Limitations of Use

Use of LIVDELZI is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy) [see Use in Specific Populations (8.7)].

2.1 Recommended Dosage and Administration

The recommended dosage of LIVDELZI is 10 mg orally once daily. Administer LIVDELZI with or without food [see Clinical Pharmacology (12.3)].

2.2 Administration Modification for Bile Acid Sequestrants

Administer LIVDELZI at least 4 hours before or 4 hours after taking bile acid sequestrants, or at as great an interval as possible [see Drug Interactions (7.1)].

5.1 Fractures

Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients [see Adverse Reactions (6.1)].

Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care.

5.2 Liver Test Abnormalities

LIVDELZI has been associated with dose-related increases in serum transaminase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels greater than 3-times upper limit of normal (ULN) in PBC patients receiving 50 mg once daily (5-times higher than the recommended dosage) and 200 mg (20-times higher than the recommended dosage) once daily. Transaminase levels returned to pretreatment levels upon LIVDELZI discontinuation. LIVDELZI 10 mg once daily did not show a similar pattern for increases in transaminase levels [see Overdosage (10)].

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

5.3 Biliary Obstruction

Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Trial 1, 193 patients were randomized to receive either LIVDELZI 10 mg (N=128) or placebo (N=65) once daily for 12 months [see Clinical Studies (14)]. LIVDELZI or placebo was administered in combination with UDCA in 94% of patients and as monotherapy in 6% of patients who were unable to tolerate UDCA.

7.1 Effect of Other Drugs on LIVDELZI

Table 2 includes clinically significant drug interactions affecting LIVDELZI.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of LIVDELZI in pediatric patients have not been established.

8.5 Geriatric Use

Of the 128 LIVDELZI-treated patients in Trial 1, 29 (23%) patients were 65 years of age and older and 2 (2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 to 75 years of age and younger adult patients. No dosage adjustment for patients 65 years of age and older is necessary.

Clinical studies of LIVDELZI did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger adult patients. Because of limited clinical experience with LIVDELZI in patients older than 75 years old, closer monitoring of adverse events in patients older than 75 years is recommended [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

The recommended dosage in patients with mild, moderate, or severe renal impairment is the same as in patients with normal renal function. Patients with end-stage renal disease on dialysis have not been studied [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is recommended for PBC patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3)].

The 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 (e.g., ascites, variceal bleeding, hepatic encephalopathy).

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).

8.8 CYP2C9 Poor Metabolizers

Monitor CYP2C9 poor metabolizers who receive a concomitant moderate to strong CYP3A4 inhibitor more frequently for adverse reactions.

Seladelpar is a CYP2C9 and CYP3A4 substrate. Increased seladelpar AUC is expected in patients who are CYP2C9 poor metabolizers with concomitant use of a moderate to strong CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.5)].

12.1 Mechanism of Action

Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-delta (δ) agonist. However, the mechanism by which seladelpar exerts its therapeutic effects in patients with PBC is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPARδ, which is a nuclear receptor expressed in most tissues, including the liver. Published studies show that PPARδ activation by seladelpar reduces bile acid synthesis through Fibroblast Growth Factor 21 (FGF21)-dependent downregulation of CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Following a single dose administration, seladelpar systemic exposure increased dose-proportionally from 2 mg (0.2 times the recommended dosage) to 15 mg (1.5 times the recommended dosage) and greater than dose proportionally at higher doses. For a dose increase from 10 mg to 200 mg (20 times the recommended dosage), mean Cmax 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) Cmax and AUC for seladelpar was 103 (29.3) ng/mL and 902 (238) ng*h/mL, respectively at steady state following once daily dosing of 10 mg.

12.5 Pharmacogenomics

CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3. Compared to CYP2C9 normal metabolizers (*1/*1, n=84) after a single dose of seladelpar 1 mg to 15 mg, dose-normalized AUC0–inf was 48% higher in CYP2C9 poor metabolizers (*2/*3, n=2) and 24% higher in CYP2C9 intermediate metabolizers (*1/*2, *1/*8, *1/*3, *2/*2, n=28). Dose-normalized Cmax was similar for CYP2C9 normal, intermediate, and poor metabolizers. Seladelpar pharmacokinetics was not evaluated in patients who are CYP2C9 poor metabolizers with two no function alleles (e.g., *3/*3). CYP2C9 poor metabolizers may have increased AUC when seladelpar is used concomitantly with a moderate to strong CYP3A4 inhibitor [see Drug Interactions (7.1), Use in Specific Populations (8.8)].

The prevalence of CYP2C9 poor metabolizers is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African American populations. Additional decreased or nonfunctional alleles (e.g., *5, *6, *11) are more prevalent in African American populations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

In a 2-year study in CD-1 mice, seladelpar produced an increased incidence of lens cataracts at 5 mg/kg/day in both sexes (6-times and 19-times the recommended dose in male and female mice, respectively, based on AUC). In a 2-year study in Sprague-Dawley rats, seladelpar produced an increased incidence of cornea inflammation at 10 mg/kg/day (14-times the recommended dose based on AUC) and cornea mineralization at 30 mg/kg/day (79-times the recommended dose based on AUC), with both effects observed in males only. The incidence of cornea inflammation was not increased in male rats at 3 mg/kg/day (5-times the recommended dose based on AUC).

