Linerixibat for Cholestasis

(LLSAT Trial)

Not currently recruiting at 135 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: GlaxoSmithKline

Must be taking: Linerixibat

Must not be taking: Obeticholic acid, IBAT inhibitors

Disqualifiers: Hepatic decompensation, Viral hepatitis, Alcoholic liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: Up to 66 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and tolerability of linerixibat, a treatment for individuals with primary biliary cholangitis (PBC) who experience severe itching (pruritus) due to bile flow problems in the liver. All participants will receive linerixibat to evaluate its long-term effectiveness. It suits those who previously participated in specific linerixibat trials for PBC-related itching and completed the main treatment period. As a Phase 3 trial, this is the final step before FDA approval, providing participants an opportunity to contribute to the potential availability of a new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use Obeticholic acid within 8 weeks before the screening and during the study, and you cannot take any other ileal bile acid transporter (IBAT) inhibitors 1 month before screening and during the study.

Will I have to stop taking my current medications?

The trial requires that you stop taking Obeticholic acid at least 8 weeks before the screening visit and not restart it until after the study ends. Additionally, you cannot take any other ileal bile acid transporter (IBAT) inhibitors for 1 month before screening and until the study ends.

Is there any evidence suggesting that linerixibat is likely to be safe for humans?

Research shows that linerixibat is generally well-tolerated. Studies have found that this treatment can significantly improve the severe itching associated with primary biliary cholangitis (PBC). In one study with many participants, only a few experienced mild side effects, such as slight stomach upset or headache.

Earlier clinical trials have tested linerixibat, indicating a good safety record. As this study is in an advanced stage, substantial safety information is already available, suggesting the treatment is safe enough for larger groups.

Overall, the evidence suggests that linerixibat is safe for most people, though it might not be suitable for everyone. Participants usually report only minor side effects, if any. Always consult a healthcare provider for personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for cholestasis?

Linerixibat is unique because it targets bile acid transport specifically, which is different from the typical focus on symptom management in cholestasis treatments. Unlike standard treatments that often involve ursodeoxycholic acid or obeticholic acid, linerixibat works by inhibiting the ileal bile acid transporter (IBAT). This mechanism can reduce bile acid levels in the liver and blood, potentially offering a more direct way to alleviate cholestasis symptoms. Researchers are excited about linerixibat because it addresses the root cause of bile accumulation, potentially providing more effective relief for patients.

What evidence suggests that linerixibat might be an effective treatment for cholestatic pruritus in primary biliary cholangitis?

Studies have shown that linerixibat, the treatment being tested in this trial, effectively treats itchiness caused by liver disease. In one study, 56% of patients taking linerixibat experienced significant improvement in their itchiness, compared to 43% of those taking a placebo (a pill with no active medicine). Another study found that after 24 weeks, more patients taking linerixibat had less itchiness. These results suggest that linerixibat can help relieve itching for people with primary biliary cholangitis (PBC), a liver disease. Overall, research indicates that linerixibat can make a meaningful difference for people suffering from this condition. ^{2 3 4 6 7}

Who Is on the Research Team?

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with primary biliary cholangitis (PBC) and itching, who've been in a prior linerixibat study. They must not be pregnant or breastfeeding, have significant liver function issues, certain cancers, severe kidney problems, or use conflicting medications.

Inclusion Criteria

I am between 18 and 80 years old and have consented to participate in a trial.

I have PBC and itching, and was in a linerixibat trial (BAT117213, GLIMMER, GLISTEN).

I am able to understand and sign the consent form.

Exclusion Criteria

I have no other cancers besides the one being treated.

Screening total bilirubin >2x upper limit of normal (ULN).

I have been diagnosed with colorectal cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive open-label linerixibat for the duration of the study

Up to 66 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Linerixibat

Trial Overview The trial tests the long-term safety of linerixibat in patients with PBC-related itching. It's an open-label study where all participants receive the drug. The duration varies until linerixibat becomes legally available to them.

How Is the Trial Designed?

Group I: Participants receiving linerixibat Experimental Treatment 1 Intervention

Participants who previously participated in the Phase 2 studies (BAT117213 and 201000 GLIMMER \[Group 1\]) and Phase 3 study (212620 GLISTEN \[Group 2\]), will receive linerixibat.

