Liver Disease

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.

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

MILAN — Tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, was more effective than was placebo in the resolution of metabolic dysfunction–associated steatohepatitis (MASH) and in the improvement of fibrosis, according to the results of the phase 2 SYNERGY-NASH trial.

Specifically, 44%-62% of participants with MASH and moderate or severe fibrosis treated with 5-15 mg of tirzepatide achieved MASH resolution without worsening of fibrosis compared with 10% on placebo; 51%-55% of those on tirzepatide achieved at least one stage of fibrosis improvement without worsening of MASH compared with 30% on placebo. Tirzepatide also led to weight loss.

The study (Abstract LBO-001) was presented at the European Association for the Study of the Liver (EASL) Congress 2024 by Rohit Loomba, MD, professor of medicine, NAFLD Research Center, University of California at San Diego in La Jolla, and published simultaneously in The New England Journal of Medicine. 

“The results are clinically meaningful,” Dr. Loomba said in an interview. 

University of California, San Diego

Both of the endpoints — improvements in MASH resolution and fibrosis — are considered approvable endpoints for MASH therapeutic development, and therefore, increase the likelihood of success of using such a strategy in a phase 3 setting, Dr. Loomba said.
 

MASH Resolution, No Worsening of Fibrosis

The dose-finding, multicenter, double-blind, placebo-controlled trial randomly assigned a total of 190 participants to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. Participants had biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. 

Overall, approximately 42% of participants had F2 fibrosis and over 57% had F3 fibrosis. The proportion of F3 fibrosis was numerically higher in the placebo (64.6%) and 5-mg tirzepatide (63.8%) groups. 

The mean age of the study cohort was 54 years; 57% were female, 86% were White, and 36% were Hispanic; the mean body mass index was 36; 58% had type 2 diabetes; and A1c was 6.5. NAFLD activity score (NAS) was 5.3. Baseline noninvasive test results were consistent with the study population of MASH with F2/F3 fibrosis and NAS ≥ 4. 

The primary endpoint was resolution of MASH without worsening of fibrosis at 52 weeks, and the key secondary endpoint was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. Other secondary endpoints included a ≥ 2-point decrease in NAS with ≤ 1-point decrease in two or more NAS components.

A total of 157 participants (83%) underwent liver biopsies at week 52, providing results for the current analysis. 

Among tirzepatide-treated patients, 43.6% in the 5-mg group, 55.5% in the 10-mg group, and 62.4% in the 15-mg group met the criteria for resolution of MASH without worsening of fibrosis compared with  10% in the placebo group (P < .001 for all three comparisons). 

Fibrosis improved by at least one stage without worsening of MASH in 54.9% of participants in the 5-mg tirzepatide group, 51.3% in the 10-mg tirzepatide group, and 51.0% in the 15-mg tirzepatide group compared with 29.7% in the placebo group (P < .001 for all risk differences with placebo). 

Changes in NAS and subscores for the individual components of NAS, including steatosis, lobular inflammation, and hepatocellular ballooning, were also seen in participants on tirzepatide. 

The researchers used a composite endpoint of a ≥ 2-point decrease in NAS with a ≥ 1-point decrease in at least two NAS components. Of the tirzepatide-treated groups, 71.7%,78.3%, and 76.6% in the 5-mg, 10-mg, and 15-mg groups, respectively, met this endpoint compared with 36.7% in placebo. 

Imaging of liver fat with MRI-based proton density fat fraction (MRI-PDFF) showed reductions from baseline of -45.7, -41.3, -57.0 in participants on 5-mg, 10-mg, and 15-mg tirzepatide, respectively. Differences from placebo were all statistically significant. 

Percentage of body weight change from baseline was -10.7%, -13.3%, and -15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared with weight loss of -0.8% in the placebo group. 

“Tirzepatide led to significant weight loss in both patients with diabetes and those without diabetes,” reported Dr. Loomba. 

There were more adverse events in patients on tirzepatide (92.3%) compared with patients on placebo (83.3%). 

