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Adding polatuzumab extends survival in relapsed/refractory DLBCL
For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.
Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.
“Patients with transplantation-ineligible [relapsed/refractory] DLBCL, including those who experienced treatment failure with [autologous stem cell transplant], have dismal outcomes with limited therapeutic options,” the investigators wrote in the Journal of Clinical Oncology. “To our knowledge, this is the first randomized trial demonstrating an [overall survival] benefit in patients with transplantation-ineligible [relapsed/refractory] DLBCL.”
In the first part of the study, 27 patients were treated with polatuzumab vedotin, bendamustine, and obinutuzumab. After a median follow-up of 27 months, this regimen returned a complete response rate of 29.6%, median progression-free survival of 6.3 months, and median overall survival of 10.8 months.
In the primary analysis, 80 patients were randomized to receive bendamustine and rituximab, with or without polatuzumab. Adding polatuzumab had a significant benefit, as 40.0% of these patients achieved a complete response, compared with 17.5% of patients who did not receive polatuzumab. After a median follow-up of 22.3 months, outcomes also were significantly improved with the addition of polatuzumab for both median progression-free survival (9.5 vs. 3.7 months) and overall survival (12.4 vs. 4.7 months).
Adding polatuzumab did come with some safety trade-offs. Rates of certain grade 3 or 4 adverse events were higher, including thrombocytopenia (41% vs. 23.1%), neutropenia (46.2% vs. 33.3%), and anemia (28.2% vs. 17.9%), while infection rates were comparable. Almost half of the patients treated with polatuzumab (43.6%) developed grade 1 or 2 peripheral neuropathy, but most cases resolved.
Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.
Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.
The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.
SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.
For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.
Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.
“Patients with transplantation-ineligible [relapsed/refractory] DLBCL, including those who experienced treatment failure with [autologous stem cell transplant], have dismal outcomes with limited therapeutic options,” the investigators wrote in the Journal of Clinical Oncology. “To our knowledge, this is the first randomized trial demonstrating an [overall survival] benefit in patients with transplantation-ineligible [relapsed/refractory] DLBCL.”
In the first part of the study, 27 patients were treated with polatuzumab vedotin, bendamustine, and obinutuzumab. After a median follow-up of 27 months, this regimen returned a complete response rate of 29.6%, median progression-free survival of 6.3 months, and median overall survival of 10.8 months.
In the primary analysis, 80 patients were randomized to receive bendamustine and rituximab, with or without polatuzumab. Adding polatuzumab had a significant benefit, as 40.0% of these patients achieved a complete response, compared with 17.5% of patients who did not receive polatuzumab. After a median follow-up of 22.3 months, outcomes also were significantly improved with the addition of polatuzumab for both median progression-free survival (9.5 vs. 3.7 months) and overall survival (12.4 vs. 4.7 months).
Adding polatuzumab did come with some safety trade-offs. Rates of certain grade 3 or 4 adverse events were higher, including thrombocytopenia (41% vs. 23.1%), neutropenia (46.2% vs. 33.3%), and anemia (28.2% vs. 17.9%), while infection rates were comparable. Almost half of the patients treated with polatuzumab (43.6%) developed grade 1 or 2 peripheral neuropathy, but most cases resolved.
Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.
Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.
The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.
SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.
For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.
Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.
“Patients with transplantation-ineligible [relapsed/refractory] DLBCL, including those who experienced treatment failure with [autologous stem cell transplant], have dismal outcomes with limited therapeutic options,” the investigators wrote in the Journal of Clinical Oncology. “To our knowledge, this is the first randomized trial demonstrating an [overall survival] benefit in patients with transplantation-ineligible [relapsed/refractory] DLBCL.”
In the first part of the study, 27 patients were treated with polatuzumab vedotin, bendamustine, and obinutuzumab. After a median follow-up of 27 months, this regimen returned a complete response rate of 29.6%, median progression-free survival of 6.3 months, and median overall survival of 10.8 months.
In the primary analysis, 80 patients were randomized to receive bendamustine and rituximab, with or without polatuzumab. Adding polatuzumab had a significant benefit, as 40.0% of these patients achieved a complete response, compared with 17.5% of patients who did not receive polatuzumab. After a median follow-up of 22.3 months, outcomes also were significantly improved with the addition of polatuzumab for both median progression-free survival (9.5 vs. 3.7 months) and overall survival (12.4 vs. 4.7 months).
