Contents of the package leaflet for the medicine LIVMARLI 9.5mg / ml oral solution

1. NAME OF THE MEDICINAL PRODUCT

Livmarli 9.5 mg/mL oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains maralixibat chloride equivalent to 9.5 mg maralixibat.

Excipient with known effect

Each mL of oral solution contains 364.5 mg propylene glycol (E1520).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution.

Clear, colourless to light-yellow liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Livmarli is indicated for the treatment of:

* Cholestatic pruritus in patients with Alagille syndrome (ALGS) 2 months of age and older,

* Progressive familial intrahepatic cholestasis (PFIC) in patients 3 months of age and older.

4.2 Posology and method of administration

Treatment with Livmarli should be initiated under the supervision of a physician experienced in themanagement of patients with cholestatic liver diseases. All doses displaying weight refer tomaralixibat base.

Alagille syndrome (ALGS)

The recommended target dose is 380 mcg/kg once daily. The starting dose is 190 mcg/kg once dailyand should be increased to 380 mcg/kg once daily after one week. Table 1 provides the dose in mL ofsolution to be given for each weight range. In case of poor tolerability, dose reduction from380 mcg/kg/day to 190 mcg/kg/day, or treatment interruption should be considered. Renewed dose-escalation can be attempted as tolerated. The maximum recommended daily dose volume for patientsabove 70 kg is 3 mL (28.5 mg).

Table 1: Livmarli 9.5 mg/mL oral solution: Individual dose volume by patient weight: ALGS

Days 1 to 7 From day 8 and after(190 mcg/kg once daily) (380 mcg/kg once daily)

Patient weight 9.5 mg/mL 9.5 mg/mL(kg) solution: solution:

Oral syringe size Oral syringe size

Volume once Volume once(mL) (mL)daily daily(mL) (mL)5-6 0.1 0.27-9 0.15 0.3 0.510-12 0.2 0.4513-15 0.3 0.5 0.616-19 0.35 0.720-24 0.45 0.925-29 0.5 130-34 0.6 1.2535-39 0.7 1.540-49 0.9 1.7550-59 1 2.2560-69 1.25 2.570 or higher 1.5 3

Progressive familial intrahepatic cholestasis (PFIC)

The starting dose is 285 mcg/kg once daily (QD) and may be increased after 1-2 weeks to 285 mcg/kgtwice daily (BID, morning and evening). After 1-2 weeks, the dose can be increased to 570 mcg/kgtwice daily if clinically indicated, as tolerated. Table 2 provides the dose in mL of solution to be givenfor each weight range. In case of poor tolerability, dose reduction or treatment interruption should beconsidered. Renewed dose-escalation can be attempted as tolerated. The maximum daily dose volumefor patients above 50 kg is 6 mL (57 mg).

Table 2: Livmarli 9.5 mg/mL oral solution: Individual dose volume by patient weight: PFIC285 mcg/kg 570 mcg/kg(once daily titrated to twice daily) (twice daily as tolerated)

Patient Weight 9.5 mg/mL 9.5 mg/mL(kg) solution: Oral syringe size solution: Oral syringe size

Volume QD or (mL) Volume BID (mL)

BID (mL) (mL)3 0.1 0.24 0.1 0.255 0.15 0.3 0.56 to 7 0.2 0.40.58 to 9 0.25 0.510 to 12 0.35 0.613 to 15 0.4 0.8 116 to 19 0.5 120 to 24 0.6 1.2525 to 29 0.8 1 1.530 to 34 0.9 235 to 39 1.25 3 2.25285 mcg/kg 570 mcg/kg(once daily titrated to twice daily) (twice daily as tolerated)

Patient Weight 9.5 mg/mL 9.5 mg/mL(kg) solution: Oral syringe size solution: Oral syringe size

Volume QD or (mL) Volume BID (mL)

BID (mL) (mL)40 to 49 1.25 2.7550 to 59 1.5 360 to 69 2 370 to 79 2.25 380 or higher 2.5 3

Alternative treatment should be considered in patients for whom no treatment benefit can beestablished following 3 months of continuous daily treatment with maralixibat.

Missed dose

If a dose is missed, the dose should be omitted, and the original dose schedule resumed with the nextscheduled intake.

Special populations
Renal impairment

Maralixibat has not been studied in patients with renal impairment or end-stage renal disease (ESRD)requiring haemodialysis. Maralixibat has minimal plasma concentrations and negligible renalexcretion (see section 5.2).

