PPAR-α (IC50 = 45 nM); PPAR-δ (IC50 = 175 nM)

Absorption
After once-daily administration, elafibranor and its major active metabolite GFT1007 reached steady state in 7 and 14 days, respectively. At steady state, the mean (standard deviation) Cmax of elafibranor was 802 (443) ng/mL, and the mean (standard deviation) Cmax of GFT1007 was 2058 (459) ng/mL. The mean (standard deviation) AUC of elafibranor was 3758 (1749) ng·h/mL, and the mean (standard deviation) AUC of GFT1007 was 11985 (7149) ng·h/mL. In patients with PBC, after once-daily administration of 80 mg, the median time to peak plasma concentration (Tmax) of elafibranor and GFT1007 was 1.25 hours (range: 0.5–2 hours). Compared to the fasting state, when taken with a high-fat, high-calorie meal, the time to peak concentration (Tmax) of elafibranor was delayed by 30 minutes, and the time to peak concentration of GFT1007 was delayed by 1 hour. After eating, the mean peak concentration (Cmax) and area under the curve (AUC) of elafibranor decreased by 50% and 15%, respectively, while the mean peak concentration (Cmax) of GFT1007 decreased by 30%, but the AUC was unaffected compared to the fasting state. This difference was not clinically significant.
Elimination Route
In healthy subjects, following a single oral dose of 120 mg (1.5 times the recommended dose) of radiolabeled elafibranor at 14C, approximately 77.1% of the dose was recovered in feces, primarily as elafibranor (56.7% of the administered dose) and its major metabolite GFT1007 (6.08% of the administered dose). Approximately 19.3% of the drug was recovered in the urine, primarily as the glucuronide conjugate GFT3351 (11.8% of the administered dose). Only trace amounts of unmetabolized elafibranor or GFT1007 were detected in the urine. Following oral administration of elafibranor to rats, 60% of the drug was excreted via bile, suggesting that elafibranor may also be excreted via bile in humans.
Volume of Distribution
The mean apparent volume of distribution (Vd/F) after a single fasting administration of 80 mg elafibranor to healthy subjects was 4731 L.
Clearance
The mean apparent total clearance (CL/F) after a single fasting administration of 80 mg elafibranor was 50.0 L/h.
Protein Binding
Elafibranor and GFT1007 bind to approximately 99.7% of plasma proteins, primarily serum albumin. Metabolites/Metabolites
Elafibranor is extensively metabolized to a major active metabolite, GFT1007, the chemical structure of which is not yet fully understood. At steady state, the mean systemic exposure (AUC) of GFT1007 is 3.2 times that of elafibranor. GFT3351, an acylglucuronide conjugate, is the major inactive metabolite, composed of four stereoisomers. In vitro studies have shown that elafibranor is metabolized to GFT1007 by the cytoplasmic enzyme 15-ketoprostaglandin 13-Δ reductase (PTGR1). Elafibranor is also metabolized via CYP2J2, UGT1A3, UGT1A4, and UGT2B7. GFT1007 is further metabolized via CYP2C8, UGT1A3, and UGT2B7.
Biological Half-Life
After a single 80 mg dose on an empty stomach, the median elimination half-life of elafibranor is 70.2 hours (range 37.1 to 92.2 hours), and the median elimination half-life of the major active metabolite GFT1007 is 15.4 hours (range 9.39 to 21.7 hours).

Hepatotoxicity
In pre-registration clinical trials, elafibranor was found to reduce serum transaminase and alkaline phosphatase levels in a significant proportion of patients with primary biliary cholangitis (PBC). In preliminary dose-exploration studