.

“This demonstrates very nicely the clear benefit of transplant,” Dr. Jalan said. “The risk of death post transplant, even with ACLF 2 or 3, is not significantly different to those patients with decompensated cirrhosis.”

There was a slightly higher risk for death in patients with ACLF 3 than in those with ACLF 2 at 14% vs 7%, but “the risk of death in these patients if they don’t have transportation is 70%-80%,” he said.

Looking at 3-month post-transplantation mortality by continent, Dr. Jalan highlighted that Latin America showed 16% risk, compared with Asia, Europe, and North America that showed 12%, 7%, and 3% risk, respectively.

“This is probably multifactorial and likely to be influenced by time on the waiting list, quality of organs available, and patient demographics, among other factors,” Dr. Jalan said. When very sick people undergo transplantation, “there is a higher risk of death.”

The patients in this study have waited a long time, “which worsens their situation,” said Dr. Jalan, reinforcing his argument for changing the international organ allocation system to allow earlier access for these patients.
 

‘The Landscape of Organ Allocation Is Extremely Complex’

Comoderator Ana Lleo, MD, PhD, full professor of internal medicine and hepatology, Humanitas University, Milan, Italy, commented that “the number of patients included in this international study is significant,” and that the issue of mortality on the wait list is of great clinical interest.

“The landscape of organ allocation is extremely complex,” she added.

The system for liver transplantation considers a large number of clinical conditions with very diverse benefit profiles, she explained.

“While we would like to offer liver transplantation for all patients with any range of benefit, the current donations are not sufficient to cover the request,” Dr. Lleo said. “Therefore, prioritization remains key.”

The findings do illustrate the inadequacy of current transplantation allocation criteria for patients with ACLF 2 and 3, said Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College Hospital, London, England, who is also serving as vice-secretary of the EASL Governing Board.

However, “this must be balanced by the recognition that the global donor pool of organs available is a finite resource,” she said, echoing Dr. Lleo’s comments.

This calls for wider ethical discussions to avoid disadvantaging more stable, often younger patients with cirrhosis who are listed for transplantation, she added.

Dr. Jalan declared he is the inventor of Ornithine Phenylacetate, licensed by UCL to Mallinckrodt Pharma; a speaker and grant reviewer for Grifols Research Collaboration: Yaqrit; and the founder of Yaqrit, Hepyx, CyberLiver, and Gigabiome. Dr. Lleo declared that she does not have any conflicts relevant to this work but received lecture fees from Gilead, Advanz Pharma, Alfasigma, GSK, Incyte, Gore, AstraZeneca, and Ipsen and consulted for Advanz Pharma, AstraZeneca, Ipsen, GSK, and Dr Falk. Dr. Shawcross declared advisory board/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.

A version of this article first appeared on Medscape.com.

MILAN — Survodutide, an investigational dual glucagon-like peptide 1 (GLP-1) and glucagon receptor agonist, led to “exceptional improvement in disease activity and fibrosis” in patients with metabolic dysfunction–associated steatohepatitis (MASH), according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.

The data were simultaneously published in The New England Journal of Medicine .

The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.

In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.

American Association for the Study of Liver Diseases

What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.

“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
 

Efficacy and Safety of Survodutide

A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).

Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m². Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.

After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.

The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.

The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).

In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.

Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.

The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.

Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.

Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.

Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
 

Dual Agonist vs Monoagonist Therapy

The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.

“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.

“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.

With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.

In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.

“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.

By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
 

The Burden of Liver Disease

Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.

Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.

Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.

Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.

Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.

Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
 

A version of this article first appeared on Medscape.com.

MILAN — Survodutide, an investigational dual glucagon-like peptide 1 (GLP-1) and glucagon receptor agonist, led to “exceptional improvement in disease activity and fibrosis” in patients with metabolic dysfunction–associated steatohepatitis (MASH), according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.

The data were simultaneously published in The New England Journal of Medicine .

The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.

In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.

American Association for the Study of Liver Diseases

What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.

“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
 

Efficacy and Safety of Survodutide

A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).

Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m². Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.

After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.

The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.

The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).

In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.

Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.

The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.

Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.

Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.

Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
 

Dual Agonist vs Monoagonist Therapy

The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.

“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.

“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.

With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.

In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.

“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.

By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
 

The Burden of Liver Disease

Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.

Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.

Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.

Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.

Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.

Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
 

A version of this article first appeared on Medscape.com.