“The most common adverse events were gastrointestinal in nature, with 96% of them mild to moderate in severity,” said Dr. Loomba. “Discontinuations occurred in 4.2% of participants, which was similar between patients on tirzepatide and those on placebo.”

He pointed out that the safety profile of tirzepatide in a MASH population “was generally similar to that observed in the phase 3 trials of type 2 diabetes and obesity.”

Incidence of serious adverse events was also similar at 6.3% for participants on tirzepatide vs 6.2% for those on placebo; 2.8% on tirzepatide and 4.2% on placebo progressed to cirrhosis. There was no evidence of drug-induced liver injury. 
 

‘Convincing Results’

Commenting on the study, co-moderator Sven Francque, MD, hepatologist and head of department at the University Hospital of Antwerp, Belgium, said that the study was in a relatively “severe” patient population, which was one of its strengths. 

“These are convincing results in terms of MASH resolution, showing a strong response and dose-dependence,” he said. 

Dr. Francque

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

WASHINGTON – Women with autoimmune liver diseases (AILD) may face increased risks for major adverse cardiovascular outcomes, according to a study presented at the annual Digestive Disease Week^® (DDW).

In particular, women with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) appear to have higher risks than women without AIH or PBC. Those with primary sclerosing cholangitis (PSC) don’t seem to have increased risks.

“We know that cardiovascular disease remains the number one cause of death, but the mortality rate for women over the last decade has plateaued, whereas in men it’s actually declining due to interventions,” said lead author Rachel Redfield, MD, a transplant hepatology fellow at Thomas Jefferson University Hospital in Philadelphia.

“This is likely because we don’t have adequate risk stratification, especially for women,” she said. “We know that immune-mediated diseases — such as rheumatoid arthritis and psoriasis — carry a higher risk of cardiovascular disease, but there’s not a lot of data on our autoimmune liver disease patients.”

Dr. Redfield

Although being a female can offer protection against some CVD risks, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk score calculator recommended by the American College of Cardiology doesn’t include chronic inflammatory diseases associated with increased CVD risk, including AILD.

Dr. Redfield and colleagues conducted a multicenter, retrospective cohort study of patients with AIH, PBC, and PSC from 1999-2019. Using TriNetX data, the researchers looked at women with AILD who also had diabetes mellitus, hypertension, and hyperlipidemia, as well as a control group of men and women with these same disorders, excluding those who used biologics, immune modulators, and steroids or had other autoimmune disorders.

The research team used 1:1 propensity-score matching for women in the study group and in the control group based on age, race, ethnicity, ASCVD risk factors, and tobacco use. Women in the study group and men in the control group were matched for age, race, ethnicity, and tobacco use.

The primary outcome was summative cardiovascular risk, including unstable angina, acute myocardial infarction, presence of coronary angioplasty implant, coronary artery bypass, percutaneous coronary intervention, and cerebral infarction.

Overall, women with AIH had a significantly higher cardiovascular risk compared to women without AIH, at 25.4% versus 20.6% (P = .0007).

Specifically, women with PBC had a significantly higher cardiovascular risk compared to women without PBC, at 27.05% versus 20.9% (P < .0001).

There wasn’t a significant difference in risk between women with and without PSC, at 27.5% versus 21.8% (P = .27).

When compared to men without disease, women with AIH didn’t have a statistically significant higher risk, at 25.3% versus 24.2% (P = .44). Similarly, there didn’t appear to be a significant difference between women with PBC and men without PBC, at 26.9% versus 25.9% (P = .52), or between women with PSC and men without PSC, at 27.7% versus 26.2% (P = .78).

Dr. Redfield and colleagues then compared the ASCVD-calculated risk versus database risk, finding that in each group of women with AILD — including AIH, PBC, and PSC — the ASCVD-calculated risk was around 11%, compared with database risk scores of 25% for AIH, 27% for PBC, and 28% for PSC. These database risks appeared similar to both the ASCVD and database risk percentages for men.

