Livdelzi 10 mg capsules

LIVDELZI^® is indicated for the treatment of primary biliary cholangitis (PBC), including pruritus, in adults in combination with ursodeoxycholic acid (UDCA) who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA.

The recommended dosage of LIVDELZI is 10 mg once daily.

Posology

Prior to initiation of treatment with LIVDELZI the patient's hepatic status must be known. Whether the patient has decompensated cirrhosis (including Child-Pugh Class B and C) or has had a prior decompensation event should be determined prior to initiation of treatment.

Special Populations

Paediatric population

There is no relevant use of LIVDELZI in the paediatric population in the treatment of PBC.

Elderly

Limited data exists in elderly patients aged 75 years or older. No dose adjustment is required for elderly patients (see sections 5.2). No data are available in subjects aged 80 years of age or older.

Renal impairment

No dose adjustment of LIVDELZI is required for patients with mild, moderate and severe renal impairment. Patients with end-stage renal disease on dialysis have not been studied (see section 5.2).

Hepatic impairment

No dose adjustment is required in PBC patients with mild hepatic impairment (Child-Pugh A).

Safety and efficacy of LIVDELZI in patients with decompensated cirrhosis have not been established. Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (see section 5.2).

Monitor patients with cirrhosis for evidence of decompensation. Consider discontinuing LIVDELZI if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).

Method of administration

LIVDELZI can be taken with or without food.

For patients taking a bile acid binding resin, LIVDELZI should be taken at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as long an interval as possible (see section 4.5).

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

- Patients with complete biliary obstruction

Transaminase Elevations

LIVDELZI has been associated with dose related increases in serum transaminase (AST and ALT) levels greater than 3 times upper limit of normal (ULN) in patients with PBC receiving doses of 50 and 200 mg/day (5- and 20-times the recommended 10 mg/day dose). Transaminase levels returned to pretreatment levels upon treatment discontinuation. No pattern for increases in transaminases levels was observed at lower doses (2, 5 or 10 mg).

Obtain baseline clinical and laboratory assessments at initiation of treatment with LIVDELZI and monitor thereafter according to routine clinical practice. Interrupt LIVDELZI treatment if the liver tests (ALT, AST, total bilirubin, and/or alkaline phosphatase [ALP]) worsen, or the patient develops signs and symptoms consistent with clinical hepatitis. Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI.

Bile Acid Binding Resins

Bile acid binding resins may reduce the absorption of other drugs administered concurrently. Patients should take LIVDELZI at least 4 hours before or 4 hours after taking a bile acid binding resin.

CYP2C9 and CYP3A4 Inhibitors

Concomitant administration of seladelpar with medicines that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate-to-strong CYP3A inhibitors (e.g. fluconazole, mifepristone), may result in an increase in seladelpar exposure. When seladelpar is concomitantly administered with drugs that are strong CYP2C9 inhibitors, or dual moderate CYP2C9 and moderate to strong CYP3A4 inhibitors, patients should be closely monitored for adverse effects.

Ciclosporin

Concomitant administration of seladelpar with ciclosporin may result in an increase in seladelpar exposure. When seladelpar is concomitantly administered with ciclosporin, patients should be closely monitored for adverse effects.

Probenecid

Concomitant administration of seladelpar with probenecid may result in an increase in seladelpar exposure. Avoid concomitant administration of seladelpar with probenecid.

Drug Interaction Studies

In vitro Assessment of Drug Interactions

Based on in vitro studies, seladelpar and its metabolites (M1, M2, or M3) are not expected to inhibit CYPs 1A2, 2B6, 2C8, 2C19, 2D6, or UGTs at the recommended dose of 10 mg.

Seladelpar did not induce CYP1A2, CYP2B6, or CYP2C8. Seladelpar and its metabolites (M1, M2, or M3) are not expected to inhibit drug transporters including P-gp, MATE1, MATE2-K, OCT1, OAT1, and OAT3 at the recommended dose of 10 mg.

Seladelpar is a substrate of BCRP, P-gp, and OAT3 transporters in vitro. Seladelpar is not a substrate of MATE1, MATE2-K, OAT1, OCT1, or OCT2.

Effect of Seladelpar on Other Drugs

Seladelpar has no clinically relevant effect on the pharmacokinetics of tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), simvastatin (CYP3A4 and OATP substrate), atorvastatin (CYP3A4 and OATP substrate), and rosuvastatin (OATP and BCRP substrate).

Effect of Other Drugs on Seladelpar

Fluconazole

Seladelpar AUC0-inf increased by 2.4-fold and Cmax by 1.4-fold following concomitant use of a single 10 mg seladelpar dose with 400 mg fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) in healthy subjects.

