Liver Disease

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – Contrary to expectation, sitagliptin did not reduce liver fat in patients with early diabetes and nonalcoholic fatty liver disease in a double-blind, randomized, placebo-controlled trial.

Changes in liver fat were carefully measured in the trial using the proton density fat fraction (PDFF), a well-validated liver fat biomarker using magnetic resonance imaging (MRI), but no statistical differences between baseline and posttreatment liver fat values were seen in either sitagliptin (18.1% and 16.9%, P = .28) or placebo-treated patients (16.6% and 14.0%, P = .07), or between the two groups (–1.3% difference, P = .41), according to Jeffrey Cui, a medical student at the University of California, San Diego.

Sara Freeman/Frontline Medical News

In fact, the percentage decrease in liver fat was greater for placebo (13.9%) than for sitagliptin (8.4%), although this was not statistically significant (P = .585), Mr. Cui said at the meeting, sponsored by the European Association for the Study of the Liver.

In addition, there were no changes in liver stiffness, assessed via magnetic resonance elastography (MRE), nor improvements in the liver enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT), low-density lipoprotein, or homeostatic model assessment, a measure of insulin resistance.

“Uncontrolled pilot studies have shown that sitagliptin, an oral antihyperglycemic agent that inhibits DPP-4 [dipeptidyl peptidase 4], can improve AST, ALT, and liver histology in NAFLD [nonalcoholic fatty liver disease] patients,” said Mr. Cui.

The aim was to investigate whether sitagliptin could have beneficial effects on the liver by performing a more robustly designed trial and measuring liver fat objectively via MRI-PDFF. The hypothesis was that a 100-mg/day dosage of the DDP4-inhibitor given for 24 weeks would result in a significant decrease in liver fat, compared with placebo, Mr. Cui explained.

Although the results found no benefit for the diabetes drug, the “trial provides a prototype for co-localized assessment of MRI-PDFF and MRE that helps to noninvasively assess treatment response in NAFLD clinical trials,” he said, adding that MRI-PDFF has been shown to correlate well with magnetic resonance spectroscopy, which is a reference standard to quantify liver fat.

A total of 50 patients with pre- or early diabetes (hemoglobin A_1c 5.7%-8.0%) with documented hepatic steatosis, defined as an MRI-PDFF of 5% or more, and ALT above the upper limit of normal, were recruited. Half were randomized to sitagliptin and half to placebo, with no major differences in baseline characteristics between the two. The mean age was 52-54 years, and the mean body mass index was 32 mg/m². Roughly half had a diagnosis of type 2 diabetes.

With treatment given only for 24 weeks, perhaps this was too short to show any effect on a parameter like fibrosis, it was noted during discussion. Mr. Cui said it was unlikely that there would be any benefit from longer treatment with sitagliptin as there was no signal seen in the other liver markers such as AST and ALT.

“It is always disappointing when initial research cannot be replicated in a more rigorous trial setting,” Dr. Frank Tacke of University Hospital Aachen, Germany, said in a press release issued by the EASL, “but we hope that the experiences shared of the imaging techniques employed in this study will help introduce novel, noninvasive imaging techniques into the clinical management of patients.”

Mr. Cui and Dr. Tacke had no conflicts of interest to disclose.

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver.

Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).

Sara Freeman/Frontline Medical News

The findings are important as there is currently no medical treatment approved by the Food and Drug Administration for PSC. Although ursodeoxycholic acid is commonly used, there is no proof that it actually works in PSC, and the only option for patients, who are aged 30-40 years at diagnosis, is to wait until the disease has progressed far enough to warrant liver transplantation, which usually happens within 10-15 years.

The findings provide proof of concept that aberrant gut immunity could be behind the development of PSC, said Dr. Bertus Eksteenof the Snyder Institute for Chronic Diseases at the University of Calgary (Alta.).

“Many years ago we proposed that aberrant gut immunity has a significant role to play in PSC,” Dr. Eksteen said. He explained that the gut adhesion molecules CCL25 and MAdCAM-1 are possibly to blame as these can be aberrantly expressed in the liver of patients with PSC. This results in the recruitment of T cells expressing CCR9 and alpha 4 beta 7, which move from the gut and home in on the liver.

Vedolizumab (Entyvio), which targets alpha 4 beta 7, is licensed in the United States and in Europe for the treatment of IBD. The interest in using this particular drug in patients with PSC also stems from the fact that between 70% and 85% of patients with PSC have ulcerative colitis or Crohn’s disease.

More than two-thirds of patients were aged between 20 and 40 years old, around 38% had mild and 38% had moderate fibrosis, and only two had received prior treatment with ursodeoxycholic acid. Most (n = 17) of those studied had ulcerative colitis.

Three intravenous doses of vedolizumab (300 mg) were given at week 0, 2, and 6. Dr. Eksteen noted that this was the induction phase and the maintenance dosing phase of the study was ongoing. Vedolizumab is being given every 8 weeks for maintenance, he noted during discussion.

There was no change in fibrosis but that is not surprising with a short induction treatment period. Reductions in alkaline phosphatase levels often preceded clinical IBD responses, Dr. Eksteen said.

The most common adverse events were tiredness within 24 hours in six patients and redness at the infusion site in two patients, but no serious adverse events were reported.

Whether vedolizumab would be beneficial in patients with PSC without comorbid IBD remains to be seen and specifically studied. Dr. Eksteen suggested that because many of the patients included in the study had inactive or mild to moderate IBD at baseline the results were encouraging that an effect may be seen regardless of IBD.

A grant from the Canadian Institutes of Health Research funded the study. Dr. Eksteen did not report having any relevant financial disclosures. His research is funded by grants from the American Liver Foundation, the Medical Research Council (U.K.), and the Bowel Disease Research Foundation (U.K.).

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

BARCELONA – A modified form of ursodeoxycholic acid (UDCA) could offer patients with primary sclerosing cholangitis the first real pharmacologic treatment option, it was reported at the International Liver Congress.

Phase II study findings showed that a 1,500-mg daily dose of norursodeoxycholic acid (norUDCA) significantly (P less than .0001) reduced the primary endpoint of serum alkaline phosphatase (ALP) by 26% versus baseline levels within 12 weeks of treatment.

Other doses of norUDCA that were tested in the multicenter, randomized, double-blind, dose-finding study also produced significant reductions in serum ALP: –17.3% with a 1,000-mg dose (P = .0003), and –12.3% (P = .0029) with a 500-mg dose. The 1,500-mg dose has been selected for the follow-on phase III trial.

While this investigational drug is still only a symptomatic therapy and not a cure, it brings a viable option for managing the devastating but rare liver disease that currently lacks any effective therapy other than liver transplantation.

Primary sclerosing cholangitis (PSC) is an orphan disease that affects 1-16 in 100,000 people and typically strikes at a relatively young age, at around 30-40 years, with a male predominance. Often asymptomatic at first, the chronic disease can lead to liver transplant within 13-21 years of a diagnosis, with around half of all patients needing a transplant in 10-15 years.

This is the first trial of norUDCA in patients, lead study author Dr. Michael Trauner of the Medical University Vienna pointed out during the late-breaker session at the meeting sponsored by the European Association for the Study of the Liver (EASL).

“The role of UDCA in the treatment of PSC is still under debate and discussed controversially in the current guidelines,” Dr. Trauner noted. At a press briefing earlier in the day he had observed that there was not really any good evidence that it really worked in PSC, although it was approved as a treatment for primary biliary cholangitis.

norUDCA is a derivative of UDCA that has had a side-chain shortened by removing an ethylene group, he explained, and the resulting molecule is resistant to conjugation with taurine and glycine, which is part of process known as cholehepatic shunting. The resulting effect is protection of the bile ducts through the generation of bicarbonate-rich bile flow. Preclinical studies in mice have shown that norUDCA has potent antiproliferative, antifibrotic, and anti-inflammatory effects that, if translated into humans, could mean that norUDCA could have benefits beyond just addressing cholestasis.