ALGS: No dose adjustment is required.

PFIC: The maximum recommended dose of Livmarli 9.5 mg/mL oral solution in patients withmoderate renal impairment (creatinine clearance CrCl ≥30 and < 60 ml/min) is 285 mcg/kg BID, dueto propylene glycol content. Livmarli 9.5 mg/mL oral solution should not be used in patients with

PFIC and severe renal impairment (creatinine clearance CrCl< 30 ml/min; see sections 4.3 and 4.4).

Hepatic impairment

Maralixibat has not been sufficiently studied in patients with liver impairment.

ALGS: Due to minimal absorption of maralixibat, no dose adjustment is required for patients withhepatic impairment. Close monitoring is, however, advised for patients with end-stage liver disease orprogression to decompensation.

PFIC: The maximum recommended dose of Livmarli 9.5 mg/mL oral solution in patients withmoderate hepatic impairment is 285 mcg/kg BID, due to propylene glycol content. Livmarli9.5 mg/mL oral solution should not be used in patients with PFIC and severe hepatic impairment (seesections 4.3 and 4.4).

Paediatric population

The safety and efficacy of Livmarli in infants less than 2 months of age in ALGS, or less than3 months of age in PFIC, have not been established. Currently available data are described insections 4.8, 5.1, and 5.2, and no recommendation on a posology can be made in these age groups.

ALGS (≥ 2 months of age): No dose adjustment is required.

PFIC (≥ 3 months of age): The maximum recommended dose of Livmarli 9.5 mg/mL oral solution in

PFIC patients below 5 years of age is 285 mcg/kg BID, due to propylene glycol content (seesection 4.4).

Special attention should be paid to the accurate calculation of the Livmarli dose (taking intoconsideration the different strengths, various sizes of oral syringes and variable dosingrecommendations) and clear communication of dosing instructions to caregivers and patients tominimise the risk of erroneous dosing and overdose.

Method of administration

Livmarli is administered orally via an oral syringe by a caregiver or the patient, before (up to30 minutes) or with a meal, in the morning for once daily dosing, or in the morning and evening fortwice daily dosing.

Mixing Livmarli oral solution directly into food or drink prior to administration has not been studiedand should be avoided.

Three sizes of oral syringe (0.5 mL, 1 mL and 3 mL) are provided with each bottle of Livmarli.

Tables 1 and 2 provide the correct oral syringe size for each weight range.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with PFIC, treated with Livmarli 9.5 mg/mL oral solution, who have severe hepatic and/orrenal impairment due to the potential risk of toxicity from the excipient propylene glycol (seesection 4.4).

4.4 Special warnings and precautions for use

Maralixibat acts by inhibiting the ileal bile acid transporter (IBAT) and disrupting enterohepaticcirculation of bile acids. Therefore, conditions, medicinal products or surgical procedures that impaireither gastrointestinal motility or enterohepatic circulation of bile acids, including bile salt transport tobiliary canaliculi, have the potential to reduce the efficacy of maralixibat.

For this reason patients with PFIC2 who have a complete absence or lack of function of Bile Salt

Export Pump (BSEP) protein (i.e., patients with BSEP3 subtype of PFIC2) are not expected to respondto maralixibat.

Diarrhoea has been reported as a very common adverse reaction when taking maralixibat (section 4.8).

Diarrhoea may lead to dehydration. Patients should be monitored regularly to ensure adequatehydration during episodes of diarrhoea.

Patients with chronic diarrhoea requiring intravenous fluid or nutritional intervention were not studiedin clinical trials.

ALT and AST elevation was observed in some patients receiving maralixibat (section 4.8). Liverfunction tests should be monitored in patients prior to start and during treatment with maralixibat.

Assessment of fat-soluble vitamin (FSV) levels (Vitamins A, D, E) and international normalised ratio(INR) are recommended for all patients prior to initiating Livmarli, with monitoring per standardclinical practice. If FSV deficiency is diagnosed, supplemental therapy should be prescribed.

PFIC patients with impaired ability to metabolise and/or eliminate propylene glycol (e.g., those withhepatic and/or renal impairment, patients <5 years of age) are at increased risk of developingpropylene glycol toxicity when receiving high doses of Livmarli 9.5 mg/mL oral solution. Reduceddose of Livmarli 9.5 mg/mL oral solution is recommended in such patients (see section 4.2 andsection 4.4 “Propylene glycol and potential risk of toxicity”); PFIC patients with severe hepatic and/orrenal impairment should not be treated with Livmarli 9.5 mg/mL oral solution (see section 4.3).

