Elafibranor

CPK elevation and/or myalgia occurred in patients on elafibranor monotherapy. Co-administration of elafibranor and HMG-CoA reductase inhibitors (statins) which have a risk of myalgia, can increase the risk of myopathy by a mechanism that has not been fully characterized.

Monitor for signs and symptoms of muscle injury. Consider periodic assessment (clinical exam, CPK) during treatment. Interrupt elafibranor treatment if there is new onset or worsening of muscle pain or myopathy.

Bile acid sequestrants may interfere with the action of elafibranor by reducing its absorption and systemic exposure, which may reduce elafibranor efficacy.

Administer elafibranor at least 4 hours before or 4 hours after taking a bile acid binding sequestrant, or at as great an interval as possible.

Elafibranor is a weak CYP3A4 inducer. Co-administration of elafibranor and hormonal contraceptives (e.g., birth control pills, skin patches, implant) may reduce the systemic exposure of progestin and ethinyl estradiol (CYP3A4 substrates), which may lead to contraceptive failure and/or an increase in breakthrough bleeding.

Switch to effective non-hormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with elafibranor and for at least 3 weeks after last dose.

Co-administration of elafibranor with rifampin, an inducer of metabolizing enzymes, may reduce the systemic exposure of elafibranor and its active metabolite via increased metabolism and may result in delayed or suboptimal biochemical response.

Monitor the biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during treatment with elafibranor.

The safety and efficacy of elafibranor in patients with decompensated cirrhosis have not been established. Use of elafibranor 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 elafibranor if the patient progresses to moderate or severe hepatic impairment (Child-Pugh B or C).

Risk Summary

Based on data from animal reproduction studies, elafibranor may cause fetal harm when administered during pregnancy. Treatment of pregnant rats with elafibranor during organogenesis through lactation resulted in stillbirths, reduced survival, decrease in pup body weight, and/or blue/black discoloration of the caudal section of body, which occurred at maternal plasma drug exposures lower than or approximately equal to human exposure at the recommended dose (see Data). There are insufficient data from human pregnancies exposed to elafibranor to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 300 mg/kg/day elafibranor (15-times the recommended dose based on combined AUC [area under the plasma concentration-time curve] for elafibranor and GFT1007) during the period of organogenesis.

No adverse effects on embryo-fetal development were observed in pregnant rabbits treated orally with doses up to 100 mg/kg/day elafibranor, which produced systemic exposures (combined AUC for elafibranor and GFT1007) during the period of organogenesis that were less than the human exposure. Administration of 300 mg/kg/day (3.9-times the recommended dose based on combined AUC for elafibranor and GFT1007) produced marked maternal toxicity, embryo-lethality, reduced fetal weight, and a low incidence of fetal malformations. Variations in ossification of distal limb bones occurred at 100 mg/kg/day, which was associated with strong signs of maternal toxicity (e.g., body weight loss).

A pre- and postnatal development study was performed using oral administration of 10, 30, or 100 mg/kg/day elafibranor in female rats during organogenesis through lactation. All doses produced a reduction in pup survival (during postnatal days 1-4 at 100 mg/kg/day and postnatal days 5-21 at 10 mg/kg/day and higher), a decrease in pup body weight (dose-dependent, up to -28% on postnatal day 1), blue/black discoloration of the caudal section of body, and developmental delays based on evaluation of physical landmarks and functional tests. The developmental delays were likely caused by the decrease in body weight. Adverse effects in the offspring occurred at maternal exposures at or above 0.6-times the recommended dose based on combined AUC for elafibranor and GFT1007. Stillbirths were observed in the 30 and 100 mg/kg/day groups (1.3 and 4.9-times the recommended dose, respectively, based on combined AUC for elafibranor and GFT1007). Aortic or iliac arterial thrombosis was found in decedent pups from females treated with 30 or 100 mg/kg/day. The surviving adult offspring showed no effects on learning and memory, reflex development, or reproductive capability.

There are no data available on the presence of elafibranor or its metabolites in human or animal milk, or on effects of the drug on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients not to breastfeed during treatment with elafibranor, and for 3 weeks after the last dose.

Carcinogenesis

In a 2-year study in CD-1 mice, oral administration of elafibranor produced hepatocellular tumors (adenoma or carcinoma) in both sexes at doses of 1, 3, 10, and 30 mg/kg/day (0.007 to 0.14 times the recommended dose in males and 0.003 to 0.16 times the recommended dose in females based on combined AUC for elafibranor and GFT1007).