Adding polatuzumab did come with some safety trade-offs. Rates of certain grade 3 or 4 adverse events were higher, including thrombocytopenia (41% vs. 23.1%), neutropenia (46.2% vs. 33.3%), and anemia (28.2% vs. 17.9%), while infection rates were comparable. Almost half of the patients treated with polatuzumab (43.6%) developed grade 1 or 2 peripheral neuropathy, but most cases resolved.
Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.
Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.
The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.
SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Foundation launches direct-to-patient registry in multiple myeloma
The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.
The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.
“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”
In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.
“When the MMRF was looking around for different data sources for myeloma data, it was always the claim that, ‘Sure, we have plenty of patients, we have plenty of data, and it’s rich and really complete.’ However, as we approached an array of organizations – big organizations – as we dug into the details and reviewed patient counts or data completeness, they either didn’t have a sufficient number of patients, they didn’t have sufficiently complete data for our needs, and in the case where some did have sufficient numbers and complete data sets, they simply weren’t in a position to share that data outside their institution,” Dr. Labkoff said.
Undeterred, the MMRF switched tactics to the current, patient-centric approach.
“We’re leveraging one aspect of the HIPAA legislation,” Dr. Labkoff said, referring to patients’ rights to request their own medical records and an institution’s legal obligation to provide those records.
In the short-term, the registry will collect three types of data: patient donated data (answers from a patient survey), electronic medical records abstracted from all relevant past providers, and genomic test results. Participating patients will have blood drawn at home by a phlebotomist for the genomic assay. Additional tubes of blood will be concurrently collected and biobanked. This will eventually allow for immune profiling, Dr. Labkoff said.
Future goals include a patient-reported outcomes module and the ability to link data with medical claims.
So far, 79 patients have participated in the pilot program, according to the MMRF. As the database builds, Ms. Quinn Young and Dr. Labkoff anticipate that it will yield answers to a variety of real-world questions.
Dr. Labkoff offered two examples. “Of all the patients who have been exposed to ‘name your drug,’ what were the costs of their therapy, and what were the outcomes?” he said. In addition, researchers will be able to query clinical trial inclusion criteria to search for data on a specific patient profile, such as patients with a 4:14 translocation, who have had a bone marrow transplant in the last 2 years, and have been exposed to a certain drug regimen.
Ms. Quinn Young noted that doctors may be able to use the database to reliably identify high-risk patients and guide agent selection. Common patient questions also will be addressed, she said, including best treatment regimens for certain types of patients.
“For patients who may have run out of all commercially available options, or for patients who are perhaps seen at a community center, where certainly this type of profiling is not standard, it’s opening up a whole new set of options for them,” Ms. Quinn Young said. “And if their physician doesn’t pursue those options, they have the report that they can use to seek a second opinion.”
The Direct-to-Patient registry is unique because it aims to empower patients in a way that hasn’t been done before, Ms. Quinn Young said. “We are committed ... ever since we conceived of this project, to giving results back to patients. That is disruptive because right now that doesn’t exist.”
But the cost of implementing the registry, which has an approximate budget of $20 million, stands in the way of a completely free flow of anonymized data. MMRF leaders are exploring different strategies to sustain funding for the program.
Another MMRF program, CoMMpass, uses a precompetitive consortium model, in which several pharmaceutical companies pay for a preview of the data 6 months in advance of nonprofit researchers. A similar model may be used with the Direct-to-Patient registry, but this has yet to be determined, according to Dr. Labkoff and Ms. Quinn Young.
For now, Ms. Quinn Young said she hopes that physicians will be receptive to the program. “[The short term goal is that] when patients come to their doctors asking about this, that there is support and open-mindedness,” she said.
Looking to the future, Dr. Labkoff described how the registry could accelerate myeloma research, ultimately toward a cure.
“It is generally accepted that it can take 17 years to get something – a therapy, a new drug, or a guideline – from the bench to the bedside,” he said. “It’s my hope that we can take next generation sequencing and the results of this registry and bend that curve, maybe ... to 10 [years], or very aggressively, to 7 or 5 [years], where doctors are able to use the information in these reports for the patients that have literally given themselves, and use this to help guide the choices of their therapy or the trials they apply for, to help them get a better outcome in general.”
The Direct-to-Patient registry is a collaborative effort between the MMRF and multiple organizations, including the health care technology company COTA, the Broad Institute of Harvard and MIT, Prometheus Research, Tempus, and the Dana Farber Cancer Institute.
The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.
The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.
“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”
In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.
