Beyond symptom relief: The promise of Linerixibat as a mechanism-based therapy for cholestatic pruritus in primary biliary cholangitis

Dear Editor,

Primary biliary cholangitis (PBC) is an autoimmune liver disease in which the small bile ducts are progressively destroyed. This destruction causes exhausting symptoms, and about 60%–70% of patients experience severe pruritus. This, in turn, greatly reduces their quality of life, often leading to sleep disturbances, fatigue, and depression.¹ The current main treatment for cholestatic pruritus is cholestyramine, which works by binding bile acids. Other options for treatment include rifampin, opioid antagonists, and additional therapies such as phototherapy or albumin dialysis. However, due to various adverse effects, increased costs, and the limited efficacy of currently available therapies, complete relief from pruritus is often difficult to achieve.²

A novel class of drugs, ileal bile acid transporter (IBAT) inhibitors, has shown potential in improving pruritus in patients with PBC. Among these, Linerixibat (Lynavoy; GSK) was approved by the US Food and Drug Administration (FDA) on March 17, 2026, as the first drug specifically indicated for cholestatic pruritus in PBC.³ It has emerged as a promising candidate in mechanism-based therapy, directly targeting enterohepatic bile acid recirculation and offering a more disease-specific approach than conventional symptomatic therapies.⁴ Linerixibat works by inhibiting the uptake of bile acids in the terminal ileum, where bile acid reabsorption normally occurs. In PBC, bile acids are elevated and are thought to contribute to pruritus. Thus, the interventions that reduce the enterohepatic load of bile acids greatly ameliorate pruritus, and inhibition of IBAT becomes a mechanistically rational therapeutic target. By reducing reabsorption, Linerixibat decreases serum bile acid levels and the overall bile acid pool.⁵ Fig. 1 illustrates the mechanism of action of Linerixibat and the downstream consequences of IBAT inhibition.

Fig. 1.

Mechanism of action of Linerixibat and consequences of ileal bile acid transporter (IBAT) inhibition in primary biliary cholangitis (PBC). Left panel: Under normal conditions, the liver produces and secretes bile acids into the small intestine. In the terminal ileum, IBAT reabsorbs approximately 95% of the bile acid pool, returning them to the liver via the portal vein. Ileal enterocytes simultaneously release FGF19, which suppresses hepatic CYP7A1 and limits de novo bile acid synthesis through negative feedback. In PBC, progressive bile duct injury disrupts this balance, elevating serum bile acid levels and leading to pruritus, sleep disruption, fatigue, and cholestatic liver injury. Right panel: Linerixibat (Lynavoy; GSK) is an oral IBAT inhibitor with 0.05% systemic bioavailability that acts luminally to block ileal bile acid reabsorption. Reduced FGF19 signalling derepresses hepatic CYP7A1, transiently raising C4 levels and stimulating compensatory bile acid synthesis, resulting in a reduced enterohepatic bile acid pool. Diverted bile acids enter the colon, increasing colonic bile acid load. In the Phase 3 GLISTEN trial, Linerixibat significantly reduced WI-NRS pruritus scores compared with placebo (adjusted mean difference −0.72; P = 0.0013). The most common adverse effects were diarrhoea (61% vs. 18%) and abdominal pain (18% vs. 3%), consistent with increased colonic bile acid exposure; treatment discontinuation occurred in 7% of patients. Abbreviations: CYP7A1, cholesterol 7alpha-hydroxylase; FGF19, fibroblast growth factor 19; WI-NRS, Worst Itch Numerical Rating Scale.

Linerixibat was designed to have minimal absorption, with an oral bioavailability of 0.05%. This minimized off-target systemic effects. This was confirmed in a phase 1 pharmacokinetic (PK)/absorption, disposition, metabolism, and excretion (ADME) study, driven mainly by a fractional intestinal absorption of about 0.17%, with high hepatic extraction (77%) as a secondary barrier to systemic exposure. The drug showed flip-flop absorption-limited kinetics. The oral half-life (6–7 h) was substantially longer than the half-life following intravenous administration (0.8 h). The drug was excreted almost exclusively as the unchanged parent drug in the faeces.⁶

Current management follows a sequential approach, including bile acid sequestrants, rifampicin, opioid antagonists, and selective serotonin reuptake inhibitors. The clinical efficacy of these agents, however, continues to be variable and frequently incomplete. This is largely attributed to their indirect modulation of pruritogenic pathways. This is reinforced by a systematic review of current therapies for pruritus, which showed inconsistent efficacy, poor tolerance, and high rates of treatment failure in refractory cases.⁴

The Phase 2b GLIMMER trial evaluated Linerixibat across multiple doses over 12–16 weeks in PBC patients with pruritus. The primary endpoint was the change in Worst Itch Numerical Rating Scale (WI-NRS) score for worst daily itch at Week 16. This endpoint was not statistically significant in the intention-to-treat population. This underachievement was primarily due to a significant placebo response and the inclusion of patients with milder pruritus symptoms (which were less likely to improve); however, exploratory analyses provided meaningful evidence of efficacy. Itch reductions were dose-dependent, and improvements began as early as week 1 and continued for 8 weeks when the daily dose was doubled. In patients with moderate-to-severe pruritus at baseline, the 40 mg twice daily (BID) group showed statistically significant improvement compared with the placebo. Changes in biomarkers, including a decrease in total serum bile acids and fibroblast growth factor 19 (FGF-19), and an increase in C4, confirmed on-target IBAT inhibition and decreased bile acid reabsorption, further favouring twice-daily regimens.⁵ Further building on these observations, the GLISTEN Phase 3 trial randomly assigned 238 patients with PBC and moderate-to-severe pruritus to either Linerixibat 40 mg BID or placebo for 24 weeks at 115 locations across 19 countries. In this trial, Linerixibat showed a statistically significant and clinically meaningful decrease in WI-NRS pruritus scores compared with placebo (adjusted mean difference −0.72; P = 0.0013). Moreover, these improvements persisted over the course of the 24-week evaluation period. Secondary outcomes included improvements in the quality of life and reductions in sleep disruption. Consistent with the mechanism of action, the most frequently reported side effects were gastrointestinal, with diarrhoea occurring in 61% of patients treated with Linerixibat compared to 18% on placebo and abdominal pain occurring in 18% versus 3%. Seven percent of patients in the Linerixibat group had treatment discontinuations due to gastrointestinal effects.⁷ Table 1 summarizes key features of the GLIMMER (Phase 2b) and GLISTEN (Phase 3) trials of Linerixibat in PBC.