“So potentially there’s an oversight in women with any kind of inflammatory disease, but specifically here, autoimmune liver diseases,” she said. “We really need to enhance our risk assessment strategies to take into account their risk and optimize patient outcomes.”

Dr. Redfield noted the limitations with using TriNetX data, including coding consistency among providers and healthcare organizations, unknown patient follow-up dates, and the inability to capture various inflammatory disease phenotypes, such as autoimmune hepatitis with multiple flares, which may be associated with higher cardiovascular risks.

As an attendee of the DDW session, Kenneth Kelson, MD, a gastroenterologist with Fremont Medical Group and Washington Hospital Healthcare System in Fremont, California, noted the importance of investigating the effects of different types of statins in these patients. Although the research team looked at top-level differences among statin users, finding that women with AILD were more likely to be on a statin, they didn’t incorporate statin therapy in the propensity-score matching model.

“Lipid-soluble statins are known to cause more liver trouble, even though it’s pretty low,” Dr. Kelson said. “Whereas the water-soluble statins have a lower incidence of liver issues.”

Dr. Redfield and Dr. Kelson reported no relevant disclosures.

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

The intelligent Liver Function Testing (iLFT) platform can improve diagnosis and management of chronic liver disease in a primary care setting, new data show. 

METHODOLOGY:

• At the European Association for the Study of the Liver (EASL) Congress 2024, researchers presented 5-year, real-world data of the iLFT platform from its use in NHS Tayside in Dundee, Scotland, which serves a population of 400,000. The platform has been available since 2018.
• The iLFT platform uses an automated algorithm that analyzes standard liver function test results.
• Abnormal results prompt the system to initiate further fibrosis scoring and relevant etiologic testing to determine the cause of liver dysfunction.
• The results of these tests combined with practitioner-entered clinical information produce a probable diagnosis and recommend a patient-management strategy.

TAKEAWAY: 

• Of the 26,459 iLFT tests performed between 2018 and 2023, 68.3% (18,079) required further testing beyond the initial liver function test, whereas 31.7% (8380) did not.
• Further testing generated 20,895 outcomes, of which, isolated abnormal alanine transaminase (ALT) without fibrosis was most frequent (23.7%). Abnormal ALT was found to be most likely due to metabolic dysfunction–associated steatotic liver disease (MASLD).
• Overall, half of cascaded samples had a positive etiologic diagnosis. Alcoholic liver disease (ALD) and MASLD were the most common etiologic outcomes identified.
• In addition, 20% of cascaded tests identified potentially significant liver fibrosis.
• A total of 69.9% of outcomes recommended that patients could be safely managed in primary care. The inclusion of automatic Enhanced Liver Fibrosis (ELF) testing in 2020 further reduced the requirement for referral to secondary care by 34%.

IN PRACTICE:

“Without this algorithm, the 18,000 patients who had algorithm-directed further testing would have had to go back to the [primary care practitioner] to obtain the additional tests, and the [primary care practitioner] would need to interpret them too,” said Damien Leith, MD, trainee hepatologist at Ninewells Hospital, Dundee, Scotland, who presented the findings. “iLFTs ensure the right patients get automated, appropriate follow-up testing and subsequent recommendation of referral to secondary care if necessary, and importantly iLFT helps the primary care practitioner identify the cause of chronic liver disease.” 

SOURCE:

This study was presented on June 6, 2024 at the EASL Congress 2024 (abstract OS-007-YI).

LIMITATIONS:

Limitations include the need for further refinement of the algorithm to increase the proportion of positive etiologic iLFT outcomes. More analysis is needed to optimize the cost-effectiveness of iLFT. 

DISCLOSURES:

Dr. Leith reports no relevant financial relationships.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Iqirvo (elafibranor; Ipsen) for treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who do not respond adequately to UDCA or as monotherapy in patients unable to tolerate UDCA. 

PBC is a rare, chronic cholestatic liver disease that destroys interlobular bile ducts and leads to cholestasis and liver fibrosis. Left untreated, the disease can worsen over time, leading to cirrhosis and liver transplant and, in some cases, premature death. PBC also harms quality of life, with patients often experiencing severe fatigue and pruritus.