“When the MMRF was looking around for different data sources for myeloma data, it was always the claim that, ‘Sure, we have plenty of patients, we have plenty of data, and it’s rich and really complete.’ However, as we approached an array of organizations – big organizations – as we dug into the details and reviewed patient counts or data completeness, they either didn’t have a sufficient number of patients, they didn’t have sufficiently complete data for our needs, and in the case where some did have sufficient numbers and complete data sets, they simply weren’t in a position to share that data outside their institution,” Dr. Labkoff said.
Undeterred, the MMRF switched tactics to the current, patient-centric approach.
“We’re leveraging one aspect of the HIPAA legislation,” Dr. Labkoff said, referring to patients’ rights to request their own medical records and an institution’s legal obligation to provide those records.
In the short-term, the registry will collect three types of data: patient donated data (answers from a patient survey), electronic medical records abstracted from all relevant past providers, and genomic test results. Participating patients will have blood drawn at home by a phlebotomist for the genomic assay. Additional tubes of blood will be concurrently collected and biobanked. This will eventually allow for immune profiling, Dr. Labkoff said.
Future goals include a patient-reported outcomes module and the ability to link data with medical claims.
So far, 79 patients have participated in the pilot program, according to the MMRF. As the database builds, Ms. Quinn Young and Dr. Labkoff anticipate that it will yield answers to a variety of real-world questions.
Dr. Labkoff offered two examples. “Of all the patients who have been exposed to ‘name your drug,’ what were the costs of their therapy, and what were the outcomes?” he said. In addition, researchers will be able to query clinical trial inclusion criteria to search for data on a specific patient profile, such as patients with a 4:14 translocation, who have had a bone marrow transplant in the last 2 years, and have been exposed to a certain drug regimen.
Ms. Quinn Young noted that doctors may be able to use the database to reliably identify high-risk patients and guide agent selection. Common patient questions also will be addressed, she said, including best treatment regimens for certain types of patients.
“For patients who may have run out of all commercially available options, or for patients who are perhaps seen at a community center, where certainly this type of profiling is not standard, it’s opening up a whole new set of options for them,” Ms. Quinn Young said. “And if their physician doesn’t pursue those options, they have the report that they can use to seek a second opinion.”
The Direct-to-Patient registry is unique because it aims to empower patients in a way that hasn’t been done before, Ms. Quinn Young said. “We are committed ... ever since we conceived of this project, to giving results back to patients. That is disruptive because right now that doesn’t exist.”
But the cost of implementing the registry, which has an approximate budget of $20 million, stands in the way of a completely free flow of anonymized data. MMRF leaders are exploring different strategies to sustain funding for the program.
Another MMRF program, CoMMpass, uses a precompetitive consortium model, in which several pharmaceutical companies pay for a preview of the data 6 months in advance of nonprofit researchers. A similar model may be used with the Direct-to-Patient registry, but this has yet to be determined, according to Dr. Labkoff and Ms. Quinn Young.
For now, Ms. Quinn Young said she hopes that physicians will be receptive to the program. “[The short term goal is that] when patients come to their doctors asking about this, that there is support and open-mindedness,” she said.
Looking to the future, Dr. Labkoff described how the registry could accelerate myeloma research, ultimately toward a cure.
“It is generally accepted that it can take 17 years to get something – a therapy, a new drug, or a guideline – from the bench to the bedside,” he said. “It’s my hope that we can take next generation sequencing and the results of this registry and bend that curve, maybe ... to 10 [years], or very aggressively, to 7 or 5 [years], where doctors are able to use the information in these reports for the patients that have literally given themselves, and use this to help guide the choices of their therapy or the trials they apply for, to help them get a better outcome in general.”
The Direct-to-Patient registry is a collaborative effort between the MMRF and multiple organizations, including the health care technology company COTA, the Broad Institute of Harvard and MIT, Prometheus Research, Tempus, and the Dana Farber Cancer Institute.
The Multiple Myeloma Research Foundation (MMRF) recently launched its Direct-to-Patient registry, in what the organization’s leaders are describing as a “disruptive” step toward improving outcomes for patients with multiple myeloma.
The new registry is intended to build upon CoMMpass, a program started 8 years ago that now represents the largest genomic database of any type of cancer. Although CoMMpass includes data from about 1,150 patients with myeloma, it’s not enough information, according to the chief marketing and development officer at the MMRF, Anne Quinn Young.
“For a disease as heterogenous as myeloma is, we need more, particularly because we don’t have all the samples for later-stage disease,” Ms. Quinn Young said in an interview. “And even with the clinical data, given the patient population, both [in terms of] demographics and the nature of the disease, the numbers of patients still living after multiple relapses is rather small.”
