Large placebo effect seen in trial of maralixibat for primary biliary cholangitis

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.

BARCELONA – An international phase II trial with the investigational bile acid transporter inhibitor maralixibat chloride failed to meet its primary endpoint of reducing the weekly itch score to a greater extent than placebo in patients with primary biliary cholangitis.

Results of the CLARITY trial reported at the International Liver Congress showed similar mean reductions in the Adult Itch Reported Outcome (ItchRO) weekly sum score with maralixibat and placebo from the start to end of treatment at 13 weeks (–26.49 vs. –23.36), giving a nonsignificant –3.13 difference vs. placebo.

Dr. Marlyn Mayo of the University of Texas, Dallas, reported the findings at the meeting, which was sponsored by the European Association for the Study of the Liver. Dr. Mayo pointed out that the “pronounced placebo effect may have confounded pruritus assessments.”

Ursodeoxycholic acid (UDCA) is the only therapy for primary biliary cholangitis at the moment, but approximately 40% of patients have an inadequate biochemical response, Dr. Mayo said. Therefore, other treatments are being sought that might help improve liver function and cholestatic pruritus.

Maralixibat, which was previously known as LUM001, is an apical sodium–dependent bile acid transporter inhibitor and the aim of the randomized, double-blind, placebo-controlled CLARITY trial was to evaluate its efficacy, safety, and tolerability when used in adults with primary biliary cholangitis and itching.

CLARITY was conducted in 24 centers in the U.S., U.K., and Canada. It was designed to assess the benefit of 13 weeks of treatment with maralixibat or placebo on top of daily treatment with UDCA. For inclusion in the study, adults aged 18-80 years had to have a confirmed diagnosis of primary biliary cholangitis with moderate pruritus for 2 consecutive weeks. This was defined as a score of 4 or more on a scale of 1-10 (with 10 being the worst possible itch) of the self-assessed ItchRO score. Patients needed to be intolerant to or not responding to UDCA. Those who were taking UDCA needed to have been on the drug for at least 6 months and taking stable doses for at least 3 months before study entry.

A total of 66 patients were randomized into the study, which consisted of an initial (up to 5 weeks) screening phase, a 3 to 4 week dose escalation phase, then a 9 to 10 week stable dose phase, and 4 weeks of follow up. Two cohorts of patients were studied with one eventually receiving a 10-mg daily dose of maralixibat and the second a 20-mg dose.

The primary efficacy endpoint was the weekly change in ItchRO sum score from baseline to week 13 of treatment, or early termination. Dr. Mayo highlighted that patients used a handheld electronic device that reminded patients to record the level of itch twice daily and the average of the morning and evening reading taken. From this an average daily score over 7 days was derived, and the primary endpoint of a weekly sum score was the sum of daily scores during each 7-day evaluation, with the final total score ranging from 0 to 70.

The average age of patients was about 53 years and the majority was female (more than 80%). There was variability in the time since diagnosis, averaging around 6.5 to 7 years. Baseline ItchRO weekly sum scores averaged about 50, the 5-D itch score was around 19 (scores can range up to 25 indicating the worst possible itch). “So patients had moderate to severe pruritus at baseline,” Dr. Mayo said. Serum bile acids were “all over the map,” she added, ranging from around 33 micromol/L in the maralixibat 10-mg group to 55 micromol/L in the placebo group.

“There was a significant reduction in itch in all of the maralixibat groups as well as placebo,” Dr. Mayo reported. As well as no difference between the active and placebo groups using the ItchRO weekly sum score, there was no difference using the 5-D itch score or another pruritus measure, the PBC-40 itch domain score.

There was a significant reduction in serum bile acids in the maralixibat groups: –14 micromol/L overall, and –11 and –17 micromol/L for the 10-mg and 20-mg groups, respectively, whereas there was an increase of 10 micromol/L in the placebo group. The expected opposite pattern was seen for C4 levels, with an overall increase of 13 ng/mL for maralixibat and –2.21 ng/mL for placebo. This indicates that bile acid transport is successfully being inhibited in the terminal ileum, Dr. Mayo noted.

One patient treated with 10 mg maralixibat needed a dose reduction to 5 mg and overall two (4.8% vs. 0% for placebo) discontinued treatment. Gastrointestinal-related disorders were the most common treatment-related adverse events, occurring in around 60% of patients (vs. 25% for placebo). There was also a higher percentage of patients with upper abdominal pain (23.8% vs. 8.3%) or abdominal pain generally (23.8% vs. 4.2%), and 11.9% (vs. 0%) experienced cough.

Dr. Mayo noted that the GI side effects were “consistent with the mechanism of action and localized exposure of the drug in the gut.” Despite having looser stools, she observed that “very few patients wanted to stop treatment for it”.

As for the high placebo response, this is not uncommon in trials, with rates of 20% being previously seen in studies evaluating pain or itching. “There are some interesting theories about what goes on with the placebo effect, it is real and physiologic,” she said.

The study was funded by Lumena (part of the Shire Group of Companies). Dr. Mayo disclosed receiving honoraria or research funding from Gilead Sciences, Intercept Pharmaceuticals, Lumena, NGM Biopharmaceuticals, and Salix Pharmaceuticals.