Carbamazepine

Seladelpar AUC_0-inf decreased by approximately 44% and C_max by 24% following administration of a single 10 mg seladelpar dose after carbamazepine 300 mg twice daily in healthy subjects.

Quinidine

Seladelpar exposures were not significantly altered when a single dose of 600 mg quinidine (P-gp inhibitor) was co-administered in healthy subjects.

Ciclosporin

Seladelpar AUC_0-inf increased by 2.1-fold and C_max by 2.9-fold following concomitant use of a single 10 mg seladelpar dose with 600 mg ciclosporin (OATP1B1, OATP1B3, P-gp, BCRP, MRP2, and CYP3A inhibitor) in healthy subjects.

Probenecid

Seladelpar AUC0-inf increased by 2-fold and Cmax by 4.7-fold following concomitant use of a single 10 mg seladelpar dose with 500 mg probenecid (OAT1, OAT3, OATP1B1, and UGT inhibitor) in healthy subjects.

Other drugs

No clinically significant differences in seladelpar pharmacokinetics were predicted with concomitant use of strong CYP3A4 inhibitors or CYP2C8 inhibitors.

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of seladelpar in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of LIVDELZI during pregnancy.

Breast-feeding

It is unknown whether seladelpar/metabolites are excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI or from the underlying maternal condition.

Fertility

No fertility data are available in humans. Seladelpar did not affect fertility in male or female rats at oral doses up to 100 mg/kg/day (see section 5.3).

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

Summary of Safety Profile

Based on clinical trial experience, the most frequently reported adverse reactions were headache, nausea, abdominal pain and abdominal distension which occurred in more than 5% of patients.

Tabulated list of adverse reactions

The frequencies of the adverse drug reactions observed in the pivotal RESPONSE study are provided in the table below.

Adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT).

Frequencies are defined according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 1: Adverse drug reactions reported in PBC patients treated with LIVDELZI

Safety profile from open label study

In ASSURE, an open label safety study, LIVDELZI was evaluated in 280 PBC patients, of whom 206 were treated with LIVDELZI for at least 6 months, 144 were treated for at least 12 months, and 19 were treated for at least 2 years. In this study the safety profile was similar to that in the pivotal study (RESPONSE).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website. https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no specific treatment for overdose with LIVDELZI. General supportive care of the patient is indicated, as appropriate. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because LIVDELZI is highly bound to plasma proteins, haemodialysis should not be considered.

Pharmacotherapeutic group: Bile and liver therapy, other drugs for bile therapy ATC code: A05AX07.

Mechanism of action

Seladelpar is a potent and selective PPARδ agonist, or delpar. PPARδ is a nuclear receptor expressed in the liver and other tissues. PPARδ activation reduces bile acid synthesis in the liver through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol, and by decreasing cholesterol synthesis and absorption. These actions result in lower bile acid exposure in the liver and reduced circulating bile acid levels. Seladelpar also has positive effects on serum lipids, inflammation, and fibrosis.

Pruritus is a common symptom in patients with PBC, but its origins are not completely understood. Seladelpar treatment has been shown to reduce pruritus, which was associated with decreased serum bile acids and Interleukin-31 (IL-31). Both bile acids and IL-31 have been found to be involved in pruritus.

Pharmacodynamic Markers

In clinical studies, seladelpar treatment resulted in reduction of ALP, a biomarker of cholestasis. ALP reduction was observed within 1 week of treatment initiation, continued to decrease through Month 3, and was sustained through Month 24.

In RESPONSE, the median decrease in serum 7α-hydroxy-4-cholesten-3-one (a bile acid synthesis intermediate) and total bile acids at Month 12 were 41.9% and 32.0%, respectively, after treatment with seladelpar, reflecting action leading to diminished cholestatic accumulation of total bile acids. Seladelpar also increased mean serum FGF21 levels by 76.2% after 12 months of treatment; this increase is a known effect of PPARδ activation in hepatocytes that leads to decreased bile acid synthesis.

In RESPONSE, treatment with seladelpar led to a 44.9% and 31.6% mean decrease in IL-31 after 6 and 12 months of treatment in patients with moderate-to-severe pruritus, which was associated with improvements in pruritus severity.

Decreases in triglycerides, LDL-C, and total cholesterol were noted with seladelpar treatment.

Pharmacodynamic Effects

Cardiac Electrophysiology

At a dose of 20-times the 10 mg recommended dose, LIVDELZI was not associated with clinically significant QT prolongation.