In an earlier effort to gather more data, the MMRF first turned to other organizations for help, but this approach fell short because of scarcity of data, and in some cases, unwillingness to share. Steven Labkoff, MD, chief data officer at the MMRF, described this experience in an interview.
“When the MMRF was looking around for different data sources for myeloma data, it was always the claim that, ‘Sure, we have plenty of patients, we have plenty of data, and it’s rich and really complete.’ However, as we approached an array of organizations – big organizations – as we dug into the details and reviewed patient counts or data completeness, they either didn’t have a sufficient number of patients, they didn’t have sufficiently complete data for our needs, and in the case where some did have sufficient numbers and complete data sets, they simply weren’t in a position to share that data outside their institution,” Dr. Labkoff said.
Undeterred, the MMRF switched tactics to the current, patient-centric approach.
“We’re leveraging one aspect of the HIPAA legislation,” Dr. Labkoff said, referring to patients’ rights to request their own medical records and an institution’s legal obligation to provide those records.
In the short-term, the registry will collect three types of data: patient donated data (answers from a patient survey), electronic medical records abstracted from all relevant past providers, and genomic test results. Participating patients will have blood drawn at home by a phlebotomist for the genomic assay. Additional tubes of blood will be concurrently collected and biobanked. This will eventually allow for immune profiling, Dr. Labkoff said.
Future goals include a patient-reported outcomes module and the ability to link data with medical claims.
So far, 79 patients have participated in the pilot program, according to the MMRF. As the database builds, Ms. Quinn Young and Dr. Labkoff anticipate that it will yield answers to a variety of real-world questions.
Dr. Labkoff offered two examples. “Of all the patients who have been exposed to ‘name your drug,’ what were the costs of their therapy, and what were the outcomes?” he said. In addition, researchers will be able to query clinical trial inclusion criteria to search for data on a specific patient profile, such as patients with a 4:14 translocation, who have had a bone marrow transplant in the last 2 years, and have been exposed to a certain drug regimen.
Ms. Quinn Young noted that doctors may be able to use the database to reliably identify high-risk patients and guide agent selection. Common patient questions also will be addressed, she said, including best treatment regimens for certain types of patients.
“For patients who may have run out of all commercially available options, or for patients who are perhaps seen at a community center, where certainly this type of profiling is not standard, it’s opening up a whole new set of options for them,” Ms. Quinn Young said. “And if their physician doesn’t pursue those options, they have the report that they can use to seek a second opinion.”
The Direct-to-Patient registry is unique because it aims to empower patients in a way that hasn’t been done before, Ms. Quinn Young said. “We are committed ... ever since we conceived of this project, to giving results back to patients. That is disruptive because right now that doesn’t exist.”
But the cost of implementing the registry, which has an approximate budget of $20 million, stands in the way of a completely free flow of anonymized data. MMRF leaders are exploring different strategies to sustain funding for the program.
Another MMRF program, CoMMpass, uses a precompetitive consortium model, in which several pharmaceutical companies pay for a preview of the data 6 months in advance of nonprofit researchers. A similar model may be used with the Direct-to-Patient registry, but this has yet to be determined, according to Dr. Labkoff and Ms. Quinn Young.
For now, Ms. Quinn Young said she hopes that physicians will be receptive to the program. “[The short term goal is that] when patients come to their doctors asking about this, that there is support and open-mindedness,” she said.
Looking to the future, Dr. Labkoff described how the registry could accelerate myeloma research, ultimately toward a cure.
“It is generally accepted that it can take 17 years to get something – a therapy, a new drug, or a guideline – from the bench to the bedside,” he said. “It’s my hope that we can take next generation sequencing and the results of this registry and bend that curve, maybe ... to 10 [years], or very aggressively, to 7 or 5 [years], where doctors are able to use the information in these reports for the patients that have literally given themselves, and use this to help guide the choices of their therapy or the trials they apply for, to help them get a better outcome in general.”
The Direct-to-Patient registry is a collaborative effort between the MMRF and multiple organizations, including the health care technology company COTA, the Broad Institute of Harvard and MIT, Prometheus Research, Tempus, and the Dana Farber Cancer Institute.
Over half of NASH patients have improvement in liver fibrosis after bariatric surgery
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.
REPORTING FROM THE LIVER MEETING 2019
Cilofexor passes phase 2 for primary biliary cholangitis
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.
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.
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.
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.
REPORTING FROM THE LIVER MEETING 2019
Kratom: Botanical with opiate-like effects increasingly blamed for liver injury
BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.
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.
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.
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.
REPORTING FROM THE LIVER MEETING 2019
Study spotlights severe NAFLD in lean patients
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.