MILAN — Survodutide, an investigational dual glucagon-like peptide 1 (GLP-1) and glucagon receptor agonist, led to “exceptional improvement in disease activity and fibrosis” in patients with metabolic dysfunction–associated steatohepatitis (MASH), according to phase 2 results presented here at the European Association for the Study of the Liver (EASL) Congress 2024.

The data were simultaneously published in The New England Journal of Medicine .

The primary endpoint data, reported earlier this year in a press release, showed that up to 83% of participants on survodutide showed a statistically significant improvement in MASH compared with those on placebo (18.2%) based on paired biopsy results.

In addition, 75% of patients treated with survodutide experienced resolution of MASH with no worsening of fibrosis compared with 15% of patients on placebo, and in patients with F2/F3 fibrosis, 64.5% achieved improvement in fibrosis without worsening of MASH, reported Arun J. Sanyal, MD, principal study investigator and director of the Virginia Commonwealth University (VCU) Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, Virginia.

American Association for the Study of Liver Diseases

What’s so amazing is that this “exceptional improvement” is after 48 weeks of therapy with a class of molecule that is already known to also have cardiometabolic benefits, Dr. Sanyal said in an interview.

“At the highest dose of survodutide [6.0 mg], two thirds of patients in whom we have biopsy data, at both the beginning and the end, actually showed fibrosis regression within 48 weeks,” he said. “This is pretty dramatic.”
 

Efficacy and Safety of Survodutide

A total of 293 participants with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injections of survodutide 2.4 mg (n = 73), 4.8 mg (n = 72), or 6.0 mg (n = 74) or placebo (n = 74).

Around half of study participants were women, with mean age around 50 years and a body mass index around 35 kg/m². Overall, 26%-30% had type 2 diabetes, 24%-36% had F2 fibrosis, and 23%-30% had F3 fibrosis. The total Nonalcoholic Fatty Liver Disease Activity Score was 5.2.

After completing a 24-week rapid-dose-escalation phase, participants followed a 24-week maintenance phase. Histologic improvement (reduction) in MASH without worsening of fibrosis after 48 weeks of treatment comprised the primary endpoint, whereas a reduction in liver fat content by at least 30% and biopsy-assessed reduction in fibrosis by at least one stage were among the secondary endpoints.

The main analyses of the trial were based on two treatment sets: Actual treatment (the actual dose received at the start of the maintenance phase; per protocol) and planned treatment (the maintenance dose assigned to participants at randomization). Dr. Sanyal mainly reported results based on actual treatment, which were used for the primary analysis.

The overall primary endpoint data, including nonresponders, showed a 47% improvement in MASH in the 2.4-mg treatment group, 62% in the 4.8 mg group, and 43% in the 6.0-mg group compared with 13.5% in the placebo group (P < .001).

In addition, 50% of patients on 2.4- and 6-mg doses experienced a statistically significant improvement in fibrosis (F1-F3) without worsening of MASH. In patients with F2/F3 fibrosis, 64.5% of participants in the 6-mg survodutide group showed improvement vs 25.9% in the placebo group.

Reduction in liver fat by at least 30% was achieved by up to 87% in the 6-mg group according to MRI-estimated proton density fat fraction; when nonresponders were included, the percentage was 76.9% of the 6-mg group. Other outcomes included weight loss and reductions in A1c.

The results did not differ markedly between doses, which “is really exciting news,” Dr. Sanyal said.

Patients who are intolerant of the highest dose can switch to a lower dose without a big loss of efficacy, he said, adding that even the low dose was sufficient to get near maximal glucagon effect.

Adverse events were similar between survodutide and placebo, except for gastrointestinal events, including nausea, diarrhea, and vomiting. The occurrence of serious adverse events also was similar between survodutide and placebo.

Discontinuation due to adverse events was 20% across all the survodutide groups (with 16% due to gastrointestinal events) vs 3% in the placebo group.
 

Dual Agonist vs Monoagonist Therapy

The dual agonist approach may confer clinical advantages over GLP-1 receptor monoagonist pharmacotherapies for MASH.

“GLP has no receptors in the liver, so all its effects are mediated outside the liver, particularly for weight loss and improvement in metabolic status, increase in insulin secretion and sensitivity, and overall systemic glycemia,” Dr. Sanyal explained.

“People with established fibrosis take longer to respond in terms of downstream liver scarring with extrahepatic changes alone,” he added.

With “glucagon directly targeting the liver, we believe this reduces oxidative stress and possibly stimulates FGF-21 secretion [liver-derived factor that regulates lipid and glucose metabolism] in the liver, so there are likely multiple mechanisms driving the antifibrogenic benefits,” Dr. Sanyal said.

