Will Pass

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The investigators reported financial relationships with Genentech and Gilead.

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

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

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

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

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

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

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

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

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

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

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

The investigators reported financial relationships with Genentech and Gilead.

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

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

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

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

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

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

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

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

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

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

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

The investigators reported financial relationships with Genentech and Gilead.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.

Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.

Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”

The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.

After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.

Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.

Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”

The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.

SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

Among patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer, adding trastuzumab to adjuvant chemotherapy reduces risk of recurrence for at least 10 years, according to investigators.

The benefit of trastuzumab was greater among patients with hormone receptor–positive (HR+) disease than those with HR– disease until the 5-year timepoint, after which HR status had no significant impact on recurrence rates, reported lead author Saranya Chumsri, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues. This finding echoes a pattern similar to that of HER2– breast cancer, in which patients with HR+ disease have relatively consistent risk of recurrence over time, whereas patients with HR– disease have an early risk of recurrence that decreases after 5 years.

“To the best of our knowledge, this analysis is the first to address the risk of late relapses in subsets of HER2+ breast cancer patients who were treated with adjuvant trastuzumab,” the investigators wrote. Their report is in Journal of Clinical Oncology.

They drew data from 3,177 patients with HER2+ breast cancer who were involved in two phase 3 studies: the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 trials. Patients involved in the analysis received either standard adjuvant chemotherapy with cyclophosphamide and doxorubicin followed by weekly paclitaxel or the same chemotherapy regimen plus concurrent trastuzumab. The primary outcome was recurrence-free survival, which was defined as time from randomization until local, regional, or distant recurrence of breast cancer or breast cancer–related death. Kaplan-Meier estimates were performed to determine recurrence-free survival, while Cox proportional hazards regression models were used to determine factors that predicted relapse.

Including a median follow-up of 8 years across all patients, the analysis showed that those with HR+ breast cancer had a significantly higher estimated rate of recurrence-free survival than that of those with HR– disease after 5 years (81.49% vs. 74.65%) and 10 years (73.84% vs. 69.22%). Overall, a comparable level of benefit was derived from adding trastuzumab regardless of HR status (interaction P = .87). However, during the first 5 years, HR positivity predicted greater benefit from adding trastuzumab, as patients with HR+ disease had a 40% lower risk of relapse than that of those with HR– disease (hazard ratio, 0.60; P less than .001). Between years 5 and 10, the statistical significance of HR status faded (P = .12), suggesting that HR status is not a predictor of long-term recurrence.

“Given concerning adverse effects and potentially smaller benefit of extended adjuvant endocrine therapy, particularly in patients with N0 or N1 disease, our findings highlight the need to develop better risk prediction models and biomarkers to identify which patients have sufficient risk for late relapse to warrant the use of extended endocrine therapy in HER2+ breast cancer,” the investigators concluded.

The study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, Bankhead-Coley Research Program, the DONNA Foundation, and Genentech. Dr. Chumsri disclosed a financial relationship with Merck. Coauthors disclosed ties with Merck, Novartis, Genentech, and NanoString Technologies.

SOURCE: Chumsri et al. J Clin Oncol. 2019 Oct 17. doi: 10.1200/JCO.19.00443.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.

A new draft guideline for the diagnosis and management of thrombocytopenic purpura (TTP) was recently released by the International Society on Thrombosis and Hemostasis (ISTH).

Svisio/Thinkstock

According to the panel of experts involved, the ISTH guideline takes into account the latest TTP findings, offering a more up-to-date resource for clinicians than the two previously published guidelines in 2012 from the British Committee for Standards in Haematology and in 2017 from the TTP group of Japan’s Blood Coagulation Abnormalities Research Team.

“Since the publication of these guidelines, there have been significant developments in the diagnosis and treatment of TTP, and an increase in published data on how management strategies affect objective health outcomes,” the panel members wrote in the guideline, which is available at ISTH.org.

Despite these advancements, TTP remains a challenging condition for both clinicians and patients for a variety of reasons, the panel noted, which was led by clinical cochair X. Long Zheng, MD, PhD, of the University of Alabama in Birmingham and method cochair Sara K. Vesely, PhD, of the University of Oklahoma, Oklahoma City.

The ISTH guideline provides recommendations for adult patients with either immune or hereditary TTP, from acute events through remission, including diagnostic steps to determine if a case of thrombotic microangiopathy is in fact TTP.

Nearly all the recommendations are based on very-low-certainty evidence. Some of the key treatment recommendations include the following:

• For patients with immune TTP experiencing a first acute event, add corticosteroids to therapeutic plasma exchange (TPE), rather than treating with TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a first acute event, add rituximab to corticosteroids and TPE, rather than corticosteroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing a relapse, add corticosteroids to TPE, rather than TPE alone. This is a strong recommendation.
• For patients with immune TTP experiencing a relapse, add rituximab to corticosteroids and TPE, rather than steroids and TPE alone. This is a conditional recommendation.
• For patients with immune TTP experiencing an acute event – either a first event or a relapse – use caplacizumab. This is a conditional recommendation based on moderate-certainty evidence.
• For patients with immune TTP who are in remission and have low plasma ADAMTS13 activity but no other symptoms of TMA, use rituximab for prophylaxis. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, plasma infusion or a watch-and-wait strategy is recommended. This is a conditional recommendation.
• For patients with hereditary TTP who are in remission, do not use factor VIII concentrate infusions. A watch-and-wait strategy is advised. This is a conditional recommendation.
• For patients with immune TTP who are pregnant and have decreased plasma ADAMTS13 activity but no symptoms of TMA, use prophylactic treatment. This is a strong recommendation.
• For patients with hereditary TTP who are pregnant, use prophylactic treatment. This is a strong recommendation. The panel further recommended treatment with plasma infusion rather than factor VIII products, which was a conditional recommendation.

The multidisciplinary expert panel included hematologists and pathologists with expertise in TTP, neurologists, nephrologists, intensive care specialists, and patient representatives. The panel followed the GRADE approach and the Population, Intervention, Comparison, Outcome (PICO) framework, and adhered to standards set forth by the Health and Medicine Division (HMD) of the National Academies of Sciences, Engineering, and Medicine and the GIN-McMaster Guideline Development Checklist.

Even with an experienced group of physicians and a structured plan, however, the creation of guidelines for rare diseases like TTP presents a unique set of obstacles, according to the panel members. Challenges include a small body of relevant evidence that is often inconsistent and lacking in high certainty and studies that do not address outcomes important to patients. These shortcomings can make it difficult for guideline developers to issue strong recommendations.

“However, well-developed clinical practice guidelines are vital in rare diseases; these conditions are, by their nature, encountered very infrequently by individual clinicians, who may feel unprepared to address their diagnosis and treatment,” the panelists wrote. “Well-synthesized evidence and clear recommendations play an important role in supporting clinical decision making. Systematically created guidelines can also highlight areas where evidence is uncertain, clinical judgement is required, and future research in the area is warranted.”

The guideline was supported by ISTH. Fifty percent of the panel members had no or minimal conflict of interest; those with conflicts of interest abstained from voting on recommendations relevant to their conflicts.