REPORTING FROM THE LIVER MEETING 2019
New antibody cuts the fat in NAFLD
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.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: The bispecific antibody BFKB8488A may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease.
Major finding: Among patients given well-tolerated doses, treatment with BFKB8488A reduced hepatic fat fraction by a mean of 38%, compared with 0% for placebo.
Study details: A blinded, randomized, placebo-controlled, phase 1b trial involving 62 patients with nonalcoholic fatty liver disease.
Disclosures: The investigators reported financial relationships with Genentech and Gilead.
Source: Kunder R et al. The Liver Meeting 2019, Abstract LP8.
HDV combo therapy reduces viral loads
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.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: For most patients with chronic hepatitis D virus infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads.
Major finding: After 6 months of therapy, 37% of evaluable patients achieved undetectable levels of hepatitis D virus RNA.
Study details: The phase IIa open-label LIFT trial involving 26 patients with chronic hepatitis delta virus (HDV).
Disclosures: The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.
Source: Koh C et al. The Liver Meeting 2019. Abstract LO8.
New antibody cuts the fat in NAFLD
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.
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.
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.
SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: The bispecific antibody BFKB8488A may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease.
Major finding: Among patients given well-tolerated doses, treatment with BFKB8488A reduced hepatic fat fraction by a mean of 38%, compared with 0% for placebo.
Study details: A blinded, randomized, placebo-controlled, phase 1b trial involving 62 patients with nonalcoholic fatty liver disease.
Disclosures: The investigators reported financial relationships with Genentech and Gilead.
Source: Kunder R et al. The Liver Meeting 2019, Abstract LP8.
DUR-928 shows promise for alcoholic hepatitis
BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.
In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.
In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.
The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.
Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.
DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.
A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).
“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.
The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.
SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.
BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.
In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.
In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.
The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.
Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.
DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.
A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).
“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.
The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.
SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.
BOSTON – Treatment with novel agent DUR-928 may be able to reduce mortality rates among patients with severe alcoholic hepatitis, investigators predicted.
In an open-label, phase IIa trial, 89% of patients with alcoholic hepatitis responded to treatment with the new therapy, reported lead author Tarek Hassanein, MD, of Southern California Research Center in Coronado, Calif., and colleagues.
In an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases, the investigators explained the urgent need for an agent such as DUR-928: “The mortality of severe alcoholic hepatitis remains high in the absence of effective treatment,” they wrote, noting that corticosteroids are only suitable for select patients. According to the investigators, DUR-928 is an endogenous sulfated oxysterol that has been shown to control lipotoxicity and inflammation while increasing hepatic regeneration and cell survival.
The agent was tested among 19 patients with alcoholic hepatitis, many of whom had severe disease; at baseline, 15 had Maddrey’s discriminant function (DF) scores of 32 or less, 12 had Model for End-stage Liver Disease (MELD) scores between 12 and 30, and 11 had serum bilirubin levels higher than 8 mg/dL.
Via intravenous infusion, three dose levels were given: 30 mg, 90 mg, or 150 mg. All patients received at least one dose on day 1, and if still hospitalized, a second dose on day 4, with a total follow-up of 28 days. Treatment response was defined by a Lille score of less than 0.45.
DUR-928 was well tolerated; no serious drug-related adverse events occurred and all patients survived the 28-day follow-up period. Across the population, the response rate was 89%. This figure fell slightly to 87% when considering only patients with severe disease (DF scores of 32 or less), and marginally further still to 83% for those with MELD scores between 21 and 30. Among patients with severe disease, MELD scores decreased by a median of 17.5% (P = .01) over the 28-day period, and in cases with bilirubin starting higher than 8 mg/dL, levels dropped by a median of 25.1% (P = .02) within the first week.
A comparison of these results with historical data revealed that treatment with DUR-928 led to significantly better Lille scores than previously reported (P less than .0001).
“These initial findings are encouraging for further development of DUR-928 in patients with alcoholic hepatitis, including severe alcoholic hepatitis,” the investigators concluded.
The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.
SOURCE: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: For patients with alcoholic hepatitis, treatment with novel agent DUR-928 could offer better outcomes than those of existing therapies.
Major finding: Among 15 patients with severe alcoholic hepatitis, 87% responded to treatment (Lille score less than 0.45).
Study details: A phase IIa open-label trial involving 19 patients with alcoholic hepatitis.
Disclosures: The investigators disclosed relationships with DURECT Corporation, Assembly Biosciences, Gilead, and others.
Source: Hassanein T et al. The Liver Meeting 2019, Abstract LO9.