“At the moment there is no medical treatment for PSC,” EASL spokesperson Dr. Frank Tacke of the University Hospital Aachen (Germany) commented at the press briefing. “We are very excited about these data because it is a new hope for this type of patient.” He added: “The fact that we have nothing to offer at the moment that works as a medical treatment makes this study so particular.”

Of 222 patients who were screened for inclusion into the study at 45 centers in 12 European countries, 161 met the criteria and were randomized, with 159 actually receiving their allocated treatment. There were 40 patients in the placebo arm, and 39, 41, and 39 patients, respectively, in the 500-, 1,000-, and 1,500-mg norUDCA arms. The two patients that did not receive allocated treatment had withdrawn their consent.

As expected, around 60%-70% of the patients in each group were male. The mean age was around 41-44 years, around one-fifth had a new diagnosis of PSC, and more than half (50%-77%) had inflammatory bowel disease (IBD) at screening, which was predominantly ulcerative colitis, Dr. Trauner observed. Patients also had pronounced cholestasis at the start of the study, signified by mean serum ALP of 400-500 IU/L. The normal range is between 44 and 147 IU/L.

“norUDCA reduced ALP in a dose-dependent fashion,” Dr. Trauner said. He noted that looking at changes in ALP over time, it was evident that there was a rebound effect after the treatment was stopped. The percentage of patients reaching an ALP equal to or below 1.5-fold the upper limit of normal, which has been shown to be prognostically meaningful in the disease, was 12.5% for placebo and 12.8%, 41.5%, and 30.8% for the three ascending doses of norUDCA.

Changes in serum levels of other important liver enzymes – gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase – showed a similar pattern in terms of absolute changes from baseline over time, with rebound effects once treatment stopped.

There were a comparable number of adverse drug reactions – 28%, 23%, 32%, and 28%, respectively, in the placebo, 500-, 1,000-, and 1,500-mg norUDCA groups. Treatment-emergent adverse events occurred in 80%, 59%, 73%, and 67%. The most common of these were gastrointestinal effects such as abdominal pain (12.5% for placebo vs. 2.6%-9.8% in the norUDCA groups) and diarrhea (10% vs. 0-7.7%), fatigue (10% vs. 4.9%-12.8%), arthralgia (10% vs. 0-2.4%), back pain (10% vs. 0-7.7%), headache (7.5% vs. 2.4%-17.9%), nasopharyngitis (17.5% vs. 15.4%-22%), and pruritus (10% vs. 7.7%-15.4%).

“We don’t think pruritus is an issue with norUDCA,” Dr. Trauner said in response to a delegate’s query on the numerically higher rates of itching in the active treatment groups. “Of course, we paid much attention to this, but overall pruritus was extremely mild, it led to no discontinuation of the study drug.” There is an ongoing, similar-dose study in nonalcoholic fatty liver disease where so far 150 patients have been treated and only a single patient so far has reported this side effect.

Based on these “highly encouraging” results, “the planning of the phase III trial in PSC is already ongoing,” Dr. Trauner said. Asked what the primary endpoint may be, he acknowledged that change in serum ALP was not an accepted endpoint in PSC by itself and that the trial would most likely use a combined endpoint of serum ALP and assessment of fibrosis, perhaps noninvasively with FibroScan.

He also noted that quality of life had been assessed in the phase II trial but no significant differences were seen. It could be that, at 12 weeks, the trial was too short to assess this parameter, he suggested, and that would be perhaps something to also address in the phase III trial. There was no change in IBD disease activity, which was important, he said.

Dr. Heiner Wedemeyer of Hannover (Germany) Medical School and who was not involved in the trial also commented on the importance of the study at the press briefing. Dr. Wedemeyer said that he was “extremely excited” by these data. “This is the most awful liver disease that we have because it is so difficult to judge when to transplant the patient,” he noted. This is a very difficult group of patients to handle and “this is the first time in decades that there is some hope on the horizon. This is the first time we see something that may work.”