In a 2-year study in Sprague-Dawley rats, oral administration of elafibranor produced hepatocellular tumors (adenoma or carcinoma) at 10 mg/kg/day and higher in males (0.36 times the recommended dose based on combined AUC for elafibranor and GFT1007) and at 30 mg/kg/day in females (2.1 times the recommended dose based on combined AUC for elafibranor and GFT1007). In males, elafibranor also produced pancreatic acinar cell adenoma and testicular Leydig cell adenoma at 30 mg/kg/day (2.1 times the recommended dose based on combined AUC for elafibranor and GFT1007).

The liver tumors in mice and rats may be attributed to the expected rodent-specific PPARα-related liver toxicity and its related consequences. Therefore, the relevance to humans is uncertain.

Mutagenesis

Elafibranor was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo rat micronucleus assay, and the in vivo rat comet assay. Elafibranor was mutagenic in L5178Y tk+/- mouse lymphoma cells in the absence or presence of metabolic activation and it induced the formation of micronuclei in this cell line in the presence of metabolic activation.

The metabolites GFT1007 and racemic GFT3351 were both negative in the in vitro bacterial reverse mutation (Ames) assay. GFT1007 tested negative in the in vitro micronucleus assay in L5178Y tk+/- mouse lymphoma cells, and GFT3351 tested negative in the in vitro micronucleus assay in human lymphocytes.

The overall data and weight-of-evidence from the comprehensive battery of in vivo and in vitro genotoxicity assays conducted for elafibranor, its principal active metabolite GFT1007, and the acyl glucuronide metabolite racemic GFT3351 indicate that the parent drug and its tested metabolites are unlikely to have genotoxic potential.

Impairment of Fertility

Elafibranor produced no adverse effects on rat fertility or early embryonic development at oral doses up to 100 mg/kg/day (5.9 times the recommended dose in females and 7.4 times the recommended dose in males based on combined AUC for elafibranor and GFT1007).

• Myalgia, Myopathy, and Rhabdomyolysis
• Fractures
• Drug-Induced Liver Injury
• Hypersensitivity Reactions

Clinical Trials 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.

The safety of elafibranor is based on Study 1 consisting of 161 patients who were randomized to receive elafibranor 80 mg (n=108) or placebo (n=53) once daily with a median duration of exposure during the double-blind period of 62 weeks (inter quartile range: 52, 84). Elafibranor or placebo was administered in combination with UDCA in 95% of patients and as monotherapy in 5% of patients who were unable to tolerate UDCA.

The most common adverse reaction leading to treatment discontinuation was increased CPK (4%).

Common Adverse Reactions

Table 1 presents common adverse reactions that occurred in Study 1.

Table 1. Common Adverse Reactions Occurring During the Double-Blind Period in Adult Patients with PBC (Study 1)^a:

^a Included 8 patients (5%) who were intolerant to UDCA and initiated treatment as monotherapy: 6 patients (5%) in the elafibranor arm and 2 patients (4%) in the placebo arm.
^b Occurring in greater than or equal to 5% of patients in the elafibranor treatment arm and at an incidence greater than or equal to 1% higher than in the placebo treatment arm.
^c Weight gain, abdominal pain, muscle pain, fracture, and rash include other related terms.

Myalgia, Myopathy, and Rhabdomyolysis

Muscle injury included rhabdomyolysis, CPK elevation with or without myalgia, and myopathy. Rhabdomyolysis and acute kidney injury (AKI) occurred in one elafibranor-treated patient who had cirrhosis at baseline and was also on a stable dose of an HMG-CoA reductase inhibitor for a year. Median time to development of myalgia was 85.5 days (interquartile range: 29, 291). CPK elevation and/or myalgia occurred in patients on elafibranor monotherapy as well as in patients who were concomitantly treated with an HMG-CoA reductase inhibitor.

Table 2 presents the frequency of muscle injury related adverse reactions in Study 1.

Table 2. Muscle Injury Related Adverse Reactions During the Double-Blind Period in Adult Patients with PBC in Study 1:

^a Two patients receiving elafibranor 80 mg once daily were on a concomitant HMG-CoA reductase inhibitor
^b One patient receiving elafibranor 80 mg once daily was on a concomitant HMG-CoA reductase inhibitor
^c AKI: Acute kidney injury

Fractures

Fractures occurred in 6% (n=7) of elafibranor-treated patients compared to no placebo-treated patients. The median time to fracture after receiving elafibranor was 122 days (interquartile range: 48, 258).

Less Common Adverse Reactions

Additional adverse reactions that occurred more frequently in the elafibranor-treated patients compared to placebo, but in less 5% of patients included dizziness, gastroenteritis, increased blood creatinine, and anemia.

Cholelithiasis and Cholecystitis

New onset of cholelithiasis was detected in 3 (3%) elafibranor-treated patients compared to no placebo-treated patients. The three elafibranor-treated patients were taking UDCA concomitantly. An additional patient who had gallstones at baseline developed cholecystitis requiring cholecystectomy.