Iqirvo, an oral dual peroxisome proliferator–activated receptor (PPAR) alpha and delta agonist, is the first new drug approved in nearly a decade for treatment of PBC. 

Accelerated approval of Iqirvo for PBC was based on data from the phase 3 ELATIVE trial published last year in The New England Journal of Medicine. 

The trial randomly assigned patients with PBC who had an inadequate response to or unacceptable side effects with UDCA to receive either once-daily elafibranor (80 mg) or placebo. 

The primary endpoint was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a reduction ≥ 15% from baseline, as well as normal total bilirubin levels.

Among 161 patients, a biochemical response was seen in 55 of 108 (51%) who received elafibranor vs 2 of 53 (4%) who received placebo. 

At week 52, the ALP level normalized in 15% of patients in the elafibranor group and none of the patients in the placebo group.

In a news release announcing approval of Iqirvo, the company notes that improvement in survival and prevention of liver decompensation events have not been demonstrated and that continued approval for PBC may be contingent upon verification and description of clinical benefit in confirmatory trials.

The most common adverse effects with Iqirvo, reported in ≥ 10% of study participants, were weight gain, abdominal pain, diarrhea, nausea, and vomiting. Iqirvo is not recommended for people who have or develop decompensated cirrhosis. Full prescribing information is available online. 

The data show that Iqirvo is “an effective second-line treatment for patients with PBC with favorable benefit and risk data,” Kris Kowdley, MD, AGAF, director of the Liver Institute Northwest in Seattle, Washington, and a primary investigator on the ELATIVE study, said in the news release. 

The approval of Iqirvo “will allow healthcare providers in the US to address an unmet need with the potential to significantly reduce ALP levels for our patients with PBC,” Dr. Kowdley said.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Iqirvo (elafibranor; Ipsen) for treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who do not respond adequately to UDCA or as monotherapy in patients unable to tolerate UDCA. 

PBC is a rare, chronic cholestatic liver disease that destroys interlobular bile ducts and leads to cholestasis and liver fibrosis. Left untreated, the disease can worsen over time, leading to cirrhosis and liver transplant and, in some cases, premature death. PBC also harms quality of life, with patients often experiencing severe fatigue and pruritus.

Iqirvo, an oral dual peroxisome proliferator–activated receptor (PPAR) alpha and delta agonist, is the first new drug approved in nearly a decade for treatment of PBC. 

Accelerated approval of Iqirvo for PBC was based on data from the phase 3 ELATIVE trial published last year in The New England Journal of Medicine. 

The trial randomly assigned patients with PBC who had an inadequate response to or unacceptable side effects with UDCA to receive either once-daily elafibranor (80 mg) or placebo. 

The primary endpoint was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a reduction ≥ 15% from baseline, as well as normal total bilirubin levels.

Among 161 patients, a biochemical response was seen in 55 of 108 (51%) who received elafibranor vs 2 of 53 (4%) who received placebo. 

At week 52, the ALP level normalized in 15% of patients in the elafibranor group and none of the patients in the placebo group.

In a news release announcing approval of Iqirvo, the company notes that improvement in survival and prevention of liver decompensation events have not been demonstrated and that continued approval for PBC may be contingent upon verification and description of clinical benefit in confirmatory trials.

The most common adverse effects with Iqirvo, reported in ≥ 10% of study participants, were weight gain, abdominal pain, diarrhea, nausea, and vomiting. Iqirvo is not recommended for people who have or develop decompensated cirrhosis. Full prescribing information is available online. 

The data show that Iqirvo is “an effective second-line treatment for patients with PBC with favorable benefit and risk data,” Kris Kowdley, MD, AGAF, director of the Liver Institute Northwest in Seattle, Washington, and a primary investigator on the ELATIVE study, said in the news release. 

The approval of Iqirvo “will allow healthcare providers in the US to address an unmet need with the potential to significantly reduce ALP levels for our patients with PBC,” Dr. Kowdley said.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Iqirvo (elafibranor; Ipsen) for treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who do not respond adequately to UDCA or as monotherapy in patients unable to tolerate UDCA. 