Dr. Falk Pharma, Frieburg, Germany, sponsored the trial. Dr. Trauner has received honoraria, research grants, and travel support from Dr. Falk Pharma, and is listed as co-inventor on a patent for the medical use of norUDCA. Dr. Trauner has also received honoraria, research grants, or travel support from Albireo, Genfit, Gilead, Intercept, Merck Sharp & Dohme, Novartis, Phenex, and Roche. Dr. Tacke and Dr. Wedemeyer had no relevant disclosures.

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The female-to-male predominance of primary biliary cholangitis (PBC), formerly cirrhosis, is much lower than previously believed, according to data from Swedish national registers.

Looking at a number of diseases thought to have at least some basis in autoimmunity, researchers found that the relative risk of PBC for women, compared with men, was 4.1, suggesting that, although it remains a disease predominantly affecting women, its prevalence in men might actually be higher than previously thought.

Of the three other gastrointestinal conditions among the 32 autoimmune diseases examined, one showed a female predominance, one showed no difference, and one had a male predominance, reported Dr. Jianguang Ji and his associates at Lund (Sweden) University (J Autoimmune. 2016;69:102-6).

Celiac disease had a slight female predominance, with a relative risk for women of 1.8, compared with men. There was no difference for Crohn’s disease (RR, 1.1), and ulcerative colitis had a slight male predominance (RR, 0.9), the investigators reported.

The situation was similar for the larger group of conditions: Eighteen showed a female predominance, 7 had no difference, and 7 showed a male predominance, they noted.

“Most review papers claim that the vast majority of autoimmune diseases have a striking female predominance, and most of them cited that more than 80% of cases affected are women. In this population-based study of 32 specific autoimmune diseases with more than 20 years of follow-up, we found that the incidence in women was only 60% higher as compared to that in men,” Dr. Ji and his associates wrote.

The investigators searched the Swedish Hospital Discharge Register and the Swedish Outpatient Register and found data on 403,757 individuals who had been diagnosed with one or more of the 32 autoimmune diseases between 1987 and 2010. About 62% of the subjects were female.

Dr. Ji and his associates had no conflicts of interest to report. The study was supported by the Swedish Research Council and Region Skåne.

[email protected]

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

The United States can end hepatitis B and C transmission and prevent related morbidity and mortality given enough time, resources, and will to surmount a variety of barriers, according to a new report from the National Academies of Sciences, Engineering, and Medicine.

A more feasible short-term goal is to control viral hepatitis by reducing the incidence and prevalence of hepatitis B (HBV) and C virus (HCV) infections, states the report, which is the first of a two-phase study. The second part, to be published in early 2017, will outline a strategy to achieve the goals.

“Disease elimination” once meant stopping all new infections in a population, but eliminating a public health problem “can be a less absolute goal,” Dr. Brian Strom, chancellor of Rutgers Biomedical and Health Sciences, wrote along with his associates. “The WHO has accepted a non-zero target in its work against viral hepatitis,” they added. “The organization’s provisional target is a 90% reduction in incidence, and a 65% reduction in mortality by 2030.”

Furthermore, those are global targets – countries should base their own strategies on their specific viral hepatitis disease burdens and epidemiologic features, Dr. Strom and his associates emphasized. For example, universal vaccination could eradicate HBV in the United States in two generations, but there is no cure for the 700,000-1.4 million Americans who are already infected. Mother-to-child HBV transmission is rare here, but better screening and surveillance could help prevent the 800-1,000 cases of vertical transmission that still occur annually.

More than a third of newborns in the United States do not receive the HBV vaccination on the day they are born, and 28% remain unvaccinated when they are 3 days old, “but childhood catch-up is possible,” the experts also wrote. Vaccinating adults is more complicated, but targeting high-risk groups such as prison inmates or patients at sexually transmitted disease clinics might work, they added. Vaccination is especially important, because chronically infected HBV patients need lifelong medical follow-up to prevent progression and death from cirrhosis and liver cancer, they emphasized.

The hepatitis C virus presents a different picture – there is no HCV vaccine, while the novel direct-acting antivirals can theoretically cure nearly all chronic infections. But in reality, high drug costs and the massive burden of undiagnosed HCV mean that only a small fraction of patients can be cured, the authors acknowledged. On an individual basis, the benefits of direct-acting antivirals outweigh the costs of treating genotype 1 HCV and associated morbidity, they add. But on a population level, “eliminating HCV infection would require near universal access to treatment, something that appears infeasible given the current pricing and policy environment.”

Several other barriers also impede progress against HBV and HCV. For example, only five states and two large cities receive enough funding for comprehensive viral hepatitis surveillance, Dr. Strom and his associates noted. If local and state public health departments cannot track infections, they cannot characterize their epidemics. In addition, viral hepatitis remains a source of stigma, adding to fear and avoidance of testing and undermining elimination efforts. Stigma, avoidance, and the fact that HBV and HCV are asymptomatic in the early stages all contribute to a large population of chronically infected patients who do not know their status.

Moreover, many state Medicaid programs will not cover foreigners until they have lived in the United States for 5 years, and the Affordable Care Act does not cover care for short-term residents and undocumented immigrants, the report stated. Newly infected HCV patients tend to have fewer resources, lower educational levels, and more often use injection drugs, making them harder to reach and screen through the health system. “Prisons are a promising venue in which to treat HCV, but treating HCV is expensive for the prison system. The cost of the direct-acting antivirals is high, and the staff time required to manage an inmate in treatment often far exceed the available resources,” the report stated.

The study was sponsored by the Centers for Disease Control and Prevention Office of Viral Hepatitis and the U.S. Department of Health and Human Services Office of Minority Health. The authors disclosed no conflicts of interest.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously voted in favor of accelerated approval for a novel drug to treat primary biliary cholangitis on April 7, 2016. The accelerated drug approval process allows for the use of alkaline phosphatase levels as a surrogate endpoint of efficacy.*

At the meeting of the FDA Gastrointestinal Drugs Advisory Committee, panelists wrestled with additional questions from the FDA regarding the use of obeticholic acid (OCA) for primary biliary cholangitis. Presented as discussion items, these included how to select appropriate populations for the novel drug, the proper dosing schema, and how to go forward in postmarketing confirmatory trials of OCA.

The exact indication for which the applicant, Intercept Pharmaceuticals, is seeking obeticholic acid approval is “treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.”

In discussion after the unanimous vote for accelerated approval, Dr. Maria Sjogren, a hepatologist at Walter Reed National Military Medical Center, Bethesda, Md. said, “I welcome this drug in the clinic. It will be a great addition for many patients.” Dr. Marina Silveira, of the division of gastroenterology at the Louis Stokes Cleveland VA Medical Center, agreed: “There is an unmet need, and there are no significant safety or tolerability concerns. But I do think there is more study that’s going to be needed.”

The pivotal phase III clinical trial, POISE [PBC OCA International Study of Efficacy], showed that at the final 1-year assessment, 46% of patients treated with an initial 5 mg daily dose of OCA, and 47% of those treated with 10 mg daily, achieved the primary efficacy endpoint of an alkaline phosphatase (ALP) level less than 1.67 times the upper limit of normal, and/or had bilirubin levels less than the upper limit of normal and a 15% or greater reduction in ALP.

The drug was generally well tolerated at the doses used in the POISE trial. Pruritus was common but well-managed in both OCA treatment arms. No concerning hepatic safety signals were seen in the 5-mg titration arm or the 10-mg arm.

PBC (formerly known as primary biliary cirrhosis) is a progressive autoimmune disease of unknown etiology that causes cholestasis, resulting in destruction of the biliary system over time.

Currently, the only approved treatment for PBC is UDCA. Obeticholic acid (to be marketed as Ocaliva by Intercept Pharmaceuticals) is an agonist of the farnesoid X receptor (FXR), a nuclear receptor that controls bile acid homeostasis. The direct FXR agonist activity differs from the mechanism of action of UDCA, which has no nuclear receptor action. Dosing for OCA can thus be much lower, making it attractive for PBC patients who face a considerable pill burden with weight-based dosing of UDCA.

