Summary Basis of Decision (SBD) for Livmarli

As outlined in the What steps led to the approval of Livmarli? section, the clinical pharmacology review of the New Drug Submission for Livmarli was conducted as per Method 3 and the clinical safety and efficacy review of the New Drug Submission for Livmarli was conducted as per Method 4 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Maralixibat, the medicinal ingredient in Livmarli, is an inhibitor of the ileal bile acid transporter (IBAT). It decreases the reabsorption of bile acids from the terminal ileum. Due to its large molecular weight (710 Da) with the presence of a positively charged quaternary nitrogen atom and the location of its pharmacological target (the lumen of the gastrointestinal tract), plasma levels are not required or relevant to the efficacy of maralixibat.

Pruritus is a common symptom in patients with Alagille syndrome (ALGS) and elevations in serum bile acids have been strongly linked to cholestatic pruritus. Maralixibat improves pruritus in patients with ALGS, likely through decreasing the level of serum bile acids.

Pharmacokinetic parameters cannot be reliably evaluated at the recommended dose due to the low systemic absorption of maralixibat. Concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) in the majority of plasma samples from pediatric patients with ALGS. In the pivotal study, ICONIC (Trial 304, described in the Clinical Efficacy section), the highest concentration of maralixibat detected in pediatric patients with ALGS was 5.93 ng/mL following treatment with a 380 μg/kg once daily dose of maralixibat. When single oral doses ranging from 1 mg to 500 mg were administered to healthy adults, plasma concentrations of maralixibat were below the limit of quantification (0.25 ng/mL) at doses less than 20 mg, and pharmacokinetic parameters could not be reliably estimated.

When detectable, the time to maximum plasma concentrations (T_max) were observed on average 0.75 hr after dosing. Exposure as measured by the area under the concentration-time curve from dosing time (time 0) to the time of the last measurable concentration (AUC_last) and the maximum plasma concentration (C_max) increased in a dose-dependent manner following single oral administration of maralixibat at doses of 30 mg, 45 mg, and 100 mg (liquid formulation) under fasted conditions. No accumulation of maralixibat was observed following repeated oral administration of maralixibat in healthy adults at doses up to 100 mg once daily.

Maralixibat showed high binding (91%) to human plasma proteins in vitro, and was independent of concentration over the range of 0.025 to 25 µg/mL.

No metabolites of maralixibat have been detected in plasma. Three minor metabolites, together accounting for less than 3% of maralixibat-associated radioactivity detected in feces, were identified following oral administration of [¹⁴C]-maralixibat.

Following a single oral dose of 30 mg maralixibat in healthy adults, the mean half-life (t_1/2) was 1.6 hours. Fecal excretion was found to be the major route of elimination. Following a single oral dose of 5 mg [¹⁴C]-maralixibat, 73% of the dose was excreted in the feces with 0.066% excreted in the urine. Unchanged maralixibat accounted for 94% of the fecal excretion.

The pharmacokinetics of maralixibat has not been systematically investigated in patients with decompensated liver disease or cirrhosis. In clinical trials, patients with ALGS routinely have abnormal liver laboratory values, including elevated total bilirubin levels. Because maralixibat acts locally in the ileum and has low systemic absorption, the potential change in systemic exposure to maralixibat due to hepatic impairment is not expected to be clinically significant. Nevertheless, additional monitoring for adverse events in patients with hepatic impairment is included in the labelling.

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. Given the limited systemic absorption and negligible renal excretion of maralixibat in a mass balance study, renal impairment is not expected to have a clinically relevant effect on the systemic exposure to maralixibat. As a result, dose adjustment in patients with renal impairment is not necessary.

In vitro studies indicate that maralixibat is an inhibitor of organic anion transporting polypeptide (OATP) 2B1. Drug interactions in the gastrointestinal tract are plausible, and therefore a decrease in the oral absorption of OATP 2B1 substrates due to OATP 2B1 inhibition in the gastrointestinal tract cannot be ruled out. In clinical studies, coadministration of 4.75 mg maralixibat (once daily in the morning) with daily doses of either simvastatin, or lovastatin in the evening, (both substrates of OATP 2B1) did not have a clinically relevant effect on the pharmacokinetics of these statins and their metabolites. Coadministration of 4.75 mg maralixibat did not affect the pharmacokinetics of atorvastatin (also a substrate of OATP 2B1). However, the effect of maralixibat on the pharmacokinetics of OATP2B1 substrates at higher doses has not been evaluated in a clinical study. The Livmarli Product Monograph addresses the theoretical risk of interaction of maralixibat with OATP 2B1 substrates.

For further details, please refer to the Livmarli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Livmarli was evaluated in patients 12 months of age and older with ALGS in the pivotal clinical study, Study 304 (ICONIC study; LUM001-304). This study consisted of three phases: an initial 18-week open-label study phase, a 4-week double-blind, placebo-controlled, randomised drug withdrawal (RDW) phase, and a 26-week open-label phase in which all patients were treated with Livmarli (until Week 48 of the study). Afterwards, all patients were offered continued study participation in an open-label long-term treatment extension phase. The general maintenance dose of maralixibat used was 400 µg/kg once daily of maralixibat as maralixibat chloride, equivalent to 380 µg/kg of maralixibat base once daily.

Thirty-one pediatric patients with ALGS were enrolled in this study. All patients were 12 months of age and older and had cholestasis and pruritus, with 90.3% of patients receiving at least one background medication at a stable dose to treat pruritus at study entry. Patients were administered open-label treatment with 380 µg/kg Livmarli once daily for 13 weeks after an initial 5-week dose escalation period. Two patients discontinued study treatment during the first 18 weeks of open-label treatment. Twenty-nine patients entered the 4‑week RDW phase (Weeks 19-22), with 13 patients treated with Livmarli and 16 patients receiving placebo. All 29 patients continued in the open-label phase until Week 48, with all patients receiving treatment with Livmarli. Twenty-three patients continued on to the long-term extension phase until at least Week 252 overall.

The primary endpoint of this study was the change in the level of serum bile acids (sBA) during the 4-week RDW phase (from Week 18 to Week 22) in patients who were considered to be responders. Responders were defined as patients achieving a reduction in sBA level of 50% or greater at either Week 12 or Week 18 (during the initial open-label phase of the study). Of the 29 patients that entered the RDW phase of the study, 15 patients were found to be responders, 5 of whom were subsequently randomized to Livmarli and 10 of whom were subsequently randomized to placebo. From Week 18 to Week 22, the mean difference in sBA levels was a decrease of 117.28 μmol/L (p = 0.046), in favour of Livmarli compared to placebo. At baseline, the mean sBA level in the overall study population (31 patients) was 283.4 μmol/L. The intent-to-treat (ITT) population consisted of all 29 patients who entered the RDW phase of the study (13 patients randomized to Livmarli and 16 patients randomized to placebo). A difference of 113.95 μmol/L (nominal p = 0.025) was observed between the groups, in favour of patients treated with Livmarli compared to patients who received placebo. In the overall ITT population, significant mean decreases from baseline were also noted in sBA levels during both open-label phases of the study when all patients were treated with Livmarli. A mean decrease of 87.73 μmol/L (nominal p = 0.0005) was observed from study entry to Week 18 (29 patients), and a mean decrease of 96.44 μmol/L (nominal p = 0.006) was observed leading up to Week 48 (27 patients).

Several pruritus scores were evaluated at multiple time points for all patients in the ITT population, including the Itch Reported Outcome-Observer (ItchRO[Obs]), Itch Reported Outcome-Patient (ItchRO[Pt]), and the Clinician Scratch Score (CSS). Statistical analyses of the secondary endpoints, including those related to pruritus, were not adjusted for multiplicity. Therefore, the statistical findings and p-values from the secondary endpoints are considered nominal.

The sponsor designed the ItchRO(Obs) and ItchRO(Pt) tools specifically for use in the clinical development of Livmarli for the treatment of pruritus in patients with ALGS and other pediatric cholestatic liver diseases. The sponsor also validated these tools, with a clinically relevant response determined to be equivalent to a reduction of at least 1.0 points on the 4-point scale. At the end of the initial 18-week open-label study phase, a reduction of 1.70 (95% confidence interval [CI]: 2.05, ‑1.36; nominal p<0.0001) relative to baseline was observed in the mean weekly average morning ItchRO(Obs) severity score in the ITT population with Livmarli treatment. This signifies a reduction of approximately 60% at Week 18 and is considered a clinically relevant improvement in pruritus. At Week 22 (after the 4-week RDW phase of the study) a difference of ‑1.48 (nominal p<0.0001) was observed between the two groups, in favour of Livmarli over placebo. At Week 48 (during the second open-label phase, in which all patients were treated with Livmarli), a reduction of 1.62 (nominal p<0.0001) relative to baseline was observed in the mean weekly average morning ItchRO(Obs) severity score. Consistent with improvement in pruritus, decreases from baseline in the mean weekly average morning ItchRO(Obs) severity score were observed in the ITT population with Livmarli treatment at each evaluable analysis visit during the entire observation period up to Week 240. Other efficacy analyses, such as changes in mean weekly average daily maximum ItchRO(Obs) severity scores, mean weekly average morning ItchRO(Pt) severity scores, mean weekly average daily maximum ItchRO(Pt) scores, and the Clinical Scratch Score (CSS) were consistently supportive of the results of the weekly average morning ItchRO(Obs) severity scores over various time points.

A summary of an interim report of the ongoing study, MRX-801, was included in the submission to support the inclusion of patients 2 to 12 months of age. This study includes 2 cohorts: patients with ALGS and patients with another pediatric cholestatic disease. The report was limited to 6 patients with ALGS in whom Livmarli was administered for more than 13 weeks, and provided only limited quantification of the effects of Livmarli. No results were presented for the patients with the other cholestatic disease. The data were not sufficient to establish safety and efficacy in these patients, but did not identify any additional safety concerns that were not identified in the pivotal study. Further, the pathophysiology and the mechanism of action of the drug is expected to be the same in this patient population (2 to 12 months of age). Given the substantial unmet medical need for effective treatment of pruritus in patients with ALGS 2 to 12 months of age, the rarity of this disease, and the demonstrated benefits of maralixibat in patients with ALGS over the age of 12 months, the indication stated in the Product Monograph (without an age range, but with qualifiers in the pediatric indication section) was considered to be acceptable. The sponsor has also committed to submitting the full study report of Study MRX-801 to Health Canada when available.

Livmarli may be used in adults. Due to the rarity of ALGS in adults, no adult patients were included in the pivotal study. Approximately 25% of patients survive to adulthood with their native liver. The pathophysiology and mechanism of action of maralixibat are expected to be the same in adult patients as in the pediatric patients assessed in the pivotal study. However, the long-term effects of Livmarli are unknown.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Livmarli (maralixibat) oral solution is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) 2 months of age and older.	Livmarli (maralixibat oral solution) is indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS).

Along with the revised indication, Health Canada has provided further guidance regarding the use of Livmarli in pediatric patients. Health Canada has authorized an indication for pediatric use. In patients 12 months to 18 years of age, the safety and efficacy of Livmarli have been established based on the data reviewed by Health Canada. However, in patients less than 12 months of age, safety and efficacy have not been established.

For more information, refer to the Livmarli Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety data submitted to Health Canada included data from 86 patients with ALGS aged one year and older, who were treated with Livmarli across three placebo-controlled studies and two open-label long-term extension studies. However, only the pivotal ICONIC study (Trial 304) described in the Clinical Efficacy section adequately assessed the recommended dose of Livmarli (380 μg/kg/day of maralixibat base, given as 400 μg/kg/day of maralixibat chloride). In the ICONIC study, the mean duration of exposure to Livmarli was approximately 1,030 days, with the median treatment exposure being 714 days.

The most common adverse events reported in any phase of the ICONIC study were gastrointestinal disorders. In the initial 18-week open-label study phase, gastrointestinal adverse events were reported in 67.7% of participants, with diarrhea (41.9%) being the most common, followed by abdominal pain (38.7%) and vomiting (35.5%). However, during the 4-week RDW phase that followed, gastrointestinal disorders were reported less frequently in the group treated with Livmarli (15.4%), compared to the placebo group (18.8%). Abdominal pain, diarrhea, and vomiting were each reported by a single participant treated with Livmarli (7.7%) in the RDW phase, as well as by a single participant who received placebo (6.3%). After the RDW study phase (i.e., following Week 22), all study participants received Livmarli. During this study phase, the overall proportion of participants with gastrointestinal adverse events (69.0%) was similar to the reported incidence of gastrointestinal adverse events in the initial 18‑week open-label study phase (67.7%). However, during the open-label long-term extension phase (after Week 22), gastrointestinal adverse events were reported more frequently in the 15 patients who received doses of Livmarli exceeding 400 µg/kg once daily (80.0%) than the 14 patients who received doses no higher than 400 µg/kg once daily (57.1%). Although this observed difference appeared to be meaningful, the duration of treatment for patients receiving doses exceeding 400 μg/kg was longer than those receiving doses no higher than 400 μg/kg. There appeared to be no predisposition to the increased occurrence of any individual line entry adverse event (such as abdominal pain, diarrhea, and vomiting) over that study time period. Overall, the majority of adverse events of diarrhea were reported to be mild to moderate in intensity. Only 3 study participants reported experiencing serious adverse events (SAE) related to diarrhea, one of which was assessed as related to the study drug by the sponsor. Some reported adverse events were considered related to fat-soluble vitamin deficiency, the majority of which were considered mild or moderate in severity. It remains unclear whether these adverse events are related to Livmarli, since they are known to be associated with the underlying hepatic disease of ALGS. Headaches were reported at an incidence of >10% with use of maralixibat in both the initial open-label and post-RDW open-label study phases.

In the RDW phase of the ICONIC study, no imbalances in SAE were noted between patients who received Livmarli and those who received placebo. Throughout the entire study, none of the observed SAE were considered to be treatment‑related, and no deaths were reported. Serious gastrointestinal adverse events were reported in 9.3% of patients overall, of which 5.8% consisted of diarrhea, abdominal pain or vomiting, while 3.5% were related to gastrointestinal bleeding. Adverse events led to permanent treatment discontinuation in six patients, with increases in either bilirubin or alanine transaminase (ALT) levels as the cause of permanent discontinuation in three of these patients. However, it remains unclear whether the observed increases in hepatic biomarkers (bilirubin and ALT levels) were caused by Livmarli. At baseline, all patients had elevated levels of hepatic biomarkers due to underlying hepatic disease, and no study participants were reported to experience SAE associated with elevated levels of serum transaminases.

Overall, the adverse events found to be associated with Livmarli were gastrointestinal events, particularly diarrhea and abdominal pain. They were generally mild to moderate in severity and self-limited in nature.

For more information, refer to the Livmarli Product Monograph, approved by Health Canada and available through the Drug Product Database.

As outlined in the What steps led to the approval of Livmarli? section, the review of the non-clinical component of the New Drug Submission for Livmarli was conducted using Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

In vitro pharmacodynamic studies were conducted in cells transfected with the human ileal bile acid transporter (IBAT) to measure the potency and specificity of maralixibat against its target, and in vivo pharmacodynamic studies were conducted to document the pharmacological effects of IBAT inhibition by maralixibat in mice, rats, dogs, and monkeys. Maralixibat was found to be a potent inhibitor of the human IBAT. The large increases in fecal bile acids and decreases in serum bile acids across species indicate the potency and mechanism of action of maralixibat in vivo.

The most significant toxicological effect in rodents was the reversible prolongation of coagulation times, which was observed primarily in male rats. Emesis was the primary sign of toxicity observed in the dog at doses above 200 mg/kg. These toxicological findings occur at high doses, with large safety margins to therapeutic doses in humans.

In a 26‑week carcinogenicity study in TgRasH2 transgenic mice, no drug-related tumours were observed following the oral administration of maralixibat chloride to at doses of up to 25 mg/kg/day (males) or 75 mg/kg/day (females).

Maralixibat chloride did not demonstrate evidence of genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.

The effects of maralixibat on male and female fertility and/or reproductive capacity, pre‑ and postnatal development, and juvenile development were investigated in rats, while effects on embryofetal development were investigated in rabbits. No effects on fertility were observed in female rats treated orally with up to 2,000 mg/kg/day or in male rats treated orally with up to 750 mg/kg/day. No effects on embryofetal development were observed in pregnant rats treated orally with up to 1,000 mg/kg/day (approximately 3,300 to 12,000 times the maximum recommended dose based on exposure as measured by the area under the plasma concentration-time curve [AUC]) or in pregnant rabbits treated orally with up to 250 mg/kg/day (approximately 1,200 to 4,700 times the maximum recommended dose based on the AUC) during the period of organogenesis. No effects on postnatal development were observed in a pre‑ and postnatal development study, in which female rats were treated orally with up to 750 mg/kg/day during organogenesis through lactation. Maternal systemic exposure to maralixibat at the maximum dose tested was approximately 2,500 to 9,400 times the maximum recommended dose based on the AUC.

The use of maralixibat in young children is supported by non-clinical juvenile toxicity studies. No clear adverse effects were seen in male and female juvenile rats administered maralixibat at doses of 50, 100, and 250 mg/kg/day for 14 days (Post Natal Day [PND] 7 to 21), or in male and female juvenile rats administered maralixibat for 43 days (PND 21 through 63) at doses of 50, 100, and 200 mg/kg/day (males) and 250, 500, and 1,000 mg/kg/day (females).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Livmarli Product Monograph. Considering the intended use of Livmarli, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Livmarli Product Monograph, approved by Health Canada and available through the Drug Product Database.

As outlined in the What steps led to the approval of Livmarli? section, the review of the quality component of the New Drug Submission for Livmarli was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Livmarli has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the drug product is stored at 2 ºC to 30 ºC. The drug product must be protected from light and must not be frozen. Any remaining product must be discarded 100 days after the first opening of the bottle.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

None of the excipients used in the formulation of Livmarli are of human or animal origin.