TBD Meeting (3224-19)

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – For almost half of patients with nonalcoholic steatohepatitis (NASH), bariatric surgery does not resolve severe fibrosis, even after significant weight loss and resolution of multiple metabolic comorbidities, according to investigators.

Still, bariatric surgery was highly effective at improving liver histology in patients without severe fibrosis, reported lead author Raluca Pais, MD, of Sorbonne University, Paris, and colleagues.

“There are many targeted agents for NASH at this time, but their response rate is limited to less than 30%,” Dr. Pais said in a presentation at the annual meeting of the American Association for the Study of Liver Diseases. “In very selective patients, bariatric surgery is a very attractive therapeutic option, as it promotes massive weight loss and sustained improvement in metabolic comorbidities, which are concomitant with very high rates of hepatic histological improvement in most but not all patients.” Despite the known benefits of bariatric surgery, histologic outcomes have been minimally studied, Dr. Pais said, which prompted the present trial.

The investigators began by analyzing data from 868 patients with NASH who underwent bariatric surgery with perioperative liver biopsy between 2004 and 2014. Of these patients, 181 had advanced NASH, a diagnosis that was subclassified by severe fibrosis (F3 or F4) or high activity (steatosis, activity, and fibrosis score of 3-4 with F0-2). Out of the 181 patients with advanced NASH, 65 consented to follow-up liver biopsy, which was conducted a mean of 6 years after surgery. Among these patients, 53 had undergone gastric bypass surgery, while 12 had undergone sleeve gastrectomy.

Almost one-third (29%) of the 65 patients who underwent bariatric surgery had normal livers at follow-up biopsy. Among the 35 patients who had severe fibrosis at baseline, slightly more than half (54%) had resolution of severe fibrosis. In contrast, resolution of high activity occurred in almost all affected patients (97%).

While the findings highlighted some of the benefits associated with bariatric surgery, Dr. Pais emphasized the other side of the coin; many patients did not have resolution of severe fibrosis, even years after surgery. Specifically, 45% of patients had persistent severe fibrosis at follow-up biopsy, despite improvements in comorbidities. On average, these patients lost 23% of their baseline body weight, and two-thirds of the group achieved normal ALT and resolution of NASH. Many also had improvements in insulin resistance and nonalcoholic fatty liver disease activity scores. These findings suggest that changes in severe fibrosis occur independently of many other improvements, Dr. Pais said.

Although multiple comorbidities were not correlated with changes in severe fibrosis, several other predictors were identified. Compared with patients who had resolution of severe fibrosis, nonresponders were typically older (56 vs. 49 years), more often had persistent diabetes (79% vs. 50%), and generally had shorter time between surgery and follow-up biopsy (4.2 vs. 7.5 years). Compared with nonresponders, responders were more likely to have undergone gastric bypass surgery (100% vs. 69%), suggesting that this procedure was more effective at resolving severe fibrosis than sleeve gastrectomy.

During the question-and-answer session following the presentation, multiple conference attendees suggested that the title of the study, “Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery,” was unnecessarily negative, when in fact the study offered strong support for bariatric surgery.

“This is wonderful data that shows surgery is very effective,” one attendee said.

“This is really positive data,” said another. “I mean, you’ve got reversal of advanced fibrosis in half of the population by the time you follow up for several years, so I would say this is really, very positive data.”

The investigators disclosed relationships with Allergan, Boehringer Ingelheim, Novo Nordisk, and others.

*This story was updated on November 15, 2019.

SOURCE: Pais R et al. The Liver Meeting 2019, Abstract 66.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – A machine-learning model based on standard clinical and laboratory values is able to predict nonalcoholic steatohepatitis (NASH) with a sensitivity of 72%-81%, an investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

The tool, dubbed NASHmap, could serve as an initial screening tool to reveal more potential undiagnosed patients with NASH, according to Jörn M. Schattenberg, MD, with the metabolic liver research program in the department of medicine at University Medical Centre Mainz (Germany).

While not intended to replace current scoring systems, NASHmap potentially could be applied as a clinical decision support tool within electronic medical record systems, allowing greater numbers of patients with suspected NASH to be evaluated and referred to specialists for further testing, according to Dr. Schattenberg.

“To me, this is an at-risk population,” Dr. Schattenberg said in an interview. “There’s a lot of talk of increasing numbers of end-stage liver disease, and these are the cases that are waiting to happen. I think if we identify them, we can manage them better.”

“I’m not saying they should all get drugs – I’m saying they have to be informed about their condition because they may not have a clue they have liver disease,” he continued.

The machine-learning approach described here by Dr. Schattenberg included an exploratory analysis based on 704 patients with NASH or non-NASH nonalcoholic fatty liver disease (NAFLD) in the NAFLD Adult Database from the National Institute of Diabetes, Digestive, and Kidney Diseases.