Though committee members acknowledged unmet needs for more and better therapies for PBC patients who don’t respond to or can’t tolerate UDCA, they repeatedly asked for high-quality longitudinal data collection and analysis. Clinical trial data show a signal for early low-density lipoprotein elevation with OCA, as well as long-term lowering of high-density lipoprotein levels.

Regarding the proposed dosing of OCA, FDA analysts agreed with the applicant that a starting dose of 5 mg daily is appropriate, since a dose-dependent increase in pruritus-related discontinuations was seen in phase III clinical trials. Also, a better tolerability profile is seen over time with a lower starting dose, with fewer discontinuations, fewer days of severe pruritus, and delayed time to the first episode of pruritus with the 5-mg starting dose.

Additionally, efficacy was preserved with dose titration, with similar efficacy seen at 1 year for the titration arm, compared with the 10-mg fixed-dose arm in the POISE trial that compared titration from 5 to 10 mg and fixed 10-mg dosing with placebo.

However, the FDA took issue with Intercept’s proposal not to adjust dosing in moderate or severe hepatic impairment, instead proposing a starting dose of 5 mg once weekly, and titrating up to 5 mg twice weekly and finally to a maximum of 10 mg twice weekly, depending on response and tolerability. The FDA’s rationale for this was the lack of clear benefit of high exposures to OCA in moderate or severe hepatic impairment. Another factor was the increased incidence of hepatic adverse events and the higher rate of discontinuation at higher exposures that were seen in earlier clinical trials that used higher doses of OCA.

Panelists, in their critique of the FDA’s proposed hepatic impairment dose adjustments, felt there was insufficient data to support this adjusted regimen and called for more study.

An especially thorny issue for panelists and the FDA was the design of the phase IV trial, which is a double-blind, placebo-controlled, multi-center international trial comparing OCA with placebo for PBC. This trial has already begun to enroll patients and will continue to recruit for a total of 2 years; follow-up will continue for 6 years with quarterly visits. Historical control data from a global PBC database are also available for analysis.

Panelist Dr. Timothy Lipman, emeritus chief of the GI-hepatology-nutrition center at the Department of Veterans Affairs Medical Center in Washington, said, “As a clinician who is very interested in clinical study methodology, I am concerned about possible bias. And the use of historical control data is a nonstarter,” since the study quality would suffer. “Changes in protocol as a study goes on are always problematic,” so the FDA’s request for feedback on how to tinker with study design was a concern.

But the biggest concern voiced by Dr. Lipman and others on the committee, including FDA representatives, was the huge barrier to enrollment that’s presented by a placebo-controlled study for a drug that has already been approved. “This is always a major issue for the FDA in approving drugs under accelerated approval,” acknowledged Dr. Amy Egan, deputy director of the FDA’s office of drug evaluation III, office of new drugs. The anticipation of difficulty in enrolling is one reason the historical control arm is held in reserve, she said. Intercept’s vice president for clinical development Dr. Leigh MacConell concurred, saying of the discussions with the FDA about study design, “It was a very difficult conversation, because we agree with your assessment regarding the feasibility” of the study.

The FDA noted remaining issues requiring ongoing study of OCA for PBC. Among these is the need to confirm the clinical benefit of OCA across the full spectrum of severity of PBC, from early stage to advanced disease. “FDA would also like to evaluate additional data on use of OCA as monotherapy,” said Dr. Lara Dimick-Santos, cross-discipline team leader at the FDA.

The course of PBC is variable; it affects women approximately 10 times more frequently than men. Occurring in approximately 1 in 1,000 women over the age of 40, its prevalence is thought to be increasing. PBC is usually asymptomatic for some time; when symptoms occur, fatigue and pruritis are the most common. Concomitant autoimmune diseases are common and an earlier age at diagnosis is often associated with a worse disease course. A significant number of those affected by PBC will progress to death or liver transplantation.

Intercept Pharmaceuticals is also studying OCA for use in other liver conditions, including nonalcoholic steatohepatitis (NASH).

All committee members submitted information to the FDA regarding conflicts of interest. The FDA usually follows the recommendations of its advisory panels.

*Changes were made to this story on April 8, 2016.

[email protected]

On Twitter @karioakes