primary biliary cholangitis

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis

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Abstract

BACKGROUND

Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.

METHODS

In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).

RESULTS

A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (−1.93 vs. −1.15; difference, −0.78; 95% CI, −1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.

CONCLUSIONS

Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo.

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

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Abstract

BACKGROUND

Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator–activated receptor delta agonist, has potential benefits.

METHODS

In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).

RESULTS

Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, −3.2 vs. −1.7; least-squares mean difference, −1.5; 95% CI, −2.5 to −0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.

CONCLUSIONS

In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups.

Improved Transplant-Free Survival Observed with Obeticholic Acid in People with PBC Published in Gastroenterology

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Intercept Pharmaceuticals, Inc. (Nasdaq: ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, today announced a key publication in Gastroenterology showing that people receiving OCA for primary biliary cholangitis (PBC) in a clinical trial setting had greater transplant-free survival compared to patients with PBC selected from “real-world” patient registries who did not receive OCA.

Key findings include:

  • Patients treated with OCA had an approximately 70 percent lower relative risk of death or liver transplant than the control patients at any time during follow-up.
  • The primary outcome of time to first occurrence of liver failure or death was statistically significant, favoring OCA treatment in POISE compared to patients from “real-world” databases.
  • There was a statistically significant and clinically meaningful reduction in death, liver transplant and hepatic decompensation in OCA-treated patients versus comparable untreated patients.

“This important study is the first to demonstrate that initiating treatment with OCA in appropriate patients with PBC appears to have a meaningful impact on clinical outcomes,” said Professor Gideon Hirschfield, FRCP, Ph.D., Lily and Terry Horner Chair in Autoimmune Liver Disease at the University of Toronto. “I am proud of this innovative analysis, and further, the continued value we are deriving from large, academic-led, prospective databases like the Global PBC and UK-PBC study groups. Leveraging these registries helps advance our collective understanding of this disease to ultimately influence clinical decision-making and benefit people living with PBC.”

“Given the known challenges associated with conducting blinded, placebo-controlled trials when the treatment has been approved and is available, this study provides evidence that a well-matched external comparator group can be a credible, alternate approach to evaluating clinical efficacy,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “We look forward to further leveraging real-world databases to continue generating insights on the clinical benefit of Ocaliva in PBC.”

This study compared patients with PBC who received up to six years of OCA in the Phase 3 POISE study and its open-label extension (n=209) to external controls who were extracted from two large, academic-led patient registries. External controls met POISE entry criteria but were not treated with OCA. Treatment with ursodeoxycholic acid (UDCA) was permitted.

The primary endpoint of this study was time to first occurrence of liver transplant or death. Over the six-year follow-up, there were five deaths/liver transplants in 209 subjects in the POISE study, 135 in 1,381 patients in the Global PBC control, and 281 in 2,135 patients in the UK-PBC control. Preliminary results from this analysis were first presented at the 2021 Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Data Sources for this Study:
The Global PBC registry included 6,484 patients with PBC from eight countries in Europe and North America during the study period who were not treated with OCA. Of these, 1,381 met the entry criteria for this study.

The UK-PBC registry included over 6,900 patients with PBC from the UK during the study period who were not treated with OCA. Of these, 2,135 met the entry criteria for this study.

The POISE trial studied the safety and efficacy of once-daily treatment with Ocaliva in PBC patients with an inadequate therapeutic response to, or who were unable to tolerate, ursodeoxycholic acid (UDCA). There were 217 patients randomized to one of three groups in the trial: placebo, OCA 10 mg, or OCA 5 mg for six months titrated to 10 mg based on clinical response. Seven subjects did not participate in the open-label extension and were not included in the current study. Patients completing the double-blind phase had the option to continue in an open-label extension (OLE) phase for a maximum of five additional years, during which all patients received treatment with OCA 5-10 mg once daily. Of the 198 patients who completed the double-blind phase, more than 95 percent continued in the long-term safety extension phase of the trial. Additional information regarding the POISE trial can be found on the NIH clinical study listing website: http://clinicaltrials.gov/ct2/show/NCT01473524.

About Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is a rare, progressive and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent (approximately 1 in 10,000) in women over the age of 40. PBC causes bile acids to build up in the liver, resulting in inflammation and scarring (fibrosis), which, if left untreated, can lead to cirrhosis, liver transplant, or death.

About Intercept
Intercept is a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH). For more information, please visit www.interceptpharma.com or connect with the company on Twitter and LinkedIn.

About Ocaliva® (obeticholic acid)

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC).

  • without cirrhosis or
  • with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS

  • Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.
  • OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.
  • Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment.

Contraindications

OCALIVA is contraindicated in patients with:

  • decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event
  • compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia)
  • complete biliary obstruction

Warnings and Precautions

Hepatic Decompensation and Failure in PBC Patients with Cirrhosis

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among post-marketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis.

Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage.

Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC.

Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment.

Severe Pruritus

Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled clinical trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing.

Reduction in HDL-C

Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.

Adverse Reactions

The most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Drug Interactions

  • Bile Acid Binding Resins
    Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.
  • Warfarin
    The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.
  • CYP1A2 Substrates with Narrow Therapeutic Index
    Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA.
  • Inhibitors of Bile Salt Efflux Pump
    Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

Obeticholic acid yields fewer deaths, liver transplants in primary biliary cholangitis

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Patients who received obeticholic acid for primary biliary cholangitis experienced greater transplant-free survival compared with external control patients, according to research published in Gastroenterology.

“This important study is the first to demonstrate that initiating treatment with obeticholic acid (OCA) in appropriate patients with primary biliary cholangitis (PBC) appears to have a meaningful impact on clinical outcomes,” Gideon Hirschfield, FRCP, PhD, Lily and Terry Horner Chair in autoimmune liver disease at the University of Toronto, said in a press release.

Gideon Hirschfield quote

Although first-line therapy with ursodeoxycholic acid has been shown to improve transplant-free survival in PBC, nearly 40% of patients treated with ursodeoxycholic acid experience an inadequate response, with increased risk for hepatic complications and poor outcomes. Obeticholic acid had been given accelerated FDA approval for inadequate responders in 2016, with full approval contingent on establishing benefit for clinical outcomes, including hepatic decompensation, liver transplant and mortality.

Using data from the POISE trial, Hirschfield and colleagues compared results of patients treated with OCA from the double-blind and open label extension periods (n = 209) with those generated by “real-world controls” not treated with OCA from the Global PBC (n = 1,381) and UK PBC (n = 2,135) registry studies.

Baseline characteristics reflected a predominantly female epidemiology of PBC with most diagnosed between 50 and 60 years of age and receiving ursodeoxycholic acid therapy between 900 mg/day and 1,000 mg/day for 3.5 to 4 years at index. The primary outcome was time to first occurrence of liver transplant or death.

Over 6 years of follow-up, researchers observed liver transplantation or death among 2.4% of patients from the POISE cohort, 10% of patients from the Global PBC cohort and 13.2% of patients from the UK PBC cohort.

Pre-specified propensity scoring yielded hazard ratios of 0.29 (95% CI, 0.1-0.83) for POISE vs. Global PBC and 0.3 (95% CI, 0.12-0.75) for POISE vs. UK PBC; researchers noted these results indicated patients treated with OCA in a trial setting had a “significantly greater transplant-free survival than patients in either external control group.”

Further analysis revealed 16 incidences of death, liver transplant or hepatic decompensation among 209 patients in the POISE cohort vs. 212 incidences among 1,381 patients in the Global PBC cohort (HR = 0.42; 95% CI, 0.21-0.85).

“Given the known challenges associated with conducting blinded, placebo-controlled trials when the treatment has been approved and is available, this study provides evidence that a well-matched external comparator group can be a credible, alternate approach to evaluating clinical efficacy,” Michelle Berrey, MD, MPH, president of research and development and chief medical officer at Intercept Pharmaceuticals, said in the release. “We look forward to further leveraging real-world databases to continue generating insights on the clinical benefit of Ocaliva (OCA, Intercept) in PBC.”