The best-performing model they identified included 14 variables. Ranked by contribution to predictive power, those variables included hemoglobin A_1c, aspartate aminotransferase, alanine aminotransferase, total protein, AST/ALT ratio, body mass index, triglycerides, height, platelets, white blood cells, hematocrit, albumin, hypertension, and sex.

That 14-variable model had good performance when tested on the Optum Humedica electronic medical record database, according to Dr. Schattenberg and colleagues.

In the analysis for final evaluation, including 1,016 patients with histologically confirmed NASH, the area under the curve was 0.76, they reported.

A simplified, five-variable model including just hemoglobin A_1c, AST, ALT, total protein, and AST/ALT ratio also had good performance, with an area under the curve of 0.74, they said in their report.

Dr. Schattenberg provided disclosures related to AbbVie, Novartis, MSD, Pfizer, Boehringer Ingelheim, BMS, Intercept Pharmaceuticals, Genfit, Gilead, and Echosens. Several study coauthors reported employment with Novartis and stock ownership.

BOSTON – A machine-learning model based on standard clinical and laboratory values is able to predict nonalcoholic steatohepatitis (NASH) with a sensitivity of 72%-81%, an investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

The tool, dubbed NASHmap, could serve as an initial screening tool to reveal more potential undiagnosed patients with NASH, according to Jörn M. Schattenberg, MD, with the metabolic liver research program in the department of medicine at University Medical Centre Mainz (Germany).

While not intended to replace current scoring systems, NASHmap potentially could be applied as a clinical decision support tool within electronic medical record systems, allowing greater numbers of patients with suspected NASH to be evaluated and referred to specialists for further testing, according to Dr. Schattenberg.

“To me, this is an at-risk population,” Dr. Schattenberg said in an interview. “There’s a lot of talk of increasing numbers of end-stage liver disease, and these are the cases that are waiting to happen. I think if we identify them, we can manage them better.”

“I’m not saying they should all get drugs – I’m saying they have to be informed about their condition because they may not have a clue they have liver disease,” he continued.

The machine-learning approach described here by Dr. Schattenberg included an exploratory analysis based on 704 patients with NASH or non-NASH nonalcoholic fatty liver disease (NAFLD) in the NAFLD Adult Database from the National Institute of Diabetes, Digestive, and Kidney Diseases.

The best-performing model they identified included 14 variables. Ranked by contribution to predictive power, those variables included hemoglobin A_1c, aspartate aminotransferase, alanine aminotransferase, total protein, AST/ALT ratio, body mass index, triglycerides, height, platelets, white blood cells, hematocrit, albumin, hypertension, and sex.

That 14-variable model had good performance when tested on the Optum Humedica electronic medical record database, according to Dr. Schattenberg and colleagues.

In the analysis for final evaluation, including 1,016 patients with histologically confirmed NASH, the area under the curve was 0.76, they reported.

A simplified, five-variable model including just hemoglobin A_1c, AST, ALT, total protein, and AST/ALT ratio also had good performance, with an area under the curve of 0.74, they said in their report.

Dr. Schattenberg provided disclosures related to AbbVie, Novartis, MSD, Pfizer, Boehringer Ingelheim, BMS, Intercept Pharmaceuticals, Genfit, Gilead, and Echosens. Several study coauthors reported employment with Novartis and stock ownership.

BOSTON – A machine-learning model based on standard clinical and laboratory values is able to predict nonalcoholic steatohepatitis (NASH) with a sensitivity of 72%-81%, an investigator reported at the annual meeting of the American Association for the Study of Liver Diseases.

The tool, dubbed NASHmap, could serve as an initial screening tool to reveal more potential undiagnosed patients with NASH, according to Jörn M. Schattenberg, MD, with the metabolic liver research program in the department of medicine at University Medical Centre Mainz (Germany).

While not intended to replace current scoring systems, NASHmap potentially could be applied as a clinical decision support tool within electronic medical record systems, allowing greater numbers of patients with suspected NASH to be evaluated and referred to specialists for further testing, according to Dr. Schattenberg.

“To me, this is an at-risk population,” Dr. Schattenberg said in an interview. “There’s a lot of talk of increasing numbers of end-stage liver disease, and these are the cases that are waiting to happen. I think if we identify them, we can manage them better.”

“I’m not saying they should all get drugs – I’m saying they have to be informed about their condition because they may not have a clue they have liver disease,” he continued.

The machine-learning approach described here by Dr. Schattenberg included an exploratory analysis based on 704 patients with NASH or non-NASH nonalcoholic fatty liver disease (NAFLD) in the NAFLD Adult Database from the National Institute of Diabetes, Digestive, and Kidney Diseases.

