LYNAVOY Film-coated tablet Ref.[116436] Active ingredients: Linerixibat

Linerixibat reduces total serum bile acids in healthy volunteers and PBC patients with cholestatic pruritus. In healthy volunteers, serum bile acids were reduced within 1 day of LYNAVOY treatment compared to placebo treatment. In Study 1, total serum bile acids were reduced from baseline over the 24-week treatment period in the LYNAVOY group when compared to the placebo group.

Due to the low systemic absorption of linerixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Following a single dose administration of 40 mg of linerixibat, concentrations of linerixibat in healthy volunteers were below the limit of quantification (10 pg/mL) in the majority of plasma samples. Following multiple doses of linerixibat ranging from 3 mg (0.08 times the approved recommended dose) twice daily to 90 mg (2.25 times the approved recommended dose) twice daily in healthy volunteers, the majority of plasma samples were below the limit of quantification (1,000 pg/mL).

Absorption

Linerixibat is minimally absorbed following oral administration and the absolute oral bioavailability of linerixibat is 0.05%. Following a single oral administration of linerixibat 40 mg in healthy adults under fasted conditions, median T_max was 4.5 hours and mean linerixibat (%CV) C_max and AUC_0-t were 31.1 pg/mL (173) and 105 h·pg/mL (419), respectively. Following multiple doses of LYNAVOY 40 mg twice daily in PBC patients with cholestatic pruritus, the mean linerixibat C_max (95% CI) was 922 pg/mL (347, 1,500).

Effect of Food

Concomitant administration of a high-fat meal with a single dose of linerixibat 40 mg oral tablets delayed median T_max from 4.5 hours to 8.0 hours and resulted in decreases of 21.9% and 33.7% in AUC_0-t and C_max, respectively, compared to administration under fasted conditions in healthy adults. Pharmacokinetic parameters in the food effect study were highly variable. The effect of food on the changes of systemic exposures to linerixibat is not clinically significant. Despite the lack of clinically important pharmacokinetic effects with food, LYNAVOY should be administered at least 30 minutes prior to food or beverage (other than water) to allow linerixibat to enter the gastrointestinal lumen prior to release of bile acids upon eating [see Dosage and Administration (2.1)].

Distribution

The in vitro plasma protein binding range of linerixibat was 71.0-76.4%.

Elimination

Following a single oral dose of linerixibat 90 mg (2.25 times the approved recommended dose) in healthy adults, the mean half-life (t_1/2) was 6.76 hours.

Metabolism

Following administration of oral radiolabeled linerixibat, no linerixibat metabolites were detected in plasma. Three minor oxidative metabolites were detected in feces, and each accounted for negligible radioactivity (<1%), demonstrating that linerixibat is minimally metabolized in humans.

Excretion

Following administration of oral radiolabeled linerixibat, approximately 97% of the dose was excreted in feces; approximately 0.04% of the dose was excreted in urine. More than 99% of fecal radioactivity was determined to be unchanged and unabsorbed linerixibat. Following intravenous administration of radiolabeled linerixibat, systemic linerixibat elimination was approximately 20% renal and 80% fecal.

Specific Populations

No clinically significant differences in changes of total serum bile acid concentrations were observed with linerixibat based on body weight, age, sex, or race (White, Black, or Asian).

Patients with Hepatic Impairment

Of 238 patients enrolled in Study 1, 25 (11%) patients were diagnosed with cirrhosis (F4, Child-Pugh A), out of which 13 (5%) patients received linerixibat treatment. A general trend of higher exposure of linerixibat was observed in patients with cirrhosis compared to patients without cirrhosis, although the number of patients was very small. In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B), the mean AUC_(0-∞) and C_max values were approximately 13-fold and 9.4-fold higher than matched healthy patients. The clinical significance of this increase is unknown. Pharmacokinetics of linerixibat have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Drug Interaction Studies

Effect of Bile Acid Binding Resins on Linerixibat: Approximately 78% to 95% of linerixibat was bound to cholestyramine and colesevelam in in vitro studies. Cholestyramine and colesevelam can potentially inhibit the effects of linerixibat on IBAT [see Drug Interactions (7.1)].

Effect of Linerixibat on Ursodeoxycholic Acid (UDCA): In a dose-ranging study, adult PBC patients received placebo or linerixibat dosages ranging from 20 mg once a day (0.25 times the recommended dosage) to 90 mg twice a day (2.25 times the recommended dosage) for 12 weeks. In this clinical trial, concomitant administration of UDCA and linerixibat had no effect on UDCA plasma concentrations but reduced concentrations of UDCA conjugates, glyco-UDCA and tauro-UDCA, at 12 weeks of therapy. The concentrations of UDCA conjugates, glyco-UDCA and tauro-UDCA, were reduced by 69% and 90%, respectively, in patients receiving concomitant administration of UDCA with linerixibat versus with placebo. However, concomitant administration of UDCA with linerixibat resulted in no clinically significant increases in ALP over 12 weeks of treatment.

In in vitro studies, linerixibat did not inhibit cytochrome P450 (CYP)s 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1, but was an inhibitor of CYP3A4. Due to the low fraction absorbed, an interaction is not likely. Linerixibat did not induce CYPs 1A2, 2B6, and 3A4.

