linerixibat (GSK2330672) / GSK - LARVOL DELTA

Linerixibat New Drug Application (NDA) accepted for review by the US FDA for cholestatic pruritus in patients with primary biliary cholangitis (PBC) (GSK Press Release) - "GSK plc...announced the US Food and Drug Administration (FDA) has accepted for review the NDA for linerixibat, an investigational targeted inhibitor of the ileal bile acid transporter (IBAT), for the treatment of cholestatic pruritus in patients with PBC, a rare autoimmune liver disease. The Prescription Drug User Fee Act (PDUFA) goal date is 24 March 2026...The application is based on positive data from the GLISTEN phase III trial, presented in May at the European Association for the Study of the Liver (EASL) Congress."

FDA filing • PDUFA • Primary Biliary Cholangitis

EARLY PRESENTATION AND UNDERTREATMENT OF CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS (PBC): INSIGHTS FROM THE PHASE 3 GLISTEN TRIAL BASELINE DATA (DDW 2025) - P3 | "Linerixibat, an investigational targeted ileal bile acid transporter inhibitor, is a twice-daily oral tablet for the treatment of cholestatic pruritus in PBC...Participants were either treatment-naïve, had received prior therapy or continued stable concomitant therapies commonly used for PBC and/or pruritus, except for obeticholic acid...Overall, 97% of participants were receiving ursodeoxycholic acid. The most common prior therapies for pruritus were antihistamines (16%), bile acid–binding resins (13%) and rifampin (5%)... This analysis included 238 participants. The duration of pruritus was longer than the duration of PBC diagnosis (mean standard deviation [SD]: 7.7 [7.3] vs 6.3 [5.7]) years, respectively). At baseline, 42% had moderate pruritus and 58% had severe pruritus."

P3 data • Dermatology • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

GLISTEN phase III trial results show linerixibat significantly improves cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC) (GSK Press Release) - P3 | N=238 | GLISTEN (NCT04950127) | Sponsor: GlaxoSmithKline | "GSK plc...announced positive results from the GLISTEN phase III trial evaluating linerixibat, an investigational targeted inhibitor of the ileal bile acid transporter (IBAT), in adults with cholestatic pruritus and PBC, a rare autoimmune liver disease. The full data were presented in a late-breaker oral presentation at the EASL Congress 2025....GLISTEN met the primary endpoint of change from baseline in monthly itch score and showed linerixibat (n=119) significantly improved itch versus placebo (n=119) over 24-weeks, as measured on a 0-10 numerical rating scale (NRS) for the worst itch (WI-NRS) (least squares [LS] mean difference [95% CI]: -0.72 [-1.15, -0.28], p=0.001). Monthly itch score evaluated the worst weekly itch of each month over the 24-week treatment period. This finding supports linerixibat’s potential to address a major symptom of PBC, relentless itch."

P3 data • Primary Biliary Cholangitis • Pruritus

Linerixibat significantly improves cholestatic pruritus in primary biliary cholangitis: results of the pivotal phase 3 GLISTEN trial (EASL 2025) - P3 | "In patients with PBC and moderate-to-severe pruritus, linerixibat rapidly and significantly improved pruritus and pruritus- related sleep interference versus placebo. While GI AEs were more common with linerixibat than placebo, they rarely led to treatment discontinuation."

Late-breaking abstract • P3 data • Dermatology • Gastrointestinal Disorder • Hepatology • Immunology • Pain • Primary Biliary Cholangitis • Pruritus

Insufficient Control of Cholestatic Pruritus in Primary Biliary Cholangitis (PBC) With Current Therapies: Baseline Data From the East Asian Population Enrolled in the Phase 3 GLISTEN (Global Linerixibat Itch STudy of Efficacy and safety iN PBC) Study (APASL 2025) - P3 | "Participants are either pruritus treatment-naïve, have received prior pruritus therapy or continue stable concomitant therapies commonly used for PBC and/or pruritus, except for obeticholic acid...Antihistamines were the most common type of prior medication taken for pruritus among East Asian participants (20%), while prior use of bile acid binding resins was low (3%; 2 participants from China) and none had received opioid antagonists, selective serotonin reuptake inhibitors or rifampicin... Prior use of bile acid binding resins was low in the GLISTEN population, despite its first-line position in treatment guidelines in many countries, including China. Similarly, use of nalfurafine was low among Japanese participants, despite being approved in Japan for treating pruritus in chronic liver diseases. Regardless of the use of multiple off-label therapies that may impact pruritus, including fibrates, participants showed evidence of ongoing moderate–severe pruritus,..."

Clinical • P3 data • Dermatology • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Linerixibat Has Low Potential of Ethnic Differences for the Treatment of Cholestatic Pruritus in Primary Biliary Cholangitis (APASL 2025) - P3 | "The localised target site and limited systemic absorption of linerixibat meant measurable PK was limited. Target engagement (measured by proximal biomarkers TSBA and C4), was consistent between Japanese and Western pts. The safety profile of linerixibat was also consistent between both populations."

Dermatology • Gastrointestinal Disorder • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN) (clinicaltrials.gov) - P3 | N=238 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Pervasive role of pruritus in impaired quality of life in patients with primary biliary cholangitis: Data from the GLIMMER study. (PubMed, Hepatol Commun) - P2 | "This analysis of patients in the largest investigational trial of cholestatic pruritus to date shows a clear association between pruritus and impaired HRQoL. Patients with severe pruritus had HRQoL comparable to patients with severe Parkinson's disease. Severe pruritus alongside depression was associated with extremely poor HRQoL, indicating the importance of evaluating itch and managing depression. Sleep interference appears to be a major cofactor for reduced HRQoL. For each 1-point improvement in NRS HRQoL improved, clinicians should offer appropriate and timely intervention."

Clinical • HEOR • Journal • CNS Disorders • Depression • Dermatology • Hepatology • Immunology • Movement Disorders • Parkinson's Disease • Primary Biliary Cholangitis • Pruritus • Psychiatry

Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat. (PubMed, CPT Pharmacometrics Syst Pharmacol) - P2 | "Increases in patient-reported diarrhea scores were linerixibat dose-dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient-reported diarrhea bother is important to support treatment adherence."

Journal • Dermatology • Gastrointestinal Disorder • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

LLSAT: Linerixibat Long-term Safety, and Tolerability Study (clinicaltrials.gov) - P3 | N=251 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | Trial completion date: Feb 2027 ➔ Aug 2027 | Trial primary completion date: Feb 2027 ➔ Aug 2027

Enrollment closed • Trial completion date • Trial primary completion date • Cholestasis • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Validation of the Worst Itch Numerical Rating Scale (WI-NRS) and Related Patient-Reported Outcomes (PROs) to Assess Severity and Impact of Cholestatic Pruritus in Primary Biliary Cholangitis (PBC): An Observational Study (ISPOR-EU 2024) - P3 | "CONCLUSIONS : NRS items assessing worst itch, sleep interference and fatigue, and the 7-day PBC-40 are valid and reliable PRO measures, strongly supporting their use as assessments for patient-centric trial endpoints, including in the Phase 3 GLISTEN trial (NCT04950127) of linerixibat for pruritus treatment in PBC. FUNDING : GSK (212144)"

Clinical • Observational data • Patient reported outcomes • CNS Disorders • Dermatology • Fatigue • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus • Sleep Disorder

SERUM AUTOTAXIN AND FIBROBLAST GROWTH FACTOR-19 ARE BIOMARKERS OF LINERIXIBAT TREATMENT RESPONSE IN PATIENTS WITH CHOLESTATIC PRURITUS ASSOCIATED WITH PRIMARY BILIARY CHOLANGITIS (UEGW 2024) - P2 | "Serum ATX and FGF-19 may function as biomarkers of itch response to linerixibat treatment. Reductions in these biomarkers are associated with clinical response in patients with PBC and pruritus."

Biomarker • Clinical • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus • FGF19

INSUFFICIENT CONTROL OF CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS (PBC) WITH CURRENT THERAPIES: BASELINE DATA FROM THE ONGOING PHASE 3 GLISTEN (GLOBAL LINERIXIBAT ITCH STUDY OF EFFICACY AND SAFETY IN PBC) TRIAL (AASLD 2024) - P3 | "Participants are either treatment-naïve, have received prior therapy or continue stable concomitant therapies commonly used for PBC and/or pruritus, except for obeticholic acid...Overall, 97% of participants were receiving ursodeoxycholic acid...In total, 42% of participants were receiving concomitant therapy that may reduce pruritus, including 22% receiving fibrates, 10% selective serotonin reuptake inhibitors, 8% bile acid binding resins, 6% antihistamines, 4% gabapentin, 3% rifampin, 3% naltrexone, 3% pregabalin, and 2% nalfurafine. Prior use of bile acid binding resins was low in the GLISTEN population despite its first-line position in treatment guidelines. Regardless of the use of multiple "off label" therapies, participants living with PBC globally had evidence of ongoing moderate–severe pruritus, underscoring the unmet need for a symptom-specific therapy targeting pruritus in PBC."

Clinical • P3 data • Dermatology • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

VALIDATION OF THE WORST ITCH NUMERICAL RATING SCALE (NRS) AND RELATED PATIENT-REPORTED OUTCOMES (PROS) TO ASSESS SEVERITY AND IMPACT OF PRURITUS IN PRIMARY BILIARY CHOLANGITIS (PBC) (AASLD 2024) - P2, P3 | "This study examined the psychometric properties of NRS items (worst itch, sleep, and fatigue) and the PBC-40 (modified 7-day recall) used in GLIMMER (NCT02966834), a placebo-controlled Phase 2b trial of linerixibat in patients with PBC and pruritus... Findings confirm that NRS items utilized in GLIMMER (and ongoing Phase 3 GLISTEN study; NCT04950127) to assess itch, pruritus-related sleep interference, and fatigue are valid and reliable measures that can detect changes in patient status over time. Results also support use of the new 7-day recall version of the PBC-40. Routine clinical use of these validated measures for PBC may aid improved patient care."

Clinical • Patient reported outcomes • Dermatology • Fatigue • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Development of the commercial supply route to linerixibat (ACS-Fall 2024) - "Key to the route is the sulfur-controlled strategy to stereospecifically construct the highly functionalized benzothiazepine core via an episulfonium-controlled Ritter reduction followed by a sulfoxide-directed imine reduction. Additional highlights will include the use of High-Throughput Experimentation (HTE) and Process Analytical Technologies (PAT) to develop safe, scalable processes, particularly for a Pd-catalyzed cyanation and subsequent benzonitrile reduction."

Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN) (clinicaltrials.gov) - P3 | N=241 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting

Enrollment closed • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Relationship between pruritus and sleep in participants with primary biliary cholangitis in the Phase 2b GLIMMER trial. (PubMed, J Patient Rep Outcomes) - P2 | "A strong correlation exists between changes in pruritus severity and sleep interference in patients with PBC; pruritus reduction could generate concomitant improvement in sleep."

Clinical • Journal • P2 data • P2b data • CNS Disorders • Dermatology • Fatigue • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus • Sleep Disorder

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat. (PubMed, Liver Int) - "Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC."

