LYNAVOY Film-coated tablet Ref.[117086] Active ingredients: Linerixibat

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy
ATC code: A05AX08

Mechanism of action

Linerixibat is a locally acting, minimally absorbed reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids in the ileum leading to increased faecal elimination. Linerixibat improves pruritus in PBC patients which is assumed to be due to a decrease in mediators of pruritus including serum bile acids, lysophosphatidic acid (LPA) [via measurement of autotaxin as a surrogate] and interleukin 31 (IL-31).

Pharmacodynamic effects

Linerixibat reduces total serum bile acids in healthy volunteers and patients with cholestatic pruritus in PBC. In healthy volunteers, serum bile acids were reduced within 1 day of treatment with linerixibat compared to placebo treatment.

Clinical efficacy

The efficacy and safety of linerixibat in the treatment of cholestatic pruritus in patients with PBC were evaluated in a randomised, double-blind, placebo-controlled, multicentre, global Phase 3 study, GLISTEN. Patients (N=238) were randomised to Lynavoy 40 mg twice daily (N=119) or placebo (N=119) for 24 weeks. Seventeen patients who participated remotely (fully decentralised site) were not included in the efficacy analyses (Lynavoy N=111, placebo N=110). One patient randomised to placebo withdrew before initiating treatment.

Eligible patients had a confirmed diagnosis of PBC and moderate or severe pruritus (assessed by the Worst Itch Numerical Rating Scale [Worst Itch NRS] in the 4 weeks prior to randomisation. Patients who were on stable UDCA, fibrates, bile acid binding resins or other antipruritic therapy at baseline were eligible to enrol and to continue their PBC and/or pruritus treatment regimen unchanged throughout the duration of the study. Exclusion criteria included hepatic decompensation, chronic viral hepatitis, symptomatic cholelithiasis, active cholecystitis, primary sclerosing cholangitis, alcoholic liver disease, current malignancies, active inflammatory ileal disease, bariatric surgery with ileal bypass, skin disorders with itch, clinically significant diarrhoea, severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) and treatment with obeticholic acid (OCA).

The mean age of patients was 55.5 years (range 30 to 80), 95% were female, 56% were Caucasian. The mean (range) ALP at baseline was 234 IU/L (46.5-1102): 24% of subjects were ≤1 times the upper limit of normal (x ULN), 28% were >1 x ULN and <1.67 x ULN, and 48% were ≥1.67 x ULN. Mean (SD) baseline itch severity was 7.4 (1.5) based on Worst Itch NRS with 41% categorized as having moderate itch and 59% as having severe itch. At baseline 97% of patients were receiving UDCA. A total of 43% of patients randomised to linerixibat and 48% randomised to placebo were receiving concomitant fibrates, selective serotonin reuptake inhibitors, bile acid binding resins, gabapentin, antihistamines, opiate antagonists, rifampicin and/or pregabalin which could impact itch.

Worst Itch NRS Scores

In GLISTEN, linerixibat demonstrated a significant improvement from baseline in pruritus compared with placebo over 24 weeks of treatment (primary endpoint) as shown in Table 2.

Table 2. Change from baseline in worst itch NRS score^a over 24 weeks:

SD = standard deviation; LS = least squares; CI = confidence interval
^a Worst Itch NRS: 0 = no itching to 10 = worst imaginable itching.
^b Baseline determined from all placebo patients, n=110
^c Based on a least squares mean from a mixed-effect model for repeated measures (MMRM) for change from baseline in Monthly Itch Score over the 24-week period with terms for treatment, visit, treatment by visit interaction, baseline itch, baseline itch by visit interaction, and use of baseline concomitant itch medication.

Change from baseline in weekly itch scores through Week 24 are shown in Figure 1. There was significant improvement in pruritus by Week 2 based on the Worst Itch NRS (Weekly Itch Score) for the linerixibat treatment group compared with placebo (LS mean difference -0.69 [95% CI: -1.06, -0.31], p<0.001).

Figure 1. Mean treatment group change from baseline in worst itch NRS score through Week 24:

Itch responders

A higher proportion of patients randomised to linerixibat compared with placebo achieved a clinically meaningful itch response at Week 24 when defined as an improvement of ≥2-, ≥3-, or ≥4-points from baseline in the Worst Itch NRS Score (Table 3).

Table 3. Analysis for difference in itch responder rates at Week 24:

^a Based on Cochran-Mantel-Haenszel (CMH) stratified analysis adjusting for baseline stratification factors (Baseline Itch Severity and concomitant cholestatic pruritus treatment regimen). Combined results from multiple imputation.
^b The lower limit of the 95% CI represents a rounded value of -0.2%
^c The lower limit of the 95% CI represents a rounded value of 0.4%

Pruritus-related sleep interference

Patients randomised to linerixibat had significantly improved pruritus-related sleep interference compared with placebo over 24 weeks of treatment (-2.70 linerixibat vs -2.16 placebo; LS mean difference -0.54 [95% CI: -1.02, -0.06], p=0.027).

Additional pruritus-related assessments

At baseline, patients randomised to both linerixibat and placebo reported similar levels of pruritus severity based on the Patient Global Impression of Severity (PGI-S) item (recall: past 7 days; score range: 1 [absent] to 5 [very severe]). Treatment with linerixibat resulted in more improvement in the PGI-S score when compared to placebo over 24 weeks (LS mean change from baseline -1.17 vs. -0.80; LS mean difference -0.37 [95% CI: -0.55, -0.18]). At Week 24, a larger proportion of the linerixibat group (66%) compared to placebo (48%) reported 'absent' or 'mild' itch.

Patients randomised to linerixibat reported more itch improvement over 24 weeks compared to placebo as measured by Patient Global Impression of Change (PGI-C) scores (range: 1 [very much improved] to 7 [very much worse]) (LS mean 1.97 vs. 2.51; LS mean difference -0.53 [95% CI: -0.81, -0.25]). At Week 24, a larger proportion of the linerixibat group (54%) compared to placebo (36%) reported itch severity to be 'very much improved', and a larger proportion of patients in the placebo group (26%) reported 'no change' compared to the linerixibat group (3%).

Maintenance of efficacy

In the open label, long term extension study (LLSAT), the majority of responders following 24 weeks of linerixibat treatment maintained their response at Week 52: 72.7% of those with ≥2-point response, 80.8% with a ≥3-point response and 81.8% with a ≥4-point response.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Lynavoy in all subsets of the paediatric population in the treatment of cholestatic pruritus with PBC (see section 4.2 for information on paediatric use).