Linerixibat for Cholestasis
(LLSAT Trial)
Recruiting in Palo Alto (17 mi)
+120 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: GlaxoSmithKline
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
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.
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.
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.
12345What 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.
12367Eligibility 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.
+2 more
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.
+11 more
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Participants receiving linerixibatExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GSK Investigational SiteToronto, Canada
GSK Investigational SiteNew York, NY
GSK Investigational SiteColorado Springs, CO
GSK Investigational SiteColumbus, OH
More Trial Locations
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Who Is Running the Clinical Trial?
GlaxoSmithKlineLead Sponsor
References
Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. [2023]PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis.
GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. [2023]GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC).
Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers. [2022]Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [14C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs. 0.8 hours). The short intravenous half-life was consistent with high systemic clearance (61.9 l/h) and low volume of distribution (16.3 l). In vitro studies predicted rapid hepatic clearance via cytochrome P450 3A4 metabolism, which predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ∼80% elimination via biliary/fecal excretion (>90%-97% as unchanged parent) and ∼20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily because of a very low fraction absorbed (0.167%; fraction escaping first-pass gut metabolism (fg) ∼100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ∼20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (<0.04% of dose). Linerixibat unequivocally exhibited minimal gastrointestinal absorption and oral systemic exposure. Linerixibat represents a unique example of high CYP3A4 clearance in vitro but nearly complete excretion as unchanged parent drug via the biliary/fecal route. SIGNIFICANCE STATEMENT: This study conclusively established minimal absorption and systemic exposure to orally administered linerixibat in humans. The small amount of linerixibat absorbed was eliminated efficiently as unchanged parent drug via the biliary/fecal route. The hepatic clearance mechanism was mispredicted to be mediated via cytochrome P450 3A4 metabolism in vitro rather than biliary excretion of unchanged linerixibat in vivo.
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]Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus.
Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy. [2023]Label="Background & Aims" NlmCategory="UNASSIGNED">Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce.
Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis. [2023]Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects.
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]Benign recurrent intrahepatic cholestasis (BRIC) is a peculiar familial disease caused by mutations of the genes encoding hepatocanalicular flippase for phosphatidylserine (ATP8B1; BRIC type 1) or the bile salt export pump (ABCB11; BRIC type 2). Here, we report on a patient with nasobiliary drainage-refractory BRIC type 2 who improved under plasma separation and anion absorption therapy. We also suggest that nasobiliary drainage might be an ineffective approach in carriers of severe loss-of-function mutations of the bile salt export pump ABCB11. (Hepatology Communications 2018;2:152-154).
Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. [2023]Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re-absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain. GLIMMER (NCT02966834) was a placebo-controlled phase IIb dose-ranging trial of linerixibat once (q.d.) or twice daily (b.i.d.) in adults with moderate to severe pruritus and PBC. To determine the optimal dose for maximum itch reduction while minimizing diarrhea, a kinetic-pharmacodynamic (k-PD) model was developed using data from GLIMMER. The PD end point modeled was worst daily itch, derived from itch score reported by patients b.i.d. A proportional odds model was developed post hoc to indicate the probability of diarrhea occurrence, a patient-reported outcome (GI-5) recorded weekly. The final k-PD model successfully described the effects of linerixibat and placebo on itch. Model simulations were consistent with the observed dose-dependent increase in the average number of itch responders (patients with a ≥ 2-point improvement in itch). This was paralleled by a dose-dependent increase in the probability of higher diarrhea frequency scores. The b.i.d. dosing regimens led to a modest increase in the number of itch responders as compared with q.d. dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg b.i.d. in the phase III GLISTEN trial (NCT04950127).
A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans. [2023]Cholestasis is characterized by intrahepatic accumulation of bile constituents, including bile acids (BAs), which promote liver damage. The apical sodium-dependent BA transporter (ASBT) plays an important role in BA reabsorption and signaling in ileum, bile ducts, and kidneys. Our aim was to investigate the pharmacokinetics and pharmacological activity of A3907, an oral and systemically available ASBT inhibitor in experimental mouse models of cholestasis. In addition, the tolerability, pharmacokinetics, and pharmacodynamics of A3907 were examined in healthy humans.