In comparison, the study authors highlighted that data on the GLP-1 receptor monoagonist semaglutide suggest a significantly higher proportion of patients on semaglutide achieve MASH resolution than those on placebo but that it does not result in “a significantly higher percentage of patients with improvement in fibrosis stage.

“It might be that it takes longer to get an effect in the liver with semaglutide,” Dr. Sanyal said.

By year-end, we’ll know how the GLP-1 alone approach (eg, semaglutide) and the dual agonist approach work, and we’ll eventually have data on triple agonists, Dr. Sanyal added.
 

The Burden of Liver Disease

Comoderator Debbie Shawcross, MBBS, PhD, professor of hepatology and chronic liver failure, King’s College, London, England, remarked on the importance of new drugs, including survodutide, in reducing the burden of steatotic liver disease.

Approximately one third of the world’s population and between 7% and 9% of children have steatotic liver disease, she noted. The buildup of fat causes inflammation and scarring of the liver, which may then progress to liver cirrhosis and primary liver cancers.

Survodutide offers much hope “as a drug that will reduce both liver inflammation and scarring, while also providing the benefit of improved diabetic control,” Dr. Shawcross said.

Reflecting on the dual agonism, she said that both the glucagon and GLP-1 receptors are critical to controlling metabolic functions.

Survodutide is currently being investigated in five phase 3 studies for people living with overweight and obesity, both of which are associated with MASH. There is also a trial looking at people with overweight/obesity with confirmed or presumed diagnosis of MASH, according to a company press release.

Dr. Sanyal reported grants, consultancy fees, and speaker fees from a wide range of companies working in the field of liver medicine. Dr. Shawcross reported no conflicts in relation to this drug and advisory board membership/consultancy for EnteroBiotix, Norgine, Satellite Bio, and MRN Health.
 

A version of this article first appeared on Medscape.com.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.

MILAN — Seladelpar, an investigational selective peroxisome proliferator-activated receptor delta agonist, achieves both biochemical and clinically meaningful improvements in pruritus and liver injury in patients with primary biliary cholangitis (PBC), both with and without compensated liver cirrhosis, according to two interim analyses of the ASSURE long-term extension study.

The first analysis of 337 patients with PBC, with and without cirrhosis, showed that treatment with seladelpar had a durable effect up to 2 years on cholestasis and markers of liver injury, as well as a sustained reduction in pruritus, Palak Trivedi, MD, associate professor at the National Institute for Health Research Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, England, reported in a poster presented at the European Association for the Study of the Liver (EASL) Congress 2024.

The 2-year analysis also showed that seladelpar, a first-in-class, orally active agent, was safe and well tolerated in this patient population, he added.

These “results are consistent with the pivotal phase 3 RESPONSE study,” Dr. Trivedi noted. The RESPONSE study showed that seladelpar significantly improved liver biomarkers of disease activity and symptoms of pruritus at 12 months in patients with PBC who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the standard of care, and had no history of hepatic decompensation. Patients with cirrhosis were allowed to enroll.

A total of 158 patients from the RESPONSE trial, both from the placebo and from the active treatment arm, were rolled over into the ASSURE trial. Another subset of 179 patients were drawn from prior seladelpar placebo-controlled studies (referred to as “legacy studies”), including the ENHANCE study. All participants in the current analysis received 10 mg of seladelpar, once daily, for up to 155 weeks.

Of the participants from the legacy studies, 99 completed 24 months of treatment with seladelpar, and 164 completed 12 months of treatment. In the 24-month treatment group, 70% met the composite response endpoint, which included alkaline phosphatase (ALP) levels below 1.67 times the upper limit of normal, a decrease in ALP levels of at least 15%, and total bilirubin levels at or below the upper limit of normal, according to a press release of the study findings. In addition, 42% of these participants achieved ALP normalization at 24 months, a marker of liver disease progression. In the 12-month treatment group, 73% achieved the clinically meaningful composite response endpoint, with 42% experiencing ALP normalization.

For patients rolled over from RESPONSE, 102 received 18 months of treatment with seladelpar, and 29 received 24 months of treatment. A total of 62% of patients in the 18-month group achieved the composite endpoint, and 33% achieved ALP normalization, while 72% of the 24-month group reached the composite endpoint, and 17% had ALP normalization.

