Linerixibat for Cholestasis

(LLSAT Trial)

Recruiting at 120 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

245 Participants Needed

Trial Summary

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.

What data supports the idea that Linerixibat for Cholestasis (also known as: Linerixibat, GSK2330672) is an effective treatment?

The available research shows that Linerixibat is being developed to help with itching in people with primary biliary cholangitis, a condition related to cholestasis. In a study called GLIMMER, Linerixibat was tested for its effectiveness and safety, and it showed promise in reducing itching. This is important because the usual treatment, ursodeoxycholic acid, doesn't work well for itching. Another study confirmed that Linerixibat is mostly not absorbed into the body, which means it works mainly in the gut where it's needed. This makes it a unique option compared to other treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Linerixibat for cholestasis?

Research shows that Linerixibat, a drug that blocks a specific transporter in the intestine, has been studied for its ability to reduce itching in patients with primary biliary cholangitis, a liver condition. This suggests it might help with symptoms related to cholestasis, as both conditions involve bile acid issues. ^{1 2 3 4 5}

What safety data is available for Linerixibat?

The GLIMMER trial assessed the safety of Linerixibat in patients with primary biliary cholangitis and pruritus. This study was a randomized Phase 2b dose-ranging trial that evaluated the dose-response, efficacy, and safety of Linerixibat, an ileal bile acid transporter inhibitor. Additionally, the pharmacokinetics study of Linerixibat in healthy male volunteers provided insights into its minimal absorption and systemic exposure, with most of the drug excreted unchanged via the biliary/fecal route, indicating a favorable safety profile. ^{1 2 3 6 7}

Is Linerixibat safe for humans?

Linerixibat has been studied in humans and shows minimal absorption in the body, with most of it being excreted unchanged in feces, suggesting it is generally safe with low systemic exposure. ^{1 2 3 6 7}

Is the drug Linerixibat a promising treatment for cholestasis?

Yes, Linerixibat is a promising drug for cholestasis because it helps reduce itching by blocking the re-absorption of bile acids in the gut, which lowers their levels in the body. ^{1 2 3 8 9}

How does the drug Linerixibat differ from other treatments for cholestasis?

Linerixibat is unique because it is an oral drug that specifically inhibits the ileal bile acid transporter, reducing bile acids in the bloodstream and alleviating itch associated with cholestasis. Unlike other treatments, it is minimally absorbed into the body, acting primarily in the gut and being excreted unchanged, which reduces systemic side effects. ^{1 2 3 8 9}

What is the purpose of this trial?

This is an open-label, non-comparator, global, multi-center, long-term safety study for evaluating safety and tolerability of linerixibat in participants with cholestatic pruritus in primary biliary cholangitis (PBC) who participated in a prior clinical trial with linerixibat (BAT117123 \[NCT01899703\], 201000 GLIMMER \[NCT02966834\] (group 1) or 212620 GLISTEN \[NCT00210418\]) (group 2). All participants will receive open-label linerixibat for the duration of the study. The study duration is expected to last until the study's end or until linerixibat can be lawfully made available to participants. However, the total duration of study participation will vary by participant depending upon the time of entry relative to study end in their respective country.

Research Team

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. [2023]

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

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

3. 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]

4. 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]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis. [2023]

7. United States 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. [2020]

8. 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]

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

A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. [2023]