Obeticholic acid gains recommendation for accelerated approval in primary biliary cholangitis

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