Journal • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN) (clinicaltrials.gov) - P3 | N=230 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: May 2024 ➔ Dec 2024 | Trial primary completion date: May 2024 ➔ Sep 2024

Trial completion date • Trial primary completion date • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Combined inhibition of bile salt synthesis and intestinal uptake reduces cholestatic liver damage and colonic bile salts in mice. (PubMed, JHEP Rep) - "Wild-type male C57Bl6J/OlaHsd mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and received daily oral gavage with 10 mg/kg OCA, 30 mg/kg cilofexor, 10 mg/kg ASBT inhibitor (Linerixibat; ASBTi), or a combination. Combined treatment of intestinal ASBT inhibition with repression of bile salt synthesis by farnesoid X receptor agonism (using either obeticholic acid or cilofexor) or by expression of aldafermin ameliorates liver damage in cholestatic mice. In addition, compared with ASBT inhibitor monotherapy, combination treatments lower colonic bile salt load."

Journal • Preclinical • Cholestasis • Fibrosis • Hepatology • Liver Failure • Oncology • FGF19

Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase 3 Dose Selection for Linerixibat. (PubMed, Clin Pharmacol Ther) - P2, P3 | "BID dosing regimens led to a modest increase in the number of itch responders as compared with QD dosing. This quantitative framework highlights the trade-off between benefit and tolerability and supported the selection of 40 mg BID in the Phase 3 GLISTEN trial (NCT04950127)."

Journal • P3 data • Dermatology • Gastrointestinal Disorder • Hepatology • Immunology • Pain • Primary Biliary Cholangitis • Pruritus

LLSAT: Linerixibat Long-term Safety, and Tolerability Study (clinicaltrials.gov) - P3 | N=305 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Dec 2025 ➔ Feb 2027 | Trial primary completion date: Dec 2025 ➔ Feb 2027

Trial completion date • Trial primary completion date • Cholestasis • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

SERUM AUTOTAXIN (ATX) AND FIBROBLAST GROWTH FACTOR-19 (FGF-19) ARE BIOMARKERS OF LINERIXIBAT TREATMENT RESPONSE IN PATIENTS (PTS) WITH CHOLESTATIC PRURITUS ASSOCIATED WITH PRIMARY BILIARY CHOLANGITIS (PBC) (AASLD 2023) - P2 | "Serum ATX and FGF-19 may function as biomarkers of itch response to linerixibat treatment. Reductions in these biomarkers are associated with clinical response in pts with PBC and pruritus."

Biomarker • Clinical • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus • FGF19

Change in Total Serum Bile Acids Correlates With Improvement in Itch in Patients With Primary Biliary Cholangitis (PBC) Receiving Linerixibat (ACG 2023) - P2 | "The final population k-PD model successfully described the effect of linerixibat on TSBA in PBC. Linerixibat treatment resulted in a dose-dependent decrease in TSBA AUC 0-24 ; the reduction in TSBA AUC 0-24 was apparent after a single dose. BL TSBA concentrations did not correlate with change from BL in MIS at Week 16 (r=-0.13, p=0.14)."

Clinical • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

TREATMENT OF CHOLESTATIC PRURITUS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS (PBC): BASELINE DATA FROM THE PHASE 2B GLIMMER TRIAL (UEGW 2023) - P2 | "Introduction: GLIMMER (NCT02966834) was a Phase 2b study of the ileal bile acid transport (IBAT) inhibitor, linerixibat, for treatment of cholestatic pruritus in primary biliary cholangitis (PBC)...GLIMMER had few restrictions on concomitant medications with the exceptions of other IBAT inhibitors, bile acid sequestrants and obeticholic acid; stable doses of other treatments were permitted...This post hoc analysis included all treatments prescribed for itch; guideline treatments were defined as bile acid sequestrants, naloxone, naltrexone, nalmefene, nalfurafine, sertraline, rifampicin or gabapentin... Consistent with the literature, increased itch severity is associated with younger age. Many patients do not receive treatment despite lengthy history of pruritus, while prior use of cholestyramine is limited despite its position in treatment guidelines.Funding: GSK (201000).Encore statement: This abstract was originally presented at the American Association for the..."

Clinical • P2b data • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus