Livmarli maralixibat chloride 20 mg Tablet, 30-count — NDC 79378-220-30 (Billing 79378-0220-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Maralixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum . Pruritus is a common symptom in patients with ALGS or PFIC and the pathophysiology of pruritus in patients with ALGS or PFIC is not completely understood.

Although the complete mechanism by which maralixibat improves pruritus in ALGS or PFIC patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids [see Clinical Pharmacology (12.2) ] .

12.2Pharmacodynamics ALGS In Trial 1, pediatric patients with ALGS were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period [see Clinical Studies (14.1) ] . At baseline, serum bile acids were highly variable among patients ranging from 20 to 749 µmol/L and mean (SD) serum bile acid level was 283 (210.6) µmol/L. Serum bile acid levels decreased from baseline in the majority of patients as early as at Week 12 and the reduction in serum bile acids was generally maintained for the treatment period.

PFIC In Trial 2, pediatric patients with PFIC were administered LIVMARLI 570 mcg/kg or placebo twice daily for up to 22 weeks after an initial 4–6-week dose escalation period [see Clinical Studies (14.2) ] . At baseline, serum bile acids concentrations were highly variable among patients ranging from 4 to 504 µmol/L and mean (SD) serum bile acid level was 253 (136) µmol/L. Serum bile acid concentrations decreased from baseline in the majority of patients as early as at Week 2; while the concentrations fluctuated, the reduction in serum bile acids was generally maintained for the treatment period.

12.3Pharmacokinetics Because of the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Concentrations of maralixibat in the pediatric ALGS and PFIC patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples. Following single dose administration of maralixibat oral solution in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated.

Following single dose administration of 30 mg maralixibat oral solution under fasted condition, median Tmax was 0.75 hour and mean (SD) Cmax and AUClast were 1.65 (1.10) ng/mL and 3.43 (2.13) ng·h/mL, respectively. Absorption Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Oral Solution : Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg.

No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once-daily. Tablet: After a single 100 mg dose of maralixibat tablet under fasted condition, mean (SD) AUCinf and Cmax were 13.2 (8.2) ng·h/mL and 3.0 (2.2) ng/mL, respectively. Following a single dose of maralixibat oral solution (99.75 mg) under the same conditions, mean (SD) AUCinf and Cmax were 18.4 (13.2) ng·h/mL and 4.3 (2.7) ng/mL, respectively.

Given the local site of action of maralixibat, the slightly lower exposure afforded by the tablet compared to the oral solution is not clinically meaningful. Effect of Food Concomitant administration of a high-fat meal with a single dose of maralixibat oral solution decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state w… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Maralixibat is a reversible inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids (primarily the salt forms) from the terminal ileum . Pruritus is a common symptom in patients with ALGS or PFIC and the pathophysiology of pruritus in patients with ALGS or PFIC is not completely understood.

Although the complete mechanism by which maralixibat improves pruritus in ALGS or PFIC patients is unknown, it may involve inhibition of the IBAT, which results in decreased reuptake of bile salts, as observed by a decrease in serum bile acids [see Clinical Pharmacology (12.2) ] .

12.3Pharmacokinetics Because of the low systemic absorption of maralixibat, pharmacokinetic parameters cannot be reliably calculated at the recommended doses. Concentrations of maralixibat in the pediatric ALGS and PFIC patients were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples. Following single dose administration of maralixibat oral solution in healthy adults at doses ranging from 1 mg to 500 mg, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg and PK parameters could not be reliably estimated.

Following single dose administration of 30 mg maralixibat oral solution under fasted condition, median Tmax was 0.75 hour and mean (SD) Cmax and AUClast were 1.65 (1.10) ng/mL and 3.43 (2.13) ng·h/mL, respectively. Absorption Maralixibat is minimally absorbed and plasma concentrations are often below the limit of quantification (0.25 ng/mL) after single or multiple doses at recommended doses. Oral Solution : Following a single oral administration of maralixibat 30, 45, and 100 mg liquid formulation under fasted condition, AUClast and Cmax increased in a dose-dependent manner with increase of 4.6-and 2.4-fold, respectively, following a 3.3-fold dose increase from 30 to 100 mg.

