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Significant Benefit with Liver Transplantation in ACLF: CHANCE Study
MILAN —
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%.
“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 —
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%.
“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 —
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%.
“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.
FROM EASL 2024
‘Dramatic’ Phase 2 Results for Survodutide in MASH, Fibrosis
MILAN — , 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.
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 — , 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.
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 — , 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.
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.
FROM EASL 2024
Seladelpar Shows Clinically Meaningful Improvements in PBC
MILAN — 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.
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 — 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.
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 — 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.
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.
FROM EASL 2024
Tirzepatide Shows Improvements in MASH Resolution, Fibrosis
MILAN — , 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. 
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.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
MILAN — , 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.
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.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
MILAN — , 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.
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.
“In terms of fibrosis, the results look numerically strong but are somewhat more puzzling to interpret, as there was no dose-response relationship and no data on NITs [noninvasive tests] that could support the results,” he added.
“Patients with no-end-of-treatment biopsies were handled differently than in previous trials, which makes it difficult to appreciate antifibrotic potency,” he said. But “such a strong effect on MASH should translate into a reduction in fibrosis even in the absence of direct antifibrotic effects.”
Given that “about one third of patients in the active treatment arms” did not have end-of-treatment biopsy, these “are rather small numbers precluding firm conclusions,” he added.
However, Dr. Francque said that he believes the findings are compelling enough for the drug to go into phase 3 trials.
Dr. Francque has no disclosures of relevance to this study. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. Dr. Loomba is a co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
FROM EASL 2024
Intelligent Liver Function Testing Helps Detect, Diagnose Chronic Liver Disease
TOPLINE:
, 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:
, 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:
, 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.
FROM EASL 2024
FMT Could Prevent Recurrence of Hepatic Encephalopathy in Patients With Cirrhosis
MILAN — , 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.
Donor background (including vegan or omnivore) and dose range also did not affect the efficacy of FMT, Dr. Bajaj said.
Dr. Bajaj presented the findings (Abstract GS-001) at the opening session of the annual European Association for the Study of the Liver (EASL) Congress 2024.
Hepatic encephalopathy is a complication of advanced liver disease that causes a dementia-like state. Standard treatment with lactulose and rifaximin often results in a lack of patient response, meaning the patient is constantly being readmitted to the hospital, Dr. Bajaj said.
“This is a burden for the family as well as the patients,” and is very difficult to manage from a clinical and psychosocial perspective, he said in an interview.
With FMT, “we are transferring an ecosystem of good microbes,” which modifies the gut microbiome in patients with advanced liver disease and reduces associated brain toxicity, Dr. Bajaj explained.
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.
This study was built on Dr. Bajaj’s prior work that established the safety of FMT by enema, she added, stressing that this new research was incredibly important in these immunocompromised patients who are at higher risk for infection transmission.
That the administration route doesn’t matter is also an important finding as oral administration is much more feasible than enema, said Dr. Kelly, who went on to point out the importance of finding an alternative to rifaximin and lactulose, which are often poorly tolerated.
The study highlights the central role played by the gut microbiota in dysbiosis in the pathophysiology of hepatic encephalopathy, Dr. Kelly said. “It is another exciting example of how gut microbiota can be manipulated to treat disease.”
Dr. Bajaj and Dr. Kelly report no relevant financial relationships to this study.
A version of this article appeared on Medscape.com.
MILAN — , 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.
Donor background (including vegan or omnivore) and dose range also did not affect the efficacy of FMT, Dr. Bajaj said.
Dr. Bajaj presented the findings (Abstract GS-001) at the opening session of the annual European Association for the Study of the Liver (EASL) Congress 2024.
Hepatic encephalopathy is a complication of advanced liver disease that causes a dementia-like state. Standard treatment with lactulose and rifaximin often results in a lack of patient response, meaning the patient is constantly being readmitted to the hospital, Dr. Bajaj said.
“This is a burden for the family as well as the patients,” and is very difficult to manage from a clinical and psychosocial perspective, he said in an interview.
With FMT, “we are transferring an ecosystem of good microbes,” which modifies the gut microbiome in patients with advanced liver disease and reduces associated brain toxicity, Dr. Bajaj explained.
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.
This study was built on Dr. Bajaj’s prior work that established the safety of FMT by enema, she added, stressing that this new research was incredibly important in these immunocompromised patients who are at higher risk for infection transmission.
That the administration route doesn’t matter is also an important finding as oral administration is much more feasible than enema, said Dr. Kelly, who went on to point out the importance of finding an alternative to rifaximin and lactulose, which are often poorly tolerated.
The study highlights the central role played by the gut microbiota in dysbiosis in the pathophysiology of hepatic encephalopathy, Dr. Kelly said. “It is another exciting example of how gut microbiota can be manipulated to treat disease.”
Dr. Bajaj and Dr. Kelly report no relevant financial relationships to this study.
A version of this article appeared on Medscape.com.
MILAN — , 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.
Donor background (including vegan or omnivore) and dose range also did not affect the efficacy of FMT, Dr. Bajaj said.
Dr. Bajaj presented the findings (Abstract GS-001) at the opening session of the annual European Association for the Study of the Liver (EASL) Congress 2024.
Hepatic encephalopathy is a complication of advanced liver disease that causes a dementia-like state. Standard treatment with lactulose and rifaximin often results in a lack of patient response, meaning the patient is constantly being readmitted to the hospital, Dr. Bajaj said.
“This is a burden for the family as well as the patients,” and is very difficult to manage from a clinical and psychosocial perspective, he said in an interview.
With FMT, “we are transferring an ecosystem of good microbes,” which modifies the gut microbiome in patients with advanced liver disease and reduces associated brain toxicity, Dr. Bajaj explained.
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.
This study was built on Dr. Bajaj’s prior work that established the safety of FMT by enema, she added, stressing that this new research was incredibly important in these immunocompromised patients who are at higher risk for infection transmission.
That the administration route doesn’t matter is also an important finding as oral administration is much more feasible than enema, said Dr. Kelly, who went on to point out the importance of finding an alternative to rifaximin and lactulose, which are often poorly tolerated.
The study highlights the central role played by the gut microbiota in dysbiosis in the pathophysiology of hepatic encephalopathy, Dr. Kelly said. “It is another exciting example of how gut microbiota can be manipulated to treat disease.”
Dr. Bajaj and Dr. Kelly report no relevant financial relationships to this study.
A version of this article appeared on Medscape.com.
FROM EASL 2024