The best-performing model they identified included 14 variables. Ranked by contribution to predictive power, those variables included hemoglobin A_1c, aspartate aminotransferase, alanine aminotransferase, total protein, AST/ALT ratio, body mass index, triglycerides, height, platelets, white blood cells, hematocrit, albumin, hypertension, and sex.

That 14-variable model had good performance when tested on the Optum Humedica electronic medical record database, according to Dr. Schattenberg and colleagues.

In the analysis for final evaluation, including 1,016 patients with histologically confirmed NASH, the area under the curve was 0.76, they reported.

A simplified, five-variable model including just hemoglobin A_1c, AST, ALT, total protein, and AST/ALT ratio also had good performance, with an area under the curve of 0.74, they said in their report.

Dr. Schattenberg provided disclosures related to AbbVie, Novartis, MSD, Pfizer, Boehringer Ingelheim, BMS, Intercept Pharmaceuticals, Genfit, Gilead, and Echosens. Several study coauthors reported employment with Novartis and stock ownership.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.

BOSTON – For patients with nonalcoholic fatty liver disease (NAFLD), leaner may really be meaner, according to a recent French study involving more than 100,000 individuals of the general population.

NAFLD was uncommon among participants with normal bodyweight, but when NAFLD was present, lean patients had almost twice the risk of advanced fibrosis as that of overweight and obese patients, reported principal author Lawrence Serfaty, MD, chief of the department of hepatology at Strasbourg (France) University, who conducted the project with colleagues at the French public research organization, Inserm.

“Normally, NAFLD and [nonalcoholic steatohepatitis (NASH)] are part of metabolic syndrome,” Dr. Serfaty said in an interview at the annual meeting of the American Association for the Study of Liver Diseases. “But there are some patients with no metabolic risk factors who are lean and who may have NAFLD.”

To determine the prevalence and characteristics of these patients, the investigators drew data from the CONSTANCES cohort, which is composed of 118,664 members of the general public in France. After excluding those who withdrew consent, had a history of other liver diseases, or reported an excess of alcohol consumption (more than 20 g/day), the analyzed dataset included 102,344 subjects. Among these participants, NAFLD and advanced fibrosis were diagnosed with the Fatty Liver Index (FLI) and the Forns Index (FI), respectively, in which an FLI score greater than 60 indicated NAFLD and an FI score greater than 6.9 indicated advanced fibrosis.

Participants were sorted into three weight categories by body mass index: lean (BMI less than 25 kg/m²), overweight (BMI 25-30), or obese (BMI more than 30). In addition, a variety of other health measures were recorded, including presence of metabolic risk factors, such as diabetes or metabolic syndrome, and elevated alanine transaminase (ALT).

Analysis showed that the prevalence of NAFLD in the general population was 18.2%. Of those diagnosed with NAFLD, 2.6% had advanced fibrosis. As expected, Dr. Serfaty said, NAFLD was much less common among those who were of normal bodyweight, with lean patients accounting for only 1.9% of NAFLD diagnoses. However, when NAFLD was diagnosed in lean patients, it was more often severe. Among lean patients with NAFLD, 4.5% had advanced fibrosis, compared with 2.4% of overweight patients and 2.3% of obese patients.

Dr. Serfaty noted that lean patients with NAFLD tended to have fewer metabolic risk factors, but most had at least one. Lifestyle factors were likely to blame, he said, because lean patients with NAFLD were relatively heavy users of tobacco and alcohol, compared with obese or overweight patients. Cardiovascular disease was also more common among lean patients with NAFLD.

“There are probably other factors [that are different, such as] genetic factors, the microbiome, and maybe the immune system,” Dr. Serfaty said.

While drivers of NAFLD among lean patients remain to be clarified, Dr. Serfaty highlighted the importance of recognizing this unique patient population, and if encountered, not discounting the severity of disease based on a lack of other metabolic risk factors.

“It is very important to know that these patients exist because it is very difficult to identify these patients,” Dr. Serfaty said. “If you have a lean patient with NAFLD, normally you [might] say, it’s not very severe for this patient because he’s lean; but no, [that’s not correct], because maybe he has more advanced fibrosis. So you have to go through and check with other noninvasive markers to be sure that this patient does not have advanced fibrosis.”

Concerning the difficulty of identifying such patients in the first place, Dr. Serfaty suggested that elevated ALT may be the most reliable red flag because this laboratory abnormality occurred in more than half of the lean patients diagnosed with NAFLD, despite no excessive alcohol consumption or prior hepatitis. The investigators disclosed relationships with Gilead, AbbVie, Echosens, and others.

SOURCE: Serfaty L et al. The Liver Meeting 2019, Abstract 1188.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.