Clinical efficacy and safety

A randomised, double-blind, placebo-controlled, 12-month study (RESPONSE) evaluated the safety and efficacy of LIVDELZI in 193 adult patients with PBC who had an inadequate response to or intolerance to ursodeoxycholic acid (UDCA). Patients were included in the study if their ALP was greater than or equal to 1.67-times the ULN and total bilirubin (TB) was less than or equal to 2-times the ULN. Patients were excluded from the study if they had other chronic liver diseases, clinically important hepatic decompensation (including portal hypertension with complications), or cirrhosis with complications (e.g., Model for End Stage Liver Disease [MELD] score of 12 or greater, known oesophageal varices or history of variceal bleeds, history of hepatorenal syndrome).

Patients were randomised (2:1) to receive LIVDELZI 10 mg (n=128) or placebo (n=65) once daily for 12 months. LIVDELZI or placebo was administered in combination with UDCA in 181 (94%) patients during the study, or as a monotherapy in 12 (6%) patients who were unable to tolerate UDCA.

The mean age of patients was 57 years (range: 28 to 75); 95% were female; 88% were White, 6% Asian, 2% Black or African American, and 3% American Indian or Alaska Native; 29% identified as Hispanic/Latino. At baseline, 18 (14%) of the LIVDELZI-treated patients and 9 (14%) of the placebo-treated patients met at least one of the following criteria: Fibroscan >16.9kPa; historical biopsy or radiological evidence suggestive of cirrhosis; platelet count < 140,000/µL with at least one additional laboratory finding including serum albumin < 3.5 g/dL, INR > 1.3, or TB > 1-time ULN; or clinical determination of cirrhosis by the investigator.

The mean baseline ALP concentration was 314 U/L (range: 161 to 786), corresponding to 2.7-times ULN. The mean baseline TB concentration was 0.8 mg/dL (range: 0.3 to 2.0) and was less than or equal to the ULN in 87% of the patients. Other mean baseline liver biochemistries included ALT of 48 U/L (range: 9 to 115) and AST of 40 U/L (range: 16 to 94).

LIVDELZI demonstrated greater improvement on biochemical response and ALP normalisation at Month 12 compared to placebo. In patients with moderate to severe pruritus at baseline, LIVDELZI demonstrated greater improvement in pruritus Numerical Rating Scale (NRS) at Month 6 compared to placebo. Treatment outcomes of the RESPONSE study are presented in Table 2.

Table 2: RESPONSE Study: Efficacy Results of LIVDELZI With or Without UDCA^a

^a Biochemical response is defined as an ALP value less than 1.67-times the ULN, an ALP decrease of at least 15%, and total bilirubin less than or equal to the ULN.

^b ALP normalisation is defined as ALP less than or equal to ULN.

^c p<0.0001 for LIVDELZI 10 mg versus placebo. P-value was obtained using the Cochran–Mantel–Haenszel Test stratified by baseline ALP level (<350 U/L versus ALP level ≥350 U/L), and baseline pruritus NRS (< 4 versus ≥ 4). Patients who discontinued treatment prior to Month 12 or who had missing data were considered as non-responders.

^d p<0.005 for LIVDELZI 10 mg versus placebo. LS means and p-value were obtained using the mixed-effect model for repeated measures (MMRM) in patients with moderate to severe pruritus at baseline.

Mean Reduction in ALP

Figure 1 shows the mean reductions in ALP over 12 months in LIVDELZI-treated patients compared to placebo. ALP normalisation was achieved in 25% of LIVDELZI-treated patients by Month 12 and was achieved in no placebo-treated patients. The Least Squares (LS) mean (SE) reduction in GGT, ALT, and AST was -108.0 (8.49), -12.2 (1.62), and -2.5 (1.31) U/L, respectively, in the LIVDELZI 10 mg arm, and -18.3 (11.79), -3.9 (2.22), and -1.5 (1.80) U/L, respectively, in the placebo arm at Month 12.

Figure 1 : Change from Baseline in ALP over 12 Months in RESPONSE by Treatment Arm with or without UDCA^a

^a In the study there were 12 patients (6%) who were intolerant to UDCA and initiated treatment as monotherapy: 8 patients (6%) in the LIVDELZI 10 mg arm and 4 patients (6%) in the placebo arm.

In the ASSURE study, long-term maintenance of biochemical effects was sustained beyond two years of treatment with LIVDELZI.

Monotherapy

Biochemical response at Month 3 comparing LIVDELZI as a monotherapy to placebo was evaluated in a pooled analysis of a subset of patients from RESPONSE and another randomised, double-blind, placebo-controlled study in a similar patient population. Sixty-two percent (62%) of LIVDELZI-treated patients achieved a response on the composite endpoint, compared to 17% of placebo-treated patients.

Pruritus

A single-item patient-reported outcome (PRO), the pruritus NRS, evaluated patients' daily worst itching intensity on an 11-point rating scale with scores ranging from 0 (“no itching” ) to 10 (“worst itching imaginable” ) in RESPONSE. The pruritus NRS was administered daily in a ≥14-day run-in period prior to randomisation through Month 6. After 6 months, pruritus was evaluated on a monthly basis through Month 12 using pruritus NRS for 7 consecutive days each month.

Figure 2 presents the results of the comparison between LIVDELZI and placebo on pruritus NRS through Month 12 in patients with baseline average pruritus scores greater than or equal to 4. Baseline included mean of all daily recorded scores during the run in-period and on Day 1. The pruritus scores for each patient for post-baseline months were calculated by averaging the pruritus NRS scores within the scheduled week each month. Patients treated with LIVDELZI demonstrated greater improvement in pruritus compared with placebo. This effect was sustained through Month 12 of treatment.

Figure 2: Change from Baseline in Pruritus NRS over Time in the RESPONSE Study in PBC Patients with Moderate to Severe Pruritus at Baseline

Paediatric population

The Medicines and Healthcare products Regulatory Agency has waived the obligation to submit the results of studies with LIVDELZI in all subsets of the paediatric population (see section 4.2 for information on paediatric use).

Following a single dose administration, seladelpar systemic exposure increased dose-proportionally from 2 mg to 15 mg (1.5 times the recommended dosage) and greater than dose proportionally at higher doses. For a dose increase of 20-fold from 10 mg to 200 mg, mean C_max and mean AUC for seladelpar increased 70-fold and 27-fold, respectively. Following once daily dosing, seladelpar steady-state was achieved by day 4 and AUC increase was less than 30%. In PBC patients, mean (SD) C_max and AUC for seladelpar was 103 (29.3) ng/mL and was 902 (238) ng*h/mL, respectively at steady state following once daily dosing of 10 mg.

Absorption

The median time to peak concentration (T_max) was 1.5 hours for seladelpar.

Effect of Food

No clinically significant differences in seladelpar pharmacokinetics were observed following administration of a high-fat meal in healthy subjects.

Distribution

The steady state volume of distribution of seladelpar is approximately 133.2L. Plasma protein binding of seladelpar is greater than 99%.

Elimination

The apparent oral clearance of seladelpar is 12L/h. Following administration of a single dose of 10 mg seladelpar in healthy subjects, mean elimination half-life was 6 hours for seladelpar. In PBC patients, the half-life range was 3.8 to 6.7 hours for seladelpar.

Metabolism

Seladelpar is primarily metabolised in vitro by CYP2C9 and to a lesser extent by CYP2C8 and CYP3A4 resulting in the three major metabolites: seladelpar sulfoxide (M1), desethyl-seladelpar (M2), and desethyl-seladelpar sulfoxide (M3). The metabolite-to-parent AUC ratios were 0.36, 2.32 and 0.63 for M1, M2 and M3, respectively. None of the major metabolites have pharmacological activity.

Excretion

Seladelpar is primarily eliminated in urine as metabolites. Following a single oral dose of 10 mg radiolabelled seladelpar in humans, approximately 73.4% of the dose was recovered in urine (less than 0.01% unchanged) and 19.5% in faeces (2.02% unchanged) within 216 hours.

Specific Populations

No clinically significant differences in the pharmacokinetics of seladelpar were observed based on age (19 to 79 years old), body mass index (BMI) (17.6 to 45.0 kg/m²), weight (45.8 to 127.5 kg), sex, and race (White, Black, or other). No data are available in subjects aged 80 years of age or older.

Renal Impairment

In patients with mild (eGFR ≥60 to <90 mL/min/1.73 m², Modification of Diet in Renal Disease (MDRD) equation), moderate (eGFR ≥30 to <60mL/min/1.73 m²), and severe (<30 mL/min/1.73 m² and not on dialysis) renal impairment, the AUC_inf of seladelpar was 10% higher, 54% higher, and similar to that in patients with normal renal function, respectively, after administration of a single 10 mg dose of seladelpar. The difference in C_max of seladelpar was less than 18% in patients with renal impairment compared to patients with normal renal function. The pharmacokinetics of seladelpar have not been studied in patients requiring haemodialysis.

Dose-dependent increases in serum creatinine have been observed in PBC patients taking seladelpar. Mean creatinine increases of 14% and 27% have been observed at doses of 50 and 200 mg seladelpar (5- and 20-times higher than the recommended 10 mg/day dose). Mean increases of up to 6.6% were observed with the 10 mg dose compared with up to 2.2% in patients taking placebo. Increases were not progressive and returned towards baseline with ongoing treatment with seladelpar in most patients. The clinical significance of these observations is unknown.

Hepatic Impairment

Following a single oral dose of 10 mg seladelpar, seladelpar AUC increased 1.1-fold in patients with mild (Child-Pugh A), 2.5-fold in moderate (Child-Pugh B), and 2.1-fold in severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function. Seladelpar C_max also increased 1.3-fold in patients with mild (Child-Pugh A), 5.2-fold in moderate (Child-Pugh B), and 5-fold in severe (Child-Pugh C) hepatic impairment.

Compared to PBC patients with mild hepatic impairment (Child-Pugh A) without portal hypertension, seladelpar exposures (C_max, AUC) were 1.7 to 1.8-fold higher in PBC patients with mild hepatic impairment with portal hypertension and 1.6 to 1.9-fold higher in PBC patients with moderate hepatic impairment (Child-Pugh B) after a single oral dose of 10 mg seladelpar. Accumulation ratios were less than 1.2-fold in PBC patients with mild hepatic impairment with portal hypertension and PBC patients with moderate hepatic impairment following 10 mg seladelpar once daily dosing for 28 days.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development, or phototoxicity.

Seladelpar was not mutagenic or clastogenic in conventional genotoxicity assays. In 2-year carcinogenicity studies in mice and rats, treatment-related tumours were observed (hepatocellular carcinomas and adenomas and forestomach squamous cell carcinomas in both species; pancreatic acinar cell adenoma and benign testicular interstitial cell tumours in male rats). The forestomach tumours are likely of no clinical relevance to humans and occurred at doses that were associated with exposures 40-fold the clinical AUC at the recommended dose of 10 mg seladelpar. The hepatocellular tumours, benign pancreatic acinar cell and testis tumours were associated with respective exposures of 5-fold, 65-fold and 65-fold the clinical AUC and are typical of tumours related to rodent-specific PPARα agonism, therefore unlikely to be clinically relevant.

Seladelpar had no effects on fertility or reproductive function in male and female rats at oral doses of up to 100 mg/kg/day (223.2-times and 94.5-times the clinical exposure (based on AUC) in male and female rats, respectively).

In embryo-foetal developmental studies, no malformations or effects on embryo-foetal survival occurred in pregnant rats or rabbits after seladelpar treatment at exposures of up to 145.2-times and 40.6-times the recommended dose based on AUC, respectively. In pregnant rabbits, reduced foetal body weight, which was likely due to maternal toxicity including decreases in food consumption, body weight, and gravid uterine weight was observed at 40.6-times, but not at 2.4-times, the recommended dose based on AUC.

In the pre- and postnatal development study, oral administration of seladelpar at doses 5, 20, or 100 mg/kg/day (5-times, 15.2-times, and 145.2-times, the recommended dose based on AUC, respectively) in pregnant rats during organogenesis through lactation resulted in a dose-dependent reduction in pup body weight during the pre-weaning period. The weight reduction in offspring was associated with minor delays in developmental milestones (i.e., eye opening and pinna unfolding at 5 mg/kg/day and higher; hair growth and sexual maturity at 100 mg/kg/day). Reduction in pup body weight at 100 mg/kg/day (145.2-times the recommended dose based on AUC), which continued into the post-weaning maturation period, was associated with a slight decrease in pre-weaning survival and was considered adverse. No adverse effects were found in clinical observations, neurobehavioral assessment, or reproductive performance testing in the offspring of females treated with seladelpar. At 20 mg/kg/day (15.2-times the recommended dose based on AUC), none of the observed effects in offspring were considered to be adverse.

Capsule contents:

Microcrystalline cellulose

Mannitol

Croscarmellose sodium

Butyl hydroxytoluene

Magnesium stearate

Colloidal silicon dioxide

Capsule shell:

Gelatine

Titanium dioxide

Black iron oxide (E172)

Red iron oxide (E172)

Yellow iron oxide (E172)

Indigo carmine (E132)

Black ink used to imprint “10” on the body of the capsule shell:

Shellac (E904)

Propylene glycol (E1520)

Potassium hydroxide (E525)

Black iron oxide (E172)

White ink used to imprint “CBAY” on the cap of the capsule:

Shellac (E904)

Propylene glycol (E1520)

Sodium hydroxide (E524)

Povidone (E1201)

Titanium dioxide

Not applicable.

4 years.

Store below 25ºC.

LIVDELZI capsules are packaged in a 75 mL high density polyethylene bottle closed with a 38 mm polypropylene child resistant cap containing an induction seal. Each bottle contains 30 capsules.

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