PBC is a rare, chronic cholestatic liver disease that destroys interlobular bile ducts and leads to cholestasis and liver fibrosis. Left untreated, the disease can worsen over time, leading to cirrhosis and liver transplant and, in some cases, premature death. PBC also harms quality of life, with patients often experiencing severe fatigue and pruritus.

Iqirvo, an oral dual peroxisome proliferator–activated receptor (PPAR) alpha and delta agonist, is the first new drug approved in nearly a decade for treatment of PBC. 

Accelerated approval of Iqirvo for PBC was based on data from the phase 3 ELATIVE trial published last year in The New England Journal of Medicine. 

The trial randomly assigned patients with PBC who had an inadequate response to or unacceptable side effects with UDCA to receive either once-daily elafibranor (80 mg) or placebo. 

The primary endpoint was a biochemical response, defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a reduction ≥ 15% from baseline, as well as normal total bilirubin levels.

Among 161 patients, a biochemical response was seen in 55 of 108 (51%) who received elafibranor vs 2 of 53 (4%) who received placebo. 

At week 52, the ALP level normalized in 15% of patients in the elafibranor group and none of the patients in the placebo group.

In a news release announcing approval of Iqirvo, the company notes that improvement in survival and prevention of liver decompensation events have not been demonstrated and that continued approval for PBC may be contingent upon verification and description of clinical benefit in confirmatory trials.

The most common adverse effects with Iqirvo, reported in ≥ 10% of study participants, were weight gain, abdominal pain, diarrhea, nausea, and vomiting. Iqirvo is not recommended for people who have or develop decompensated cirrhosis. Full prescribing information is available online. 

The data show that Iqirvo is “an effective second-line treatment for patients with PBC with favorable benefit and risk data,” Kris Kowdley, MD, AGAF, director of the Liver Institute Northwest in Seattle, Washington, and a primary investigator on the ELATIVE study, said in the news release. 

The approval of Iqirvo “will allow healthcare providers in the US to address an unmet need with the potential to significantly reduce ALP levels for our patients with PBC,” Dr. Kowdley said.
 

A version of this article appeared on Medscape.com.

MILAN — Fecal microbiota transplantation (FMT), also known as intestinal microbiota transplantation, significantly reduced recurrence of hepatic encephalopathy, compared with placebo, in patients with cirrhosis on standard-of-care treatment, results of a phase 2 randomized controlled trial show. 

“Not only was FMT more beneficial, but also it didn’t matter which route of administration was used — oral or enema — which is good because people don’t really like enemas,” said Jasmohan S. Bajaj, MD, AGAF, professor, School of Medicine, Virginia Commonwealth University, Richmond, and hepatologist at Richmond VA Medical Center.

Resetting the Gut

The double-blind, randomized, placebo-controlled trial enrolled a total of 60 patients with cirrhosis who had experienced hepatic encephalopathy. Aged 61-65 years, participants had Model for End-Stage Liver Disease (MELD) scores of 12-13, all were taking lactulose and rifaximin, and all had experienced their last hepatic encephalopathy episode 8-13 months prior. 

Participants had similar baseline cognition, Sickness Impact Profile (SIP), and cirrhosis severity. Those with recent infections, taking other antibiotics, with a MELD score > 22, had received a transplant, or were immunosuppressed were excluded. 

Study participants were divided into four dose administration groups (n = 15 each): oral and enema active FMT therapy (group 1), oral active FMT and enema placebo (group 2), oral placebo and enema active FMT (group 3), and oral and enema placebo (group 4). 

The range of FMT dose frequency was zero (all placebo), or one, two, or three FMT administrations, each given 1 month apart. 

Two thirds of those receiving active FMT were given omnivore-donor FMT, and one third were given vegan-donor FMT, in addition to receiving standard of care. 

“Colony-forming units were standard and the same whether given via oral capsule or enema,” Dr. Bajaj said. This is “similar to what we used in our phase 1 study.”