Excipients with known effect

Propylene glycol and potential risk of toxicity

This medicinal product contains 364.5 mg propylene glycol (E1520) in each mL of oral solution.

ALGS: administration of 380 mcg/kg QD dose of Livmarli 9.5 mg/mL oral solution will result inexposure up to 17 mg/kg/day propylene glycol.

PFIC: Administration of 285 mcg/kg BID dose of Livmarli 9.5 mg/mL oral solution will result inexposure up to 26 mg/kg/day propylene glycol and 570 mcg/kg BID dose of Livmarli 9.5 mg/mL oralsolution will result in exposure up to 50 mg/kg/day propylene glycol.

Total amounts of propylene glycol from all medicines and food supplements, including Livmarli oralsolution, should be taken into account when assessing the potential risk of toxicity from propyleneglycol, especially in patients with limited ability to metabolise or excrete propylene glycol (e.g.,patients below 5 years of age, or those with reduced renal, or hepatic function) (see sections 4.2 and4.3). Co-administration with any substrate for alcohol dehydrogenase such as ethanol may increaserisk of toxicity from propylene glycol.

Adverse events related to potential propylene glycol toxicity include: e.g., hyperosmolality (with orwithout lactic acidosis), renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity(arrhythmia, hypotension); central nervous system depression (depression, coma, seizures), respiratorydepression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) andhaemoglobinuria; or multisystem organ dysfunction. Patients should be monitored for signs andsymptoms of possible propylene glycol toxicity.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Maralixibat is an OATP2B1 inhibitor based on in vitro studies. A decrease in the oral absorption of

OATP2B1 substrates (e.g. fluvastatin or rosuvastatin) due to OATP2B1 inhibition in thegastrointestinal tract cannot be ruled out. Consider monitoring the effects of OATP2B1 substrates asneeded.

Maralixibat is also an inhibitor of CYP3A4 based on in-vitro studies. An increase of plasma levels of

CYP3A4 substrates (e.g., midazolam, simvastatin) can therefore not be excluded and caution isadvised when administering such compounds concomitantly.

Maralixibat, being an inhibitor of bile acid absorption, has not been fully evaluated with regard to theinteraction potential with the bile acid ursodeoxycholic acid (UDCA).

Maralixibat is minimally absorbed, is not significantly metabolised, and is not a substrate of activesubstance transporters; therefore, other concomitant medicinal products are not known to affect thedisposition of maralixibat.

Maralixibat is not known to inhibit or induce other cytochrome P450 in patients; therefore, maralixibatis not predicted to affect the disposition of concomitant medicinal products through those mechanisms.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of maralixibat in pregnant women. Animal studies do not indicatedirect or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No effects onthe foetus during pregnancy are anticipated, since systemic exposure to maralixibat is negligible. As aprecautionary measure, it is preferable to avoid the use of Livmarli during pregnancy.

Breast-feeding

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of thebreast-feeding woman to maralixibat is negligible. Due to the propylene glycol content, as aprecautionary measure, it is preferable to avoid the use of Livmarli oral solution during breastfeeding.

Fertility

There are no clinical data on the effect of maralixibat on fertility. Animal studies do not indicate anydirect or indirect effects on fertility or reproduction (see section 5.3).

4.7 Effects on ability to drive and use machines

Livmarli has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

Over 280 patients with cholestatic liver diseases aged 1 month to 24 years have been treated withmaralixibat in blinded and open-label clinical studies, including 94 patients with ALGS treated for upto 5 years, and 134 patients with PFIC treated for up to 7 years.

The safety profile of maralixibat is consistent across all indications and age groups. The mostfrequently occurring adverse reactions in ALGS and PFIC patients older than 12 months of age werediarrhoea (36.0% and 27.7%, respectively) followed by abdominal pain (29.1% and 6.4%,respectively). The most frequently occurring adverse reaction in ALGS and PFIC patients youngerthan 12 months of age was diarrhoea (20.0% and 23.5%, respectively).

Tabulated list of adverse reactions

For ALGS, the safety profile of maralixibat is based on a pooled analysis of data from a review of 5clinical studies in patients (n=86) aged between 1 and 17 (median of 5 years); median duration ofexposure was 2.5 years (range: 1 day to 5.5 years).

For PFIC, the safety profile is primarily based upon analysis of the double-blind placebo-controlleddata in the pivotal PFIC trial and the open label extension study (n=93, with 88 patients treated withthe recommended dose of maralixibat). Patients treated with maralixibat were aged between 1 and17 years old (median of 4 years); median duration of exposure was 83.5 weeks (range: 1.7 to177.1 weeks). Additional evidence on long-term safety was collected on lower dose of maralixibat(≥266 mcg/kg/day) in a phase 2 clinical study (LUM001-501) and an open-label long-term follow-upstudy (MRX-800; total duration of exposure up-to 7 years).

In the age group younger than 12 months of age 17 patients with ALGS and 10 patients with PFIChave been treated with recommended doses of maralixibat (see section 5.1).

Table 3 presents the adverse reactions reported from these analyses.

Adverse reactions in patients treated with maralixibat are listed below by MedDRA system organ classand frequency grouping. Frequencies are defined as follows: very common (≥1/10), common (≥1/100to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), not known (cannot beestimated from the available data).

Table 3: Adverse reactions reported in patients with ALGS and PFIC

System organ class Frequency Adverse reactions

Gastrointestinal disorders Very common Diarrhoea

Abdominal pain

ALT and AST

Hepatobiliary disorders Commonincreased

Description of selected adverse reactions

All reported events of diarrhoea were mild to moderate in severity; a severe adverse reaction ofabdominal pain was reported in 1 ALGS patient. No adverse reactions of diarrhoea or abdominal painwere serious. The time to onset for diarrhoea and abdominal pain in the majority of cases was withinthe first month of treatment. For both ALGS and PFIC, the median duration for diarrhoea andabdominal pain episodes was less than 1 week. No dose response relationship was observed fordiarrhoea or abdominal pain. Treatment was interrupted or dose was reduced due to adversegastrointestinal reactions in 4 (4.7%) of ALGS patients and 3 (6.4%) of PFIC patients, and led toimprovement or resolution of the adverse reactions. One PFIC patient (2.1%) with mild diarrhoeadiscontinued treatment; otherwise, no patients discontinued Livmarli due to gastrointestinal adversereactions.

If diarrhoea and/or abdominal pain persist and no other etiologies are found, reducing the dose orinterrupting treatment should be considered. Dehydration should be monitored and treated promptly. Ifdosing with Livmarli is interrupted, Livmarli can be restarted as tolerated when diarrhoea orabdominal pain improve (section 4.2).

Elevations in ALT and AST, partly accompanied with increase in bilirubin were mostly transitory andmild or moderate in intensity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

Maralixibat is minimally absorbed from the gastrointestinal tract and overdose is not expected to resultin high plasma levels of the active substance. Single doses of up to 500 mg, approximately 18-foldhigher than the recommended dose, have been administered in healthy adults without any adverseconsequences.

Livmarli contains propylene glycol; overdose could result in overdose of propylene glycol (seesection 4.4).

In the event of an overdose, general supportive measures should be followed and the patient should bemonitored for signs and symptoms of propylene glycol toxicity (see section 4.4). In the event ofoverdose, propylene glycol can be removed from the body through dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy. ATC code: A05AX04

Mechanism of action

Maralixibat is a minimally absorbed, reversible, potent, selective inhibitor of the ileal bile acidtransporter (IBAT).

Maralixibat acts locally in the distal ileum to decrease the reuptake of bile acids and increase theclearance of bile acids through the colon, reducing the concentration of bile acids in the serum.

Clinical efficacy in ALGS

The efficacy of maralixibat in ALGS patients was assessed in a 48-week trial which included an 18-week open-label active substance run-in period, a 4-week double-blind randomised withdrawal periodand a long-term, open-label extension period.

Thirty-one ALGS paediatric patients with cholestasis and pruritus were enrolled, with 90.3% ofpatients receiving at least one medication to treat pruritus at trial entry (74.2% and 80.6% of patientsreceiving rifampicin and ursodeoxycholic acid, respectively). Concomitant use of these medicationswas allowed during the trial, but dose adjustments were prohibited during the first 22 weeks. Allpatients had ALGS due to JAGGED1 mutation.

Exclusion criteria included surgical interruption of the enterohepatic circulation, history or presence ofany condition known to interfere with the absorption, distribution, metabolism or excretion of drugs,including bile salt metabolism in the intestine, and chronic diarrhoea requiring intravenous fluid ornutritional intervention.

After an initial 5-week dose-escalation period, patients were administered open-label treatment withmaralixibat 380 mcg/kg once daily for 13 weeks; two patients discontinued treatment during this first18 weeks of open-label run-in treatment. The 29 patients who completed the open-label run-in phasewere then randomised to either continue treatment with maralixibat or receive matching placebo (n=16placebo, n=13 maralixibat) during the 4-week double-blind randomised withdrawal period atweeks 19-22. All 29 patients completed the blinded randomised withdrawal period; subsequently, allpatients received open-label maralixibat at 380 mcg/kg once daily dose for up to 48 weeks. Patientswho were switched from placebo went through a dose escalation schedule similar to the initialescalation.

Randomised patients had a median age of 5 years (range: 1 to 15 years) and 66% were male. Thebaseline mean (standard deviation [SD]) of liver test parameters were as follows: serum bile acid(sBA) levels 280 (213) µmol/L, aspartate aminotransferase (AST) 158 (68) U/L, alanine transaminase(ALT) 179 (112) U/L, gamma glutamyl transferase (GGT) 498 (399) U/L, and total bilirubin (TB) 5.6(5.4) mg/dL.

Serum bile acids (sBA)

A statistically significant mean (SD) reduction in sBA versus baseline of 88 (120) and96 (166.6) μmol/L was observed at week 18 and week 48 when patients were administeredmaralixibat. At the end of the placebo-controlled period, a statistically significant least squares mean(SE) difference was demonstrated between maralixibat and placebo in change in sBA from week 18 toweek 22 (-114 [48.0] µmol/L; p=0.025). When the placebo group resumed treatment with maralixibatat the end of the withdrawal period, sBA reduced to levels previously observed with maralixibattreatment (see Figure 1).

Figure 1: Mean (± SE) change from baseline sBA, through week 48, all patients

MRX = maralixibat; PBO = placebo; SE = standard error; BL = baseline

Pruritus

Pruritus severity was evaluated in the overall population (n=31), measured by Itch Reported Outcome

Observer (ItchRO[Obs]) score. The ItchRO score is a validated 0-4 scale completed by caregivers(0=none to 4=very severe), where changes ≥1.0 have been shown to be clinically meaningful. Changesin pruritus severity between participants treated with maralixibat and those treated with placebo duringthe randomised withdrawal period and changes from baseline to week 18 and to week 48 weremeasured. The mean ItchRO(Obs) score at baseline was 2.9.

Patients administered maralixibat demonstrated a clinically meaningful change and statisticallysignificant reductions of ItchRO(Obs) of -1.7 and -1.6 points from baseline at week 18 and week 48,respectively.

During the placebo-controlled randomised withdrawal period, patients administered maralixibatmaintained pruritus reduction, whereas those in the placebo group returned to baseline pruritus scores.

The difference between maralixibat and placebo in least squares mean (SE) change in pruritus fromweek 18 to week 22 (-1.5 [0.3]; 95% CI: -2.1 to -0.8; p<0.0001; see Figure 2) was statisticallysignificant. After resuming maralixibat, patients from the placebo group regained improvement inpruritus by week 28. Patients administered maralixibat demonstrated sustained pruritus reduction up to48 weeks.

Figure 2: ItchRO(Obs) weekly average morning severity score change from baseline byrandomised treatment group over time, through week 48, all patients

MRX = maralixibat; PBO = placebo; SE = standard error; BL = baseline

Improvements of variable degree in cholesterol and xanthoma severity were observed during treatmentwith maralixibat.

The mechanism of action of maralixibat to prevent reuptake of bile acids is expected to be similaracross all age groups. Evidence of efficacy in patients younger than 12 months of age with ALGS islimited. In an open-label, single-arm study in 8 patients of 2 to 10 months of age with ALGS change inpruritus as assessed with Clinician Scratch Scale (where 0=none and 4=cutaneous mutilation,haemorrhage and scarring evident) at week 13 was mean (SD; median; range) -0.2 (1.91; -1.0; -3.0 to3.0) and in sBA mean (SD; median; range) -88.91 µmol/L (113.348; -53.65; -306.1 to 14.4). Twopatients experienced improvement in both pruritus and sBA.

Clinical efficacy in PFIC

The efficacy of maralixibat was assessed in a 26-week randomized, double-blind placebo-controlledtrial (MRX-502). Ninety-three patients with diagnosis of PFIC based on documentation of intrahepaticcholestasis with persistent pruritus, abnormal tests for liver function and/or evidence of progressiveliver disease aged >12 months and <18 years were included. Patients underwent genotyping forconfirmation of PFIC type. Persistent pruritus was defined as > 6 months with average pruritus scoreon ItchRO[Obs] equal or greater than 1.5 in the 4 weeks prior to baseline.

Patients with decompensated cirrhosis, history or presence of any condition known to interfere withthe absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism in theintestine, and chronic diarrhoea requiring intravenous fluid or nutritional intervention were excluded.

Patients were randomized 1:1 to receive maralixibat 570 mcg/kg (n=47) or placebo orally (n=46) twicedaily for 26 weeks with an initial 4-6-week dose escalation period, starting with 142 mcg/kg twicedaily. The 26-week study period was completed by 92.5% of patients (44/47 maralixibat and 42/46placebo), with 7 discontinuing from the study (4 withdrawal of consent, 1 AE for mild diarrhoea, 1liver transplantation, and 1 disease progression). Patients completing the pivotal trial were eligible toenrol in an open-label extension trial (MRX-503).

Efficacy endpoints for the pivotal trial included changes in pruritus severity, serum bile acid levels,liver function tests and growth.

Efficacy endpoints were evaluated in patients with genetic testing results consistent with biallelic

PFIC-causing variants (n=64): ABCB11/BSEP (PFIC2) n=31; ATP8B1/FIC1 (PFIC1) n=13;

ABCB4/MDR3 (PFIC3) n=9; TJP2 (PFIC4) n=7; MYO5B (PFIC 6) n=4. There were more females(53.1%) and the mean age was 4.6 years with a range of 1 to 15 years. Most patients were on stableursodeoxycholic acid (89.1%) or rifampicin (51.6%) therapy at baseline. The baseline mean (standarddeviation [SD]) of liver test parameters were as follows: serum bile acid levels 263 (143) μmol/L, AST113 (82) U/L, ALT 107 (87) U/L, and TB 69.8 (70.1) µmol/L, DB 50.6 (52.4) µmol/L. The mean (SD)of the average baseline morning ItchRO[Obs] pruritus severity score was 2.8 (0.87). There were nomeaningful differences observed between treatment groups across baseline characteristics or diseaseparameters.

Serum bile acids (sBA)

The mean change in total serum bile acid level between maralixibat and placebo treatment groupsfrom baseline to average of weeks 18, 22, and 26 was statistically significant with a LS mean changefrom placebo of -160 µmol/L (95% CI: -220.8, -100.0) (Figure 3).

Figure 3: Observed average serum bile acids levels over time in PFIC 1, 2, 3, 4, and 6 (Study

MRX-502)+ 3 (-42.3, 48.1)

- 157 (-200.3, -114.7)

Maralixibat vs. Placebo

- 160 (-220.8, -100.0)p < 0.0001

Maralixibat Placebo

Week BL

Maralixibat

Placebo

BL=Baseline; Wk=Week. Observed values are displayed. Statistics shown are averages of weeks 18, 22, and 26 using anequally weighted average of the 3 individual visit-specific estimates obtained from a mixed model for repeated measures(MMRM) with change from baseline as the dependent variable and fixed categorical effects of treatment group, PFIC type,analysis visit and treatment-by-visit interaction as well as the continuous fixed covariates of baseline score and baselinescore-by-visit interaction. The least-squares mean estimate and 95% confidence interval are presented.

The percentage of serum bile acid responders was 45.5% for maralixibat and 6.5% for placeboparticipants, difference (95% CI): 39.0% (16.5%, 58.2%). Serum bile acid responders were defined asa participant having an average sBA level of <102 µmol/L (applies only if baseline sBA level was≥102 µmol/L) OR ≥75% average reduction from baseline. For the purpose of determining response,the average sBA value from weeks 18, 22, and 26 values were used.

Pruritus

Maralixibat demonstrated difference between maralixibat and placebo treatment groups for theaverage change in morning ItchRO(Obs) severity score between baseline and weeks 15-26, with a LSmean change from placebo -1.200 (95% CI: -1.727, -0.674; Figure 4).

Serum Bile Acids (μmol/L)

Figure 4: Observed weekly average of the morning daily pruritus score over time in PFIC 1, 2,3, 4, and 6 (Study MRX-502)

Maralixibat vs. Placebo

- 1.200 (-1.727, -0.674)p < 0.0001

- 0.610 (-1.000, -0.221)

- 1.811 (-2.178, -1.444)

Maralixibat Placebo

Week BL

Maralixibat

Placebo

BL=Baseline; Wk=Week. Observed values are displayed. Statistics shown are averages of time periods weeks 15-18, 19-22,and 23-26 using an equally weighted average of the 3 individual visit-specific estimates obtained from a mixed model forrepeated measures (MMRM) with change from baseline as the dependent variable and fixed categorical effects of treatmentgroup, PFIC type, analysis visit and treatment-by-visit interaction as well as the continuous fixed covariates of baseline scoreand baseline score-by-visit interaction. The least-squares mean estimate and 95% confidence interval are presented.

Table 4 presents the results of the comparison of the ItchRO(Obs) results between maralixibat andplacebo.

Table 4: Proportion of pruritus responders (Study MRX-502)

Responder Type Maralixibat Placebo

Category (n=33) (n=31)

ItchRO(Obs) responders; average score ≤1 OR changefrom baseline of ≤-1.0

Responder(%) 63.6 25.8p-value vs. placebo difference (95% CI) 0.0023 37.8 (11.3, 59.4)p-values comparing maralixibat to placebo treatment groups are calculated using a Barnard’s exact test.

Exact 95% confidence intervals are based on a score statistic.

Exploratory analyses showed more pronounced reduction (improvement) in the mean sleepdisturbance scores in the maralixibat treatment group compared with placebo. Exploratory analysesshowed improvements in bilirubin during treatment with maralixibat (Table 5). Abnormal totalbilirubin levels at baseline normalised by week 26 in 40% (10/25) of patients on maralixibat vs. 0%(0/18) on placebo. More pronounced increase (improvement) in weight z-score was observed in themaralixibat treatment group compared with placebo (LS mean change from placebo of 0.227 (95% CI:

0.012, 0.442; Table 5)).

Observed ItchRO(Obs) Score

Table 5: Liver function tests and growth parameters for maralixibat vs. placebo over the 26-week treatment period in participants with PFIC in the pivotal trial (MRX-502exploratory analyses).

Efficacy endpoint Placebo Maralixibat(n=31) (n=33)

Alanine aminotransferase (U/L)

Baseline (mean [SE]) 127.3 (18.68) 87.8 (10.77)

LS mean change from BL [SE] to weeks 18-26 -7.0 (11.13) 9.7 (10.36)

LS mean difference vs. placebo (95% CI); 16.6 (-13.31, 46.60)

Aspartate aminotransferase (U/L)

Baseline (mean [SE]) 129.8 (18.12) 96.9 (9.57)

LS mean change from BL [SE] to weeks 18-26 -0.4 (14.91) 13.6 (14.05)

LS mean difference vs. placebo (95% CI); 14.1 (-26.57, 54.69)

Total bilirubin (mol/L)

Baseline (mean [SE]) 69.1 (13.69) 70.4 (11.32)

LS mean change from BL [SE] to weeks 18-26 15.9 (12.37) -18.3 (11.65)

LS mean difference vs. placebo (95% CI); -34.3 (-68.06, -0.46)

Direct bilirubin (mol/L)

Baseline (mean [SE]) 50.2 (10.28) 50.9 (8.40)

LS mean change from BL [SE] to weeks 18-26 13.5 (9.52) -12.9 (8.97)

LS mean difference vs. placebo (95% CI); -26.4 (-52.46, -0.26)

Height z-score

Baseline (mean [SE]) -2.06 (0.27) -2.08 (0.23)

LS mean change from BL [SE] to weeks 18-26 -0.13 (0.09) 0.08 (0.09)

LS mean difference vs. placebo (95% CI); 0.21 (-0.04, 0.5)

Weight z-score

Baseline (mean [SE]) -1.28 (0.24) -1.75 (0.23)

LS mean change from BL [SE] to weeks 18-26 0.12 (0.08) 0.35 (0.07)

LS mean difference vs. placebo (95% CI); 0.23 (0.01, 0.4)

SE=standard error; LS = least-squares; CI=confidence interval; BL=baseline. Baseline values are observed values. LS meanvalues are averages of weeks 18, 22, and 26 using an equally weighted average of the 3 individual visit-specific estimatesobtained from a mixed model for repeated measures (MMRM) with change from baseline as the dependent variable and fixedcategorical effects of treatment group, PFIC type, analysis visit and treatment-by-visit interaction as well as the continuousfixed covariates of baseline score and baseline score-by-visit interaction.