Baseline Demographics and Characteristics

The mean age of patients was 57 (Range: 28 to 75) years; 95% were female; 88% were White, 6% Asian, 2% Black or African American, and 3% American Indian or Alaska Native. Twenty-nine percent of the patients, 23% in the LIVDELZI 10 mg arm and 42% in the placebo arm, identified as Hispanic/Latino. Thirty-two percent of the patients, 38% in the LIVDELZI 10 mg arm and 20% in the placebo arm, were enrolled in the US.

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 (Range: 161 to 786) units per liter (U/L), corresponding to 2.7-times ULN. The mean baseline TB concentration was 0.8 (Range: 0.3 to 1.9) mg/dL and was less than or equal to the ULN in 87% of the patients. Other mean baseline liver biochemistries were 48 (Range: 9 to 115) U/L for ALT and 40 (Range: 16 to 94) U/L for AST.

Biochemical Results

The primary endpoint was biochemical response at Month 12, where biochemical response was defined as achieving ALP less than 1.67-times ULN, an ALP decrease of greater than or equal to 15% from baseline, and TB less than or equal to ULN. ALP normalization (i.e., ALP less than or equal to ULN) at Month 12 was a key secondary endpoint. The ULN for ALP was defined as 116 U/L. The ULN for TB was defined as 1.1 mg/dL.

Table 3 presents results at Month 12 for the percentage of patients who achieved biochemical response, achieved each component of biochemical response, and achieved ALP normalization. LIVDELZI demonstrated greater improvement on biochemical response and ALP normalization at Month 12 compared to placebo. Overall, 87% of patients had a baseline of TB concentration less than or equal to ULN. Therefore, improvement in ALP was the main contributor to the biochemical response rate results at Month 12.

Figure 1 shows the mean (95% CI) levels of ALP over 12 months. There was a trend of lower ALP in LIVDELZI arm compared to placebo arm starting at Month 1 through Month 12.

* Figure 1 presents means and 95% Wald CIs for baseline, and least squares means and corresponding 95% CIs based on a mixed-effect model for repeated measures (MMRM) for Months 1, 3, 6, 9 and 12. The MMRM adjusts for baseline ALP, baseline ALP level (<350 U/L versus ≥350 U/L), baseline pruritus NRS (< 4 versus ≥4), time (in months), treatment arm, treatment-by-baseline ALP interaction, and treatment-by-time interaction. The least squares mean change from baseline in ALP at Month 12 was -134 (-151, -117) U/L and -17 (-40, 6) U/L in the LIVDELZI 10 mg and placebo arms, respectively.

Figure 1: Mean* ALP in Adult Patients with PBC over 12 Months in Trial 1

Biochemical response at Month 3 comparing LIVDELZI as a monotherapy to placebo was evaluated in a pooled analysis of a subset of patients from Trial 1 and another randomized, double-blind, placebo-controlled trial in a similar patient population. There was a trend of improvement on biochemical response at Month 3 in the LIVDELZI monotherapy group compared to the placebo group.

Pruritus

A single-item patient-reported outcome (PRO), the pruritus Numerical Rating Scale (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 Trial 1. The pruritus NRS was administered daily in a 14-day run-in period prior to randomization through Month 6.

Table 4 presents the results of the comparison between LIVDELZI and placebo on the key secondary endpoint evaluating the change from baseline in pruritus score at Month 6 in patients with baseline average pruritus scores greater than or equal to 4. The baseline average pruritus score for each patient was calculated by averaging the pruritus NRS scores administered in the run-in period and on Day 1 before treatment initiation. The pruritus scores at Month 6 for each patient were calculated by averaging the pruritus NRS scores within the last week in the month. Patients treated with LIVDELZI demonstrated greater improvement in pruritus compared with placebo.

How Supplied

LIVDELZI (seladelpar) capsules are available as 10 mg, light gray opaque body, and a dark blue opaque cap with "CBAY" imprinted on the cap and "10" on the body.

LIVDELZI is packaged in a 75 cc high density polyethylene bottle, closed with a 38 mm polypropylene child resistant cap containing an induction seal.

• 10 mg capsules in a bottle (30 count) (NDC 61958-3301-1).

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Fractures

Inform patients that LIVDELZI may increase the risk of bone fractures. Advise patients to call their healthcare provider to report any fractures [see Warnings and Precautions (5.1)].

Liver Test Abnormalities

Instruct patients to report any signs or symptoms of liver-related adverse reactions (e.g., loss of appetite, nausea, increased fatigue, lower extremity edema, abdominal swelling, or jaundice/icterus) to their healthcare provider [see Warnings and Precautions (5.2)].

Biliary Obstruction

Instruct patients to immediately report any signs or symptoms of biliary obstruction (e.g., right upper quadrant pain, jaundice) to their healthcare provider so that LIVDELZI treatment can be interrupted while the patient is being evaluated [see Warnings and Precautions (5.3)].

Pregnancy

Advise patients that there is a pregnancy safety study that captures pregnancy outcomes in women exposed to LIVDELZI during pregnancy, and to report pregnancies and pregnancy outcomes by calling 1-800-445-3235 [see Use in Specific Populations (8.1)].