Table 1.

Comparison of key features between the GLIMMER (Phase 2b) and GLISTEN (Phase 3) trials of Linerixibat in PBC.

Parameter	GLIMMER (Phase 2b)	GLISTEN (Phase 3)
Design	Randomised, double-blind, placebo-controlled, dose-ranging	Randomised, double-blind, placebo-controlled
Population	PBC with pruritus (severity not specified)	PBC with moderate-to-severe pruritus
Sample size	Not specified (multiple dose arms)	238 patients across 115 sites, 19 countries
Duration	12–16 weeks	24 weeks
Primary endpoint	Change in WI-NRS score for worst daily itch at week 16. Primary endpoint was not met in the ITT population, largely due to placebo response.	Change in WI-NRS pruritus score over 24 weeks. Primary endpoint met (adjusted mean difference −0.72; P = 0.0013).
Key efficacy findings	Dose-dependent itch reduction; onset by week 1; significant benefit in the moderate-to-severe subgroup at 40 mg BID.	Significant, sustained pruritus reduction; improvements in sleep and quality of life.
Main adverse effect	Gastrointestinal (diarrhoea predominant)	Diarrhoea: 61% vs. 18% in placebo; abdominal pain: 18% vs. 3%; treatment discontinuation due to gastrointestinal effects: 7% in the Linerixibat group.

Abbreviations: BID, twice daily; ITT, intention-to-treat; PBC, primary biliary cholangitis; WI-NRS, Worst Itch Numerical Rating Scale.

As enterohepatic bile acid recirculation is increasingly recognized as a manageable therapeutic target, the IBAT inhibitor class continues to expand beyond Linerixibat in cholestatic liver conditions. Volixibat (Mirum Pharmaceuticals) is being assessed in two Phase 2b adaptive trials: the VANTAGE study in PBC-associated pruritus (NCT05050136) and the VISTAS study in patients with pruritus secondary to primary sclerosing cholangitis (PSC; NCT04663308), which reached its primary endpoint in May 2026. Maralixibat (Livmarli; Mirum Pharmaceuticals), an FDA-approved drug for Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), is currently being further evaluated in the Phase 3 EXPAND project (NCT06553768). This trial recently completed enrollment of patients aged six months and older with cholestatic pruritus refractory to existing therapies across a broader range of rare cholestatic liver diseases, with topline data anticipated in Q4 2026. Odevixibat (Bylvay, Ipsen), which is also approved for PFIC and Alagille syndrome, has demonstrated sustained reductions in severe pruritus and serum bile acid levels across both indications. Additional studies in other cholestatic liver diseases are ongoing.

PBC is a lifelong condition, and in many healthcare settings where structured follow-up is not routine, patients experiencing persistent diarrhoea may discontinue treatment without medical consultation. This concern is particularly relevant in lower-resource settings. While this challenge is not unique to Linerixibat, clinical efficacy depends on continued use, and even modest rates of unsupervised discontinuation could meaningfully reduce real-world effectiveness. When treatment is stopped, rising bile acid levels cause pruritus to return, and persistent pruritus may also contribute to worsening sleep quality. Beyond adherence, the 24-week duration of the GLISTEN trial, though appropriate for a Phase 3 registration study, leaves unanswered questions regarding the long-term impact of decades of colonic exposure to elevated bile acids on gastrointestinal mucosal health, particularly in a population that may already carry underlying gut vulnerability. These concerns do not diminish the value of Linerixibat; rather, they underscore the need for longer follow-up studies and post-marketing surveillance to consolidate and extend the current evidence base.

In conclusion, Linerixibat can be regarded as a promising drug for the treatment of pruritus in patients with PBC. The current treatments can provide temporary relief but not much improvement because the mode of action does not target the underlying cause, but the FDA approval of Linerixibat represents a paradigm shift towards pathophysiology-directed therapy. Linerixibat works by inhibiting enterohepatic bile acid recirculation, providing targeted, mechanism-based relief. Evidence from the GLIMMER and GLISTEN trials demonstrates clinically meaningful improvements in pruritus and quality of life, including sleep. Gastrointestinal tolerability, particularly diarrhoea, remains the primary barrier to sustained use and warrants proactive patient counselling. Future research should focus on longer-term safety data, the identification of predictive biomarkers for treatment response, and strategies to mitigate adverse effects to optimize real-world outcomes for the population that remains untreated.

Authors' contributions

Muhammad Hamza Ameer: Writing-original draft, Writing-review & editing, Project administration. Muhammad Areeb-ul-Haq: Conceptualization, Supervision, Project Administration, Writing-review & editing. Menahal Naeem: Conceptualization, Writing-original draft. Abeer Zia: Writing-original draft. Amna Siddique: Writing-original draft.

AI declaration

Claude (Anthropic, Claude Sonnet 4.6, claude.ai) was used solely to improve grammar and readability. All scientific content, interpretation, and final approval were performed by the authors.

Declaration of competing interest

The authors declare that there is no conflicts of interest.