Intent-to-treat (ITT) analysis was performed with 6-month data. The primary outcomes were safety and hepatic encephalopathy recurrence defined as ≥ grade 2 on West-Haven criteria. Secondary outcomes included other adverse events, changes in infections, severity of cirrhosis and cognition, and patient-reported outcomes. A statistical regression for hepatic encephalopathy recurrence was also performed. Patients were followed for 6 months or until death.
 

One Dose of FMT Better Than None

Hepatic encephalopathy recurrence was highest (40%) in group 4 patients, compared with those in group 1 (13%), group 2 (13%), and group 3 (0%), as were liver-related hospitalizations (47% vs 7%-20%). 

SIP total/physical and psych scores improved with FMT (P = .003).

When all patients were included in the analysis, the hepatic encephalopathy recurrence was related to dose number (odds radio [OR], 0.27; 95% CI, 0.10-0.79; P = .02), male sex (OR, 0.16; 95% CI, 0.03-0.89; P = .04), and physical SIP (OR, 1.05; 95% CI, 1.01-1.10, P = .05). However, when analyzing results from FMT recipients only, FMT dose, route of administration, and donor source were not found to affect recurrence. 

Of those on placebo alone, six patients (40%) had a recurrence, compared with four on FMT (8.8%) in the combined FMT groups. 

“As long as a patient received at least one FMT dose, they had a better response than a patient who had none,” Dr. Bajaj said.

Six patients dropped out; two in group 1 died after hepatic encephalopathy and falls, and one in group 2 died after a seizure. Three others did not return for follow-up visits. Four patients developed infections, including spontaneous bacterial peritonitis, cholecystitis, and cellulitis, all unrelated to FMT. 

“I think many patients in Western countries are underserved because apart from lactulose and rifaximin, there is little else to give them,” Dr. Bajaj said. “The assumption is because rifaximin kills everything, we shouldn’t give FMT. But here, we administered it to a harsh and hostile wasteland of microbiota, and it still got a toehold and generated a reduction in hepatic encephalopathy.”

He pointed out that in smaller prior studies, the effects lasted up to 1 year. 
 

Setting the Stage for Phase 3 Trials

Dr. Bajaj noted that this phase 2 study sets the stage for larger phase 3 trials in patients not responding to first-line therapy. 

“Given how well-tolerated and effective FMT appears to be in these patients, if the larger phase 3 trial shows similar results, I can imagine FMT becoming a standard therapy,” said Colleen R. Kelly, MD, AGAF, gastroenterologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved in the study.

A version of this article appeared on Medscape.com.

MILAN — Fecal microbiota transplantation (FMT), also known as intestinal microbiota transplantation, significantly reduced recurrence of hepatic encephalopathy, compared with placebo, in patients with cirrhosis on standard-of-care treatment, results of a phase 2 randomized controlled trial show. 

“Not only was FMT more beneficial, but also it didn’t matter which route of administration was used — oral or enema — which is good because people don’t really like enemas,” said Jasmohan S. Bajaj, MD, AGAF, professor, School of Medicine, Virginia Commonwealth University, Richmond, and hepatologist at Richmond VA Medical Center.

Resetting the Gut

The double-blind, randomized, placebo-controlled trial enrolled a total of 60 patients with cirrhosis who had experienced hepatic encephalopathy. Aged 61-65 years, participants had Model for End-Stage Liver Disease (MELD) scores of 12-13, all were taking lactulose and rifaximin, and all had experienced their last hepatic encephalopathy episode 8-13 months prior. 

Participants had similar baseline cognition, Sickness Impact Profile (SIP), and cirrhosis severity. Those with recent infections, taking other antibiotics, with a MELD score > 22, had received a transplant, or were immunosuppressed were excluded. 

Study participants were divided into four dose administration groups (n = 15 each): oral and enema active FMT therapy (group 1), oral active FMT and enema placebo (group 2), oral placebo and enema active FMT (group 3), and oral and enema placebo (group 4). 

The range of FMT dose frequency was zero (all placebo), or one, two, or three FMT administrations, each given 1 month apart. 

Two thirds of those receiving active FMT were given omnivore-donor FMT, and one third were given vegan-donor FMT, in addition to receiving standard of care. 

“Colony-forming units were standard and the same whether given via oral capsule or enema,” Dr. Bajaj said. This is “similar to what we used in our phase 1 study.”

Intent-to-treat (ITT) analysis was performed with 6-month data. The primary outcomes were safety and hepatic encephalopathy recurrence defined as ≥ grade 2 on West-Haven criteria. Secondary outcomes included other adverse events, changes in infections, severity of cirrhosis and cognition, and patient-reported outcomes. A statistical regression for hepatic encephalopathy recurrence was also performed. Patients were followed for 6 months or until death.
 

One Dose of FMT Better Than None

Hepatic encephalopathy recurrence was highest (40%) in group 4 patients, compared with those in group 1 (13%), group 2 (13%), and group 3 (0%), as were liver-related hospitalizations (47% vs 7%-20%). 

SIP total/physical and psych scores improved with FMT (P = .003).

When all patients were included in the analysis, the hepatic encephalopathy recurrence was related to dose number (odds radio [OR], 0.27; 95% CI, 0.10-0.79; P = .02), male sex (OR, 0.16; 95% CI, 0.03-0.89; P = .04), and physical SIP (OR, 1.05; 95% CI, 1.01-1.10, P = .05). However, when analyzing results from FMT recipients only, FMT dose, route of administration, and donor source were not found to affect recurrence. 

Of those on placebo alone, six patients (40%) had a recurrence, compared with four on FMT (8.8%) in the combined FMT groups. 

“As long as a patient received at least one FMT dose, they had a better response than a patient who had none,” Dr. Bajaj said.

Six patients dropped out; two in group 1 died after hepatic encephalopathy and falls, and one in group 2 died after a seizure. Three others did not return for follow-up visits. Four patients developed infections, including spontaneous bacterial peritonitis, cholecystitis, and cellulitis, all unrelated to FMT. 

“I think many patients in Western countries are underserved because apart from lactulose and rifaximin, there is little else to give them,” Dr. Bajaj said. “The assumption is because rifaximin kills everything, we shouldn’t give FMT. But here, we administered it to a harsh and hostile wasteland of microbiota, and it still got a toehold and generated a reduction in hepatic encephalopathy.”

He pointed out that in smaller prior studies, the effects lasted up to 1 year. 
 

Setting the Stage for Phase 3 Trials

Dr. Bajaj noted that this phase 2 study sets the stage for larger phase 3 trials in patients not responding to first-line therapy. 

“Given how well-tolerated and effective FMT appears to be in these patients, if the larger phase 3 trial shows similar results, I can imagine FMT becoming a standard therapy,” said Colleen R. Kelly, MD, AGAF, gastroenterologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved in the study.

A version of this article appeared on Medscape.com.

MILAN — Fecal microbiota transplantation (FMT), also known as intestinal microbiota transplantation, significantly reduced recurrence of hepatic encephalopathy, compared with placebo, in patients with cirrhosis on standard-of-care treatment, results of a phase 2 randomized controlled trial show. 

“Not only was FMT more beneficial, but also it didn’t matter which route of administration was used — oral or enema — which is good because people don’t really like enemas,” said Jasmohan S. Bajaj, MD, AGAF, professor, School of Medicine, Virginia Commonwealth University, Richmond, and hepatologist at Richmond VA Medical Center.

Resetting the Gut

The double-blind, randomized, placebo-controlled trial enrolled a total of 60 patients with cirrhosis who had experienced hepatic encephalopathy. Aged 61-65 years, participants had Model for End-Stage Liver Disease (MELD) scores of 12-13, all were taking lactulose and rifaximin, and all had experienced their last hepatic encephalopathy episode 8-13 months prior. 

Participants had similar baseline cognition, Sickness Impact Profile (SIP), and cirrhosis severity. Those with recent infections, taking other antibiotics, with a MELD score > 22, had received a transplant, or were immunosuppressed were excluded. 

