Elafibranor

Elafibranor and its main active metabolite GFT1007 are dual peroxisome proliferator-activated receptor (PPAR)α/δ agonists. PPAR α/δ are thought to be key regulators of bile acid (BA) homeostasis, inflammation and fibrosis.

Activation of PPARα and PPARδ decreases bile toxicity and improve cholestasis by modulating BA synthesis, detoxification and transporters. Activation of PPARα and PPARδ also has anti-inflammatory effects by acting on different pathways.

Pharmacodynamic effects

In the pivotal phase 3 ELATIVE study, treatment with elafibranor resulted in a marked reduction from baseline in alkaline phosphatase (ALP) as early as 4 weeks which was sustained through week 52. In alignment with the observed biochemical response, greater reductions in biomarkers of BA synthesis including the BA precursor 7 alpha-hydroxy-4-cholesten-3-one (C4) and Fibroblast Growth Factor-19 (FGF-19), a BA synthesis regulator, were observed with elafibranor treatment.

Cardiac electrophysiology

Thorough QT (TQT) analysis excluded any prolongation effect of elafibranor on QT/corrected QT (QTc) interval at repeat doses of up to 300 mg for 14 days. In clinical studies, no clinically meaningful changes in vital signs or in electrocardiogram (ECG) (including QTc interval) were observed in participants treated with elafibranor.

Elafibranor plasma exposure (AUC) increases proportionally from 50 to 360 mg (0.6 to 4.5 times the recommended dose). Steady state is achieved by day 14 following once daily dosing. The pharmacokinetics (PK) of elafibranor and its major active metabolite GFT1007 was found to be time-independent after 16-day repeated administration. Elafibranor and its active metabolite exposure in participants with PBC are listed in the following table.

Elafibranor and GFT1007 exposures in participants with PBC at steady state following 80 mg QD (once daily):

Absorption

Following repeated oral administration in participants with PBC, median peak plasma levels of elafibranor and GFT1007 at doses of 80 mg occur within 1.25 hours. When administered with a high-fat and high-calorie meal, there was a 30-minute delay in T_max for elafibranor and a 1-hour delay for GFT1007 in fed compared to fasted conditions. The plasma exposure (AUC) of elafibranor decreased by 15% and the plasma AUC of GFT1007 was not affected. Given the higher circulating plasma levels of the pharmacologically active metabolite GFT1007 compared to elafibranor, food intake was deemed to have limited clinical impact based on overall exposure of parent and active metabolite.

Distribution

Plasma protein binding of both elafibranor and GFT1007 is approximately 99.7% (mainly to serum albumin). The mean apparent volume of distribution (Vd/F) of elafibranor in humans is 4731L, following single dose of elafibranor at 80 mg in fasted conditions.

Biotransformation

In vitro, elafibranor is metabolised by 15-ketoprostaglandin 13-Δ reductase (PTGR1). In vitro neither elafibranor nor GFT1007 show major metabolism by the main cytochrome P450 (CYP) and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) isoforms. Following oral administration of ¹⁴C radiolabelled elafibranor, it was rapidly hydrolysed to the active metabolite GFT1007. Two major metabolites were identified in plasma, GFT1007 (active metabolite) and glucuronide conjugates (inactive metabolites).

Elimination

Following single 80 mg dose under fasted conditions, mean elimination half-life is 68.2 hours for elafibranor, and 15.4 hours for metabolite GFT1007. Elafibranor mean apparent total clearance (CL/F) was 50.0 L/h after a single 80 mg dose under fasted conditions.

Excretion

Following a single 120 mg oral dose of ¹⁴C radiolabelled elafibranor in healthy participants, approximately 77.1% of the dose was recovered in faeces, primarily as elafibranor (56.7% of the administered dose) and its active metabolite GFT1007 (6.08% of the administered dose). Approximately 19.3% recovered in urine, primarily as glucuronide conjugates.

Special populations

There was no evidence that age (from 18 to 80 years old), gender, race, Body Mass Index (BMI), and renal status, had any clinically meaningful impact on elafibranor and GFT1007 PK.

Hepatic impairment

The total drug exposure of the parent and active metabolite was not significantly different between participants with normal hepatic function and hepatically impaired participants (Child Pugh A, B and C). No dose adjustment is required for patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. However, the unbound fraction of elafibranor and GFT1007 increased by approximately 3-fold in the severe (Child Pugh C) hepatically impaired participants. Elafibranor is not recommended for patients with severe hepatic impairment (Child-Pugh C).

Drug-drug interactions

Based on in vitro studies, CYP and UGT enzymes were shown not to play a major role in elafibranor metabolism. Drug-drug interactions (DDI) are expected to be minimal with drugs that significantly alter CYP or UGT activity.

Clinical studies

Warfarin (CYP2C9 substrate):

Concomitant administration of elafibranor with warfarin resulted in no increase in exposure (AUC, C_max) of warfarin, and no difference in international normalized ratio (INR) compared to warfarin alone.

Simvastatin (CYP3A, Breast Cancer Resistance Protein (BCRP), organic anion transporting polypeptides 1B1 (OATP1B1) and OATP1B3 substrates) and atorvastatin (CYP3A, organic anion transporting polypeptides 1B1 (OATP1B1) and OATP1B3 substrates):

Concomitant administration of repeat doses of elafibranor with simvastatin, or atorvastatin, resulted in no increase in exposure (AUC, C_max) of simvastatin or its β-Hydroxyacid metabolite, or atorvastatin.

Sitagliptin (dipeptidyl peptidase-IV (DPP-IV) inhibitor):

No clinically significant effects on blood levels of GLP-1 were observed when co- administering 100 mg of elafibranor as a DDI perpetrator once daily for 15 days with a single oral 100 mg dose of sitagliptin during a meal test.

In Vitro Studies

Cytochrome P450 (CYP) inhibition and induction:

Elafibranor and GFT1007 were not considered inhibitors of main CYPs. No time dependent CYP inhibition was observed. Elafibranor and GFT1007 did not cause induction on CYP1A2, CYP2B6, and CYP3A4.

UGT inhibition:

Based on in vitro data elafibranor and GFT1007 were not expected to inhibit main UGTs at clinically significant concentrations.

Transporter systems:

Elafibranor was an inhibitor of OATP1B3 and BCRP. Based on the in vivo studies with simvastatin and atorvastatin, no clinical consequences are expected from the inhibition of OATP1B3 and BCRP.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity and carcinogenic potential.

Reproduction and development toxicity

Elafibranor has shown evidence of developmental toxicity in both rats and rabbits.In rat pre- and post-natal study, maternal exposures to elafibranor (at or above 2-fold the AUC exposure at the maximum human recommended dose (MHRD)) led to reduced pup survival, developmental delay, or thrombosis. In pregnant rabbits, maternal exposure (3-fold the AUC exposure at MHRD) to elafibranor caused marked maternal toxicity, increased embryo-lethality, reduced foetal weight and a low incidence of foetal malformations.