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

Published Research Related to This Trial

Seladelpar, a selective PPAR-δ agonist, was found to be safe for long-term use in 106 patients with primary biliary cholangitis (PBC), with no serious treatment-related adverse events reported over a 2-year period.

The treatment significantly improved biochemical markers of cholestasis and liver injury, with normalization rates of alkaline phosphatase increasing from 66% to 79% and bilirubin normalization in 43% of patients with elevated levels at baseline by the end of the second year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis. Mayo, MJ., Vierling, JM., Bowlus, CL., et al.[2023]

A3907, an oral ASBT inhibitor, effectively increased bile acid excretion and improved liver and bile duct injury markers in experimental mouse models of cholestasis, indicating its potential as a treatment for liver damage.

In healthy humans, A3907 was well tolerated and showed plasma levels consistent with those that provided therapeutic effects in mice, supporting its further development for cholestatic liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. Caballero-Camino, FJ., Rodrigues, PM., Wångsell, F., et al.[2023]

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 a study of 38 patients with PFIC3, those with at least one missense variation in their genotype were more likely to respond positively to ursodeoxycholic acid (UDCA) therapy, leading to improved liver function and prolonged native liver survival.

Patients with severe genotypes (no missense variation) experienced earlier onset of symptoms and cirrhosis, were refractory to UDCA treatment, and all required liver transplantation at a younger age, highlighting the importance of genetic factors in disease progression and treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy. Gonzales, E., Gardin, A., Almes, M., 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]

A patient with BRIC type 2, which is caused by mutations in the ABCB11 gene, showed improvement when treated with plasma separation and anion absorption therapy, indicating potential alternative treatment options for this condition.

The study suggests that nasobiliary drainage may not be effective for patients with severe mutations in the ABCB11 gene, highlighting the need for tailored therapeutic approaches based on genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can genetic testing guide the therapy of cholestatic pruritus? A case of benign recurrent intrahepatic cholestasis type 2 with severe nasobiliary drainage-refractory itch. Holz, R., Kremer, AE., Lütjohann, D., et al.[2020]

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]

In the PEDFIC 2 study involving 69 patients, odevixibat significantly reduced serum bile acids (sBAs) by an average of -201 μmol/L in patients who had previously participated in PEDFIC 1, indicating its efficacy in managing bile acid levels in progressive familial intrahepatic cholestasis.

Odevixibat was well tolerated, with most treatment-emergent adverse events being mild or moderate, and no serious drug-related adverse events reported, suggesting a favorable safety profile for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. Thompson, RJ., Artan, R., Baumann, U., et al.[2023]

Citations

1. gsk.com gsk.com/en-gb/media/press-releases/glisten-phase-iii-trial-results-show-linerixibat-significantly-improves-cholestatic-pruritus/

GLISTEN phase III trial results show linerixibat significantly ... More patients in the linerixibat group had clinically meaningful itch improvement (WI-NRS ≥3-point reduction) with 56% versus 43% in the placebo ...

2. gut.bmj.com gut.bmj.com/content/74/Suppl_4/A6

O8 Linerixibat significantly improves cholestatic pruritus in ... At Week 24, more patients on linerixibat than placebo achieved a ≥2-point (68% vs 64%), ≥3-point (56% vs 43%) or ≥4-point (41% vs 29%) reduction in pruritus; a ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36343847/

A Randomized Phase 2b Dose-Ranging Trial of Linerixibat ... GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04950127

NCT04950127 | Global Linerixibat Itch Study of Efficacy ... This is a 2-part study in PBC participants with cholestatic pruritus and will evaluate the efficacy, safety and impact on health-related quality of life of ...

5. gsk.com gsk.com/en-gb/media/press-releases/linerixibat-shows-positive-phase-iii-results-in-cholestatic-pruritus/

Linerixibat shows positive Phase III results in cholestatic ... Primary endpoint met with a statistically significant improvement in itch over 24 weeks compared with placebo.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04167358

Linerixibat Long-term Safety, and Tolerability Study This is an open-label, non-comparator, global, multi-center, long-term safety study for evaluating safety and tolerability of linerixibat in participants ...

7. rarediseaseadvisor.com rarediseaseadvisor.com/news/linerixibat-significantly-improves-pruritus-pbc/

Linerixibat Significantly Improves Pruritus in PBC Safety outcome measures included adverse events. The results showed that the improvement in pruritus was significantly greater in patients ...