Of the 64 patients from the pivotal trial (MRX-502) with genetic testing results consistent withbiallelic PFIC-causing variants, 57 were included in an interim analysis from the ongoing open-labelextension trial (MRX-503). Their median treatment duration with maralixibat was 47.3 weeks (range:

4.1 weeks - 119.4 weeks). Maralixibat showed maintenance of treatment effect on serum bile acid andbilirubin levels as well as pruritus. Height and weight z-scores were further improved.

In an open-label, single-arm safety study (MRX-801) in 10 patients of 1 to 11 months of age with

PFIC (no requirement for active pruritus), decrease at week 13 in sBA, total bilirubin and directbilirubin was observed in some patients. Two patients also experienced improvement in pruritus.

Exceptional circumstances

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Absorption

The target of maralixibat is in the lumen of the small intestine, such that plasma levels of maralixibatare not required and not relevant to its efficacy. Maralixibat is minimally absorbed, and plasmaconcentrations are often below the limit of detection (0.25 ng/mL) after single or multiple doses attherapeutic dose levels. The absolute bioavailability is estimated to be <1%.

Effect of food

Maralixibat absorption is relatively higher when administered in the fasted state, and no doseadjustment for food effects is necessary. Maralixibat can be taken before (up to 30 minutes) or witha meal (see section 4.2).

Distribution

Maralixibat shows high binding (91%) to human plasma in vitro.

In a clinical ADME trial dosing [14C] maralixibat, circulating radioactivity was below the limit ofdetection at all time points. There is no apparent accumulation of maralixibat.

Biotransformation

No metabolites have been detected in plasma, and maralixibat also undergoes minimal metabolism inthe gastrointestinal tract.

Elimination

Maralixibat is primarily eliminated in the faeces as unmetabolised parent compound, with 0.066% ofthe administered dose excreted in the urine.

Special populations

No clinically significant differences in the pharmacokinetics of maralixibat were observed based onage, sex, or race.

Hepatic impairment

Clinical studies of maralixibat included ALGS and PFIC patients with some level of liver impairment.

The majority of patients presented with some degree of hepatic impairment according to the NCI-

ODWG classification due to the disease. Whether this classification is, however, appropriate incholestatic disease to predict the influence on PK of the compound is currently unclear. Maralixibat isminimally absorbed, and animal data indicate that the very low plasma levels are due to lowabsorption and not a first pass effect in the liver, and plasma levels of maralixibat were not increasedin patients with liver impairment according to the NCI-ODWG. However, the PK of maralixibat havenot been systematically investigated in patients classified according to the Child-Pugh classification(patients with cirrhosis and signs of decompensation).

Renal impairment

The pharmacokinetics of maralixibat were not studied in patients with impaired renal function,including those with ESRD or those on haemodialysis. However, renal impairment is not expected toimpact maralixibat PK due to the low systemic exposure and lack of urinary excretion.

5.3 Preclinical safety data

Non-clinical data reveal no specific hazard for humans based on studies of safety pharmacology,secondary pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, fertility, toxicity toreproduction and development, and juvenile animal toxicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene glycol (E1520)

Disodium edetate

Sucralose

Grape flavour

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

After first opening

After the first opening of the bottle, the medicinal product must be used within 130 days stored below30°C. Discard unused product, even if not empty, after 130 days or at product expiry whichever comesfirst.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

30 mL amber-coloured PET bottle with a preinstalled LDPE adapter and a HDPE child-resistantclosure with a foam liner, containing 30 mL oral solution.

Pack size:

Each pack contains one 30 mL bottle and is co-packaged with three oral repeated-use syringes(0.5 mL, 1 mL and 3 mL) with the following graduations:

* 0.5 mL polypropylene syringe with a white plunger: numbers for each 0.1 mL, major hashmarks for 0.05 mL increments, and minor hash marks for 0.01 mL increments.

* 1 mL polypropylene syringe with a white plunger: numbers for each 0.1 mL increment.

* 3 mL polypropylene syringe with a white plunger: numbers for each 0.5 mL increment, andhash marks for each 0.25 mL increment between 0.5 mL and 3 mL.

6.6 Special precautions for disposal and other handling

The oral syringes may be rinsed with water, air dried and reused for 130 days.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

7. MARKETING AUTHORISATION HOLDER

Mirum Pharmaceuticals International B.V.

Kingsfordweg 1511043 GR Amsterdam,

Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/22/1704/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 December 2022

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.

Leaflet LIVMARLI 9.5mg / ml oral solution

General data about LIVMARLI 9.5mg / ml

Marketing authorisation