Linerixibat induced a dose-dependent reduction in itch among patients with primary biliary cholangitis-associated pruritus

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“Pruritus is commonly associated with primary biliary cholangitis, present in nearly 75% of patients over the disease course,” Cynthia Levy, MD, FAASLD, AGAF, of the University of Miami Miller School of Medicine, and colleagues wrote. “Pruritus substantially impairs health-related quality of life, affecting sleep and contributing to fatigue.”

Man scratching arm
“Targeting bile acid reuptake with linerixibat may provide relief for patients with PBC and cholestatic pruritus, along with improvements in health-related quality of life relating to itch,” Cynthia Levy, MD, FAASLD, AGAF, and colleagues wrote. Source: Adobe Stock

According to researchers, linerixibat — a minimally absorbed oral small molecule ileal bile acid transporter inhibitor — reduced cholestatic pruritus without serious adverse events in a phase 2a study. In addition, treatment with linerixibat reduced bile acid levels and improved sleep interference and fatigue compared with placebo.

To expand on these findings, Levy and colleagues conducted the multicenter, randomized phase 2b GLIMMER study to investigate the safety, efficacy and dose-response of linerixibat among 147 patients (mean age, 55.8 years, 94% women) with moderate to severe pruritus-associated primary biliary cholangitis (PBC), defined as an itch score of at least 4 on the numerical rating scale (NRS).

After 4 weeks of single-blind placebo, patients received linerixibat once (20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27) or twice daily (40 mg, n = 23; 90 mg, n = 22) or placebo (n = 36) for 12 weeks. Patients measured their itch score (0-10 NRS) twice daily, and researchers determined daily, weekly and monthly itch scores. The primary endpoint was change in mean worst daily itch (MWDI) score compared with baseline.

According to study results, there was a reduction from baseline in MWDI scores (mean 2 points) among patients dosed with linerixibat at week 16. Although these differences were not significant compared with placebo, post-hoc analysis of change in monthly itch score yielded “significant differences” between placebo and linerixibat 180 mg once daily (least squares mean change = –0.9; 95% CI, –1.76 to –0.03), 40 mg twice daily (–1.16; 95% CI, –2.05 to –0.28) and 90 mg twice daily (–0.95; 95% CI, –1.85 to –0.06).

Further, a linear model of total daily dose of linerixibat in the per protocol population yielded a “statistically significant” reduction vs. placebo in MWDI score at the 10% level, indicating a dose-response relationship.

According to researchers, commonly reported adverse events included diarrhea and abdominal pain, which occurred more often at higher linerixibat doses.

“Targeting bile acid reuptake with linerixibat may provide relief for patients with PBC and cholestatic pruritus, along with improvements in health-related quality of life relating to itch,” Levy and colleagues concluded. “Twice-daily dosing was associated with greater itch improvement.”

They added, “This study identified a linerixibat dose for further investigation, and a confirmatory study is ongoing in PBC patients with moderate to severe itch which includes a longer double-blind dosing period and analysis of itch intensity throughout the study period rather than at a single timepoint.”

FDA Ups Ocaliva Warning to Black Box

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Trying to stem problem with excessive dosing of cholangitis drug

The FDA said it will now require a boxed warning on obeticholic acid (Ocaliva) regarding correct dosing in patients with primary biliary cholangitis (PBC), following up on concerns the agency initially expressed last September.

Obeticholic acid is supposed to be given once or twice weekly at 5-10 mg in patients with a prior decompensation event or with PBC of Child-Pugh class B or C — but some patients in these categories have been taking the drug daily with severe adverse consequences, the FDA said. Daily dosing is allowed for patients with non-cirrhotic or compensated Child-Pugh class A PBC.

The agency did not provide updated numbers of adverse events in its announcement Thursday, but the September statement indicated that 19 deaths had been reported with the drug, some of which were clearly associated with higher-than-recommended dosing.

“FDA is adding a new Boxed Warning, FDA’s most prominent warning, to highlight [recommended dosing] in the prescribing information of the drug label,” the agency said. “FDA is also requiring a Medication Guide for patients to inform them about this issue.”

The drug, made by Intercept Pharmaceuticals, was approved in May 2016. The FDA noted that, as a condition of approval, it had required post-marketing studies of obeticholic acid in patients with advanced PBC; results are not expected until 2023, however.