In in vitro studies, linerixibat did not inhibit the transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and 3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion protein (MATE) 1 and 2K. In vitro studies suggest that there is a potential for linerixibat to inhibit organic anion transporter polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3). However, due to the low fraction absorbed, an interaction is not likely.

Carcinogenesis

Linerixibat was not tumorigenic in a 2-year oral carcinogenicity study in rats with oral administration of up to 1,000 mg/kg/day (approximately 3,900 times the recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice, no drug-related tumors were observed following administration of linerixibat up to 160 mg/kg/day.

Mutagenesis

Linerixibat was negative in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (rat bone marrow micronucleus) assays.

Impairment of Fertility

No effects on fertility or early embryonic development were observed in male and female rats treated orally with linerixibat up to 1,000 mg/kg/day.

The efficacy of LYNAVOY was evaluated in Study 1 (GLISTEN, NCT04950127), a 24-week, randomized, double-blind, placebo-controlled trial. The study included 238 adult patients, aged 30 to 80 years, with a confirmed diagnosis of PBC and presence of pruritus at baseline. Patients were randomized to LYNAVOY 40 mg orally twice daily (N=119) or placebo (N=119) for 24 weeks. At baseline, 97% of patients were receiving UDCA, and 47% of patients were receiving concomitant antipruritic drugs. Thirteen (11%) of LYNAVOY-treated and 12 (10%) of placebo-treated patients had compensated liver cirrhosis (F4, Child-Pugh A).

Baseline Demographics and Characteristics

The mean age of patients in Study 1 was 55.8 years (range 30 to 80); 95% were female, 62% were White, 30% were Asian, 3% were American Indian or Alaska Native, and <1% were Black. Twenty-three percent of patients were Hispanic or Latino.

Patients were excluded from the study if they had hepatic decompensation, chronic viral hepatitis, symptomatic cholelithiasis, active cholecystitis, primary sclerosing cholangitis, alcoholic liver disease, bariatric surgery with ileal bypass, clinically significant diarrhea, or severe renal impairment (eGFR <30 mL/min/1.73 m²).

Baseline liver tests are presented in Table 2.

Table 2. Baseline Liver Tests in Adults with PBC in Study 1:

^a IU/L = International Unit per Liter

Efficacy Assessments

Itch Severity

Patients rated their worst itch severity twice daily (in the morning and evening) using the 11-point Worst Itch Numeric Rating Scale (NRS), with possible scores ranging from 0 (no itching) to 10 (worst imaginable itching).

• The Worst Daily Itch Score was computed as the worst (highest) of the two scores recorded in a day.
• The Weekly Itch Score was computed as the average of the Worst Daily Itch Scores across the 7 days in a week.
• The Monthly Itch Score was computed as the worst (highest) Weekly Itch Score within a 4-week period. Patients were included in Study 1 if their Monthly Itch Score in the 4 weeks preceding randomization was 4 or greater. The mean (SD) Monthly Itch Score at baseline was 7.3 (1.5).

Sleep Interference

Sleep interference due to pruritus was assessed each morning using the 11-point Sleep Interference NRS, with possible scores ranging from 0 (did not interfere) to 10 (completely interfered).

• The Weekly Sleep Score was computed as the average of the daily sleep scores recorded over the 7 days in a week.
• The Monthly Sleep Score was computed as the worst (highest) Weekly Sleep Score within a 4-week period.

The mean (SD) Monthly Sleep Score at baseline was 6.3 (2.4).

Efficacy Results

Worst Itch Severity

Table 3 presents the efficacy results for LYNAVOY and placebo treatment groups, based on the primary endpoint of change from baseline in Monthly Itch Score over 24 weeks. Patients who received LYNAVOY demonstrated a greater improvement from baseline in pruritus compared with placebo over 24 weeks of treatment.

Table 3. Efficacy Results for Monthly Itch Scorea in Adults with PBC Over 24 Weeks in Study 1:

SD = Standard Deviation, LS = Least Squares; SE = Standard Error; CI = Confidence Interval.
^a The Monthly Itch Score was computed as the worst (highest) Weekly Itch Score within a 4-week period.
^b Based on least squares means from a mixed-effect model for repeated measures with terms for treatment, visit, treatment by visit interaction, baseline itch, baseline itch by visit interaction, and use of baseline concomitant itch medication.

There was greater improvement from baseline in pruritus measured by weekly itch score at Week 2 for patients who received LYNAVOY compared with placebo (LS mean difference -0.71 [-1.07, -0.34], p-value<0.001).

Pruritus-Related Sleep Interference

Table 4 presents the efficacy results for LYNAVOY and placebo treatment groups based on the secondary endpoint, change from baseline in Monthly Sleep Score over 24 weeks. Patients who received LYNAVOY demonstrated greater improvement in pruritus-related sleep interference compared with placebo over 24 weeks of treatment.

Table 4. Efficacy Results for Monthly Sleep Score in Adults with PBC Over 24 Weeks in Study 1:

p-value = 0.024
SD = Standard Deviation; LS = Least Squares; SE = Standard Error; CI = Confidence Interval
^a Based on least squares mean from a mixed-effects model for repeated measures for change from baseline in Monthly Sleep 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.