Linerixibat for Itching in Cholangitis

Recruiting at 138 trial locations

Overseen By US GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: GlaxoSmithKline

Must not be taking: Obeticholic acid, SSRIs, Antihistamines, others

Disqualifiers: Hepatitis B, Hepatitis C, Hepatic decompensation, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

238 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a medication called linerixibat to see if it can help reduce severe itching in people with a liver condition called Primary Biliary Cholangitis (PBC). The study will compare the effects of linerixibat to check its effectiveness and safety.

Will I have to stop taking my current medications?

The trial requires that you do not start, stop, or change the dose of certain medications like ursodeoxycholic acid, bezafibrate, fenofibrate, obeticholic acid, bile acid binding resins, and some others in the 8 weeks before screening. If you are on these medications, you may need to maintain your current regimen.

What data supports the effectiveness of the drug Linerixibat for itching in cholangitis?

Research shows that Linerixibat, which blocks the re-absorption of bile acids in the gut, can reduce itching in patients with primary biliary cholangitis. Studies found that patients taking Linerixibat reported a significant improvement in itchiness compared to those taking a placebo. ^{1 2 3 4 5}

Is Linerixibat safe for humans?

Linerixibat has been studied in humans and is generally safe, with minimal absorption into the body and most of it being excreted unchanged. However, it can cause diarrhea and abdominal pain due to its effect on bile acids in the colon. ^{1 2 3 4 6}

How does the drug Linerixibat work differently for itching in cholangitis?

Linerixibat is unique because it works by blocking the re-absorption of bile acids in the gut, which lowers their levels in the blood and helps reduce itching. Unlike other treatments, it specifically targets the ileal bile acid transporter, making it a novel approach for managing itch in primary biliary cholangitis. ^{1 2 3 4 7}

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

This trial is for adults aged 18-80 with Primary Biliary Cholangitis (PBC) who suffer from moderate to severe itching. Candidates must have documented PBC and cannot have certain liver complications, changes in itch medication within the last 8 weeks, primary sleep disorders, or active viral infections among other exclusions.

Inclusion Criteria

I experience moderate to severe itching.

I am between 18 and 80 years old.

You have been diagnosed with primary biliary cholangitis (PBC).

Exclusion Criteria

Your liver test results show very high levels of alanine aminotransferase, which could indicate liver problems.

I do not have ongoing severe diarrhea or active inflammatory bowel disease.

I have a diagnosed sleep disorder like sleep apnea or narcolepsy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive linerixibat or placebo for the treatment of cholestatic pruritus in PBC

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Linerixibat
• Placebo

Trial Overview The GLISTEN study is testing the effectiveness and safety of a drug called Linerixibat against a placebo in relieving itch caused by PBC. It also looks at how this treatment affects patients' quality of life.

Participant Groups

Group I: Participants receiving placebo followed by linerixibat Experimental Treatment 2 Interventions

Group II: Participants receiving linerixibat followed by placebo Experimental Treatment 2 Interventions

Group III: Participants receiving linerixibat Experimental Treatment 1 Intervention

Group IV: Participants receiving placebo Placebo Group 1 Intervention

Linerixibat is already approved in European Union, United States for the following indications:

Approved in European Union as Linerixibat for:

• None approved yet; orphan designation granted for primary biliary cholangitis (PBC) and associated cholestatic pruritus

Approved in United States as Linerixibat for:

• None approved yet; orphan drug designation granted for primary biliary cholangitis (PBC) and associated cholestatic pruritus

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Findings from Research

In a phase 2a trial involving 22 patients with primary biliary cholangitis, the drug GSK2330672 was found to be safe and effective in significantly reducing pruritus (itch) severity over 14 days, with a 57% reduction in itch scores on a numerical rating scale.

While GSK2330672 showed promising results in alleviating itch and reducing serum bile acids, the most common side effect was diarrhea, which could limit its long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Hegade, VS., Kendrick, SF., Dobbins, RL., et al.[2022]

In the Phase 2b GLIMMER study involving 147 adults with primary biliary cholangitis and moderate-to-severe itching, linerixibat showed a dose-dependent reduction in itch scores, particularly at higher doses, although the primary analysis did not show significant differences from placebo.

Diarrhea was the most common side effect associated with linerixibat, and its incidence increased with the dose, indicating a need for careful dose management in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Levy, C., Kendrick, S., Bowlus, CL., et al.[2023]

Linerixibat, a selective inhibitor of the ileal bile acid transporter, effectively reduces cholestatic pruritus in patients with primary biliary cholangitis (PBC) by lowering serum bile acids, as demonstrated in the phase IIb GLIMMER trial.

The study found a dose-dependent relationship where higher doses of linerixibat increased the number of patients experiencing significant itch relief, but also raised the likelihood of diarrhea, leading to the selection of a 40 mg twice-daily dose for further testing in the phase III GLISTEN trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. Carreño, F., Karatza, E., Mehta, R., et al.[2023]

Linerixibat, an oral medication for cholestatic pruritus, showed minimal absorption in humans, with an absolute oral bioavailability of only 0.05%, meaning most of the drug is not absorbed into the bloodstream.

The majority of linerixibat is excreted unchanged through feces (over 90%), indicating that it acts primarily in the intestine without significant systemic exposure, which may enhance its safety profile for treating conditions like primary biliary cholangitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers. Zamek-Gliszczynski, MJ., Kenworthy, D., Bershas, DA., et al.[2022]

In a study involving 44 patients with primary biliary cholangitis (PBC) suffering from moderate to severe pruritus, nalfurafine hydrochloride significantly reduced itch severity after 12 weeks of treatment, as shown by a decrease in both PBC-40 itch scores and visual analog scale (VAS) scores.

While nalfurafine effectively alleviated pruritus, it did not significantly improve overall health-related quality of life (HRQOL) measures, indicating that while it helps with itching, it may not address other quality of life issues in PBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study. Yagi, M., Tanaka, A., Namisaki, T., et al.[2019]

In a systematic review of 23 randomized controlled trials involving 2,194 patients, UDCA, methotrexate, and GSK2330672 were found to significantly relieve itching in patients with primary biliary cholangitis (PBC).

While these treatments showed promise for itching relief, the evidence for their effects on improving serum alkaline phosphatase (ALP) or γ-glutamyl transpeptidase (γ-GGT) levels was inconclusive due to high variability among studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pharmacological interventions for pruritus in primary biliary cholangitis: A systematic review and meta-analysis. Xu, C., Yue, R., Lv, X., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers. [2022]

5. Japan pubmed.ncbi.nlm.nih.gov

Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pharmacological interventions for pruritus in primary biliary cholangitis: A systematic review and meta-analysis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Evaluation and Management of Pruritus in Primary Biliary Cholangitis. [2023]