Study participants were divided into four dose administration groups (n = 15 each): oral and enema active FMT therapy (group 1), oral active FMT and enema placebo (group 2), oral placebo and enema active FMT (group 3), and oral and enema placebo (group 4). 

The range of FMT dose frequency was zero (all placebo), or one, two, or three FMT administrations, each given 1 month apart. 

Two thirds of those receiving active FMT were given omnivore-donor FMT, and one third were given vegan-donor FMT, in addition to receiving standard of care. 

“Colony-forming units were standard and the same whether given via oral capsule or enema,” Dr. Bajaj said. This is “similar to what we used in our phase 1 study.”

Intent-to-treat (ITT) analysis was performed with 6-month data. The primary outcomes were safety and hepatic encephalopathy recurrence defined as ≥ grade 2 on West-Haven criteria. Secondary outcomes included other adverse events, changes in infections, severity of cirrhosis and cognition, and patient-reported outcomes. A statistical regression for hepatic encephalopathy recurrence was also performed. Patients were followed for 6 months or until death.
 

One Dose of FMT Better Than None

Hepatic encephalopathy recurrence was highest (40%) in group 4 patients, compared with those in group 1 (13%), group 2 (13%), and group 3 (0%), as were liver-related hospitalizations (47% vs 7%-20%). 

SIP total/physical and psych scores improved with FMT (P = .003).

When all patients were included in the analysis, the hepatic encephalopathy recurrence was related to dose number (odds radio [OR], 0.27; 95% CI, 0.10-0.79; P = .02), male sex (OR, 0.16; 95% CI, 0.03-0.89; P = .04), and physical SIP (OR, 1.05; 95% CI, 1.01-1.10, P = .05). However, when analyzing results from FMT recipients only, FMT dose, route of administration, and donor source were not found to affect recurrence. 

Of those on placebo alone, six patients (40%) had a recurrence, compared with four on FMT (8.8%) in the combined FMT groups. 

“As long as a patient received at least one FMT dose, they had a better response than a patient who had none,” Dr. Bajaj said.

Six patients dropped out; two in group 1 died after hepatic encephalopathy and falls, and one in group 2 died after a seizure. Three others did not return for follow-up visits. Four patients developed infections, including spontaneous bacterial peritonitis, cholecystitis, and cellulitis, all unrelated to FMT. 

“I think many patients in Western countries are underserved because apart from lactulose and rifaximin, there is little else to give them,” Dr. Bajaj said. “The assumption is because rifaximin kills everything, we shouldn’t give FMT. But here, we administered it to a harsh and hostile wasteland of microbiota, and it still got a toehold and generated a reduction in hepatic encephalopathy.”

He pointed out that in smaller prior studies, the effects lasted up to 1 year. 
 

Setting the Stage for Phase 3 Trials

Dr. Bajaj noted that this phase 2 study sets the stage for larger phase 3 trials in patients not responding to first-line therapy. 

“Given how well-tolerated and effective FMT appears to be in these patients, if the larger phase 3 trial shows similar results, I can imagine FMT becoming a standard therapy,” said Colleen R. Kelly, MD, AGAF, gastroenterologist at Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved in the study.

A version of this article appeared on Medscape.com.

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, potentially impacting clinical decisions, according to investigators.

These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.

Houston Methodist Hospital

“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Yet the performance of the FIB-4 index in this context remains unclear.

“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”

To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.

All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).

Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.

Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.

“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”

They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.

“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”

The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, potentially impacting clinical decisions, according to investigators.

These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.

Houston Methodist Hospital

“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Yet the performance of the FIB-4 index in this context remains unclear.

“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”

To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.

All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).

Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.

Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.

“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”

They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.

“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”

The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, potentially impacting clinical decisions, according to investigators.

These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.

Houston Methodist Hospital

“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.

Yet the performance of the FIB-4 index in this context remains unclear.

“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”

To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.

All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).

Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.

Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.

“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”

They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.

“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”

The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.