Of patients who had received a placebo in the RESPONSE trial and went on to receive treatment with seladelpar, 75% achieved the composite endpoint, 27% had ALP normalization at 6 months, and 94% achieved the composite endpoint and 50% reached ALP normalization at 12 months.

Key secondary endpoints included ALP normalization and changes in liver enzymes (ALP, total bilirubin, gamma-glutamyl transferase [GGT], alanine transaminase [ALT], and aspartate aminotransferase [AST]).
 

Pruritus Relief Important for Quality of Life

Among study participants who reported a four or more at baseline on the numerical rating scale (NRS) for pruritus, legacy patients at 12 months and 24 months of treatment reported a mean reduction of 3.8 and 3.1, respectively. Participants from RESPONSE also reported a mean reduction of 3.8.

This level of reduction in NRS is “considered clinically significant” and takes patients from a level of moderate to severe itching down to mild, said Carrie Frenette, MD, executive director, Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, and a former hepatologist of 20 years with a special interest in liver transplantation.

This “is a huge benefit in quality of life for these patients,” Dr. Frenette said in an interview.

Dr. Frenette also noted that UDCA, the current first-line treatment for PBC, is inadequate in up to 40% of patients, and second-line treatments, notably obeticholic acid, can cause itching.

European Society for Organ Transplantation

Eleonora De Martin, MD, transplant hepatologist at Centre Hépato-Biliaire, Paul Brousse Hospital, Paris, France, who comoderated the session, pointed out that PBC is a complex disease.

“We need both disease control and symptom control, and they’re not always compatible,” she said. “Sometimes you can control the disease but not the symptoms, and symptomatic control is so important,” especially with pruritus.
 

Patients With PBC and Cirrhosis

A separate analysis from ASSURE looked at a subset of 17 patients with PBC and cirrhosis who completed 24 months of treatment. The findings were presented by Stuart Gordon, MD, professor of medicine, Wayne State University School of Medicine, and hepatologist at Henry Ford Hospital, both in Detroit.

In this analysis, the mean patient age was 60.8 years, 91.4% were female, 88.6% were Child-Pugh A, and 22.9% had portal hypertension, while the mean baseline liver stiffness by FibroScan was 19.9 kPa.

Baseline biochemical measures were mean ALP of 245.4 U/L, mean total bilirubin of 0.995 mg/dL, mean GGT of 216.1 U/L, and mean ALT of 36.6 U/L.

A total of 11 participants (65%) met the composite endpoint at 24 months, with ALP normalization in 4 patients (24%). The overall mean percent change from baseline in ALP was approximately −30% and in total bilirubin was around −14%. Other changes in biochemical markers included reductions from baseline in GGT and ALT of approximately −30% and −10%, respectively. No change was observed in AST.

While 80% of patients with cirrhosis “had an adverse event of some form,” there were no treatment-related serious adverse events.

“It’s interesting to see results in these patients who have advanced disease and are cirrhotic because it might stabilize disease or even provide improvement,” Dr. De Martin commented. “However, the numbers in the study are very small, so it’s hard to draw firm conclusions yet, but it is a first step in showing that this drug is safe.”

Seladelpar is an “important step forward in PBC because we’ve been stuck with ursodeoxycholic acid for so many years,” Dr. De Martin added. “We’ve seen in liver disease with other etiologies that sometimes just one drug can make a difference, and you can change the natural history of the disease.”

Dr. Frenette is an employee and stockholder of Gilead Sciences. Dr. Gordon declared grants and support from AbbVie, Arbutus, CymaBay, Cour Pharmaceuticals, GlaxoSmithKline (GSK), Ipsen, and Mirum Pharmaceuticals; and advisory board activity from CymaBay, GSK, and Ipsen Pharmaceuticals. Dr. De Martin had no disclosures of relevance to seladelpar but has received speaker fees from other companies, including GSK, Ipsen, and Astellas. Dr. Trivedi reports institutional funding support from National Institute for Health Research Birmingham (UK); lecture fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, and Dr. Falk Pharma; advisory board/consulting fees from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Chemomab Therapeutics, CymaBay, Dr. Falk Pharma, Gilead Sciences, Perspectum, and Pliant Therapeutics; and grant support from Advanz Pharma/Intercept Pharmaceuticals, Albireo/Ipsen, Bristol-Myers Squibb, Core (Guts UK), EASL, Gilead Sciences, GSK, LifeArc, NIHR, Mirum Pharma, PSC Support, The Wellcome Trust, The Medical Research Foundation (UK), and Regeneron.

A version of this article first appeared on Medscape.com.