No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once-daily. Tablet: After a single 100 mg dose of maralixibat tablet under fasted condition, mean (SD) AUCinf and Cmax were 13.2 (8.2) ng·h/mL and 3.0 (2.2) ng/mL, respectively. Following a single dose of maralixibat oral solution (99.75 mg) under the same conditions, mean (SD) AUCinf and Cmax were 18.4 (13.2) ng·h/mL and 4.3 (2.7) ng/mL, respectively.

Given the local site of action of maralixibat, the slightly lower exposure afforded by the tablet compared to the oral solution is not clinically meaningful. Effect of Food Concomitant administration of a high-fat meal with a single dose of maralixibat oral solution decreased both the rate and extent of absorption. AUC and Cmax of maralixibat values in the fed state were 64.8% to 85.8% lower relative to oral administration of 30 mg in fasted conditions.

The effect of food on the changes of systemic exposures to maralixibat is not clinically significant [see Dosage and Administration (2.1 , 2.3 )] . Distribution Maralixibat shows high binding (91%) to human plasma proteins in vitro. Elimination Following a single dose of 30 mg maralixibat oral solution in healthy adults, the mean half-life (t 1/2 ) was 1.6 hours.

Metabolism No maralixibat metabolites have been detected in plasma. Three minor metabolites, accounting for <3% of maralixibat-associated fecal radioactivity in total, were identified following administration of [ 14 C]maralixibat as an oral solution. Excretion Fecal excretion was found to be the major route of elimination.

Following a single dose of 5 mg 14 C-maralixibat as an oral solution, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. 94% of the fecal excretion was as unchanged maralixibat. Specific Populations Patients with Renal Impairment The pharmacokinetics of maralixibat were not studied in patients with impaired renal function, including those with end-stage renal disease (ESRD) or those on hemodialysis.

Drug Interaction Studies Effect of Other Drugs on Maralixibat Maralixibat is not a substrate of the drug transporters MDR1 (P-gp), BCRP, OATP1B1, OATP1B3, or OATP2B2; therefore, concomitant drug products are not predicted to affect the disposition of maralixibat. Effect of Maralixibat on Other Drugs In vitro, maralixibat did not induce CYP isoforms 1A2, 2B6, or 3A4, nor inhibit CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19 or 2D6 at clinically relevant concentrations. Maralixibat inhibits CYP3A4 in vitro, however clinically relevant effects on the pharmacokinetics of CYP3A4 substrates are unlikely.

In vitro, maralixibat did not inhibit the… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics ALGS In Trial 1, pediatric patients with ALGS were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period [see Clinical Studies (14.1) ] . At baseline, serum bile acids were highly variable among patients ranging from 20 to 749 µmol/L and mean (SD) serum bile acid level was 283 (210.6) µmol/L. Serum bile acid levels decreased from baseline in the majority of patients as early as at Week 12 and the reduction in serum bile acids was generally maintained for the treatment period.

PFIC In Trial 2, pediatric patients with PFIC were administered LIVMARLI 570 mcg/kg or placebo twice daily for up to 22 weeks after an initial 4–6-week dose escalation period [see Clinical Studies (14.2) ] . At baseline, serum bile acids concentrations were highly variable among patients ranging from 4 to 504 µmol/L and mean (SD) serum bile acid level was 253 (136) µmol/L. Serum bile acid concentrations decreased from baseline in the majority of patients as early as at Week 2; while the concentrations fluctuated, the reduction in serum bile acids was generally maintained for the treatment period.

14 CLINICAL STUDIES

14.1Alagille Syndrome The efficacy of LIVMARLI was assessed in Trial 1 (NCT02160782), which consisted of an 18-week open-label treatment period; a 4-week randomized, double-blind, placebo-controlled drug-withdrawal period; a subsequent 26-week open-label treatment period; and a long-term open-label extension period. Thirty-one pediatric ALGS patients with cholestasis and pruritus were enrolled, with 90.3% of patients receiving at least one medication to treat pruritus at study entry. All patients had JAGGED1 mutation.

Patients were administered open-label treatment with LIVMARLI 380 mcg/kg once daily for 13 weeks after an initial 5-week dose-escalation period; two patients discontinued treatment during this first 18 weeks of open-label treatment. The 29 patients who completed the open-label treatment phase were then randomized to continue treatment with LIVMARLI or receive matching placebo during the 4-week drug withdrawal period at Weeks 19-22 (n=16 placebo, n=13 LIVMARLI). All 29 patients completed the randomized, blinded drug withdrawal period; subsequently, patients received open-label LIVMARLI at 380 mcg/kg once daily for an additional 26 weeks.

Randomized patients had a median age of 5 years (range: 1 to 15 years) and 66% were male. The baseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid levels 280 (213) µmol/L, AST 158 (68) U/L, ALT 179 (112) U/L, Gamma Glutamyl Transferase (GGT) 498 (399) U/L, and TB 5.6 (5.4) mg/dL. Given the patients’ young age, a single-item observer-reported outcome was used to measure patients’ pruritus symptoms as observed by their caregiver twice daily (once in the morning and once in the evening) on the Itch Reported Outcome Instrument (ItchRO[Obs]).

Pruritus symptoms were assessed on a 5-point ordinal response scale, with scores ranging from 0 (none observed or reported) to 4 (very severe). Patients were included in Trial 1 if their average pruritus score was greater than 2.0 (moderate) in the 2 weeks prior to baseline. The average of the worst daily ItchRO(Obs) pruritus scores was computed for each week.

For randomized patients, the mean (SD) at baseline (pre-treatment) was 3.1 (0.5) and the mean (SD) at Week 18 (pre-randomized withdrawal period) was 1.4 (0.9). On average, patients administered LIVMARLI for 22 weeks maintained pruritus reduction whereas those in the placebo group who were withdrawn from LIVMARLI after Week 18 returned to baseline pruritus scores by Week 22. Results from the placebo-controlled period are presented in Table 7 .

After re-entering the open-label treatment phase, both randomized treatment groups had similar mean pruritus scores by Week 28, the first week placebo patients received the full dosage of LIVMARLI after withdrawal. These observer-rated pruritus results are supported by similar results on patient-rated pruritus in patients 5 years of age and older who were able to self-report their itching severity. Table 7: Weekly Average of Worst Daily ItchRO(Obs) Pruritus Severity Scores in Trial 1 Results based on an analysis of covariance model with treatment group and Week 18 average worst daily pruritus score as covariates Maralixibat (N=13) Placebo (N=16) Mean Difference Week 22, Mean (95% CI) 1.6 (1.1, 2.1) 3.0 (2.6, 3.5) Change from Week 18 to Week 22, Mean (95% CI) 0.2 (-0.3, 0.7) 1.6 (1.2, 2.1) -1.4 (-2.1, -0.8)

14.2Progressive Familial Intrahepatic Cholestasis The efficacy of LIVMARLI was assessed in Trial 2 (NCT03905330), a 26-week randomized, placebo-controlled trial. Efficacy was evaluated in 64 patients with documented molecular diagnosis of PFIC with presence of biallelic known pathogenic variants; this included 31 non-truncated PFIC2 patients (i.e., excluding patients with BSEP3) and 33 patients with PFIC1 (n=13), PFIC3 (n=9), PFIC4 (n=7), or PFIC6 (n=4) [see Clinical Pharmacology (12.5) ] . Additional patients with BSEP3 (n=9), prior surgical diversion (n=8), heterozygous subjects (n=2… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Maralixibat chloride was not tumorigenic in a 2-year oral carcinogenicity study in rats with administration of up to 100 mg/kg/day (approximately 233 to 870 times the maximum recommended dose based on AUC). In a 26-week oral carcinogenicity study in TgRasH2 mice with doses of up to 25 (males) or 75 (females) mg/kg/day, no drug-related tumors were observed following administration of maralixibat chloride. Mutagenesis Maralixibat chloride 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 were observed in female rats treated orally with up to 2000 mg/kg/day or in male rats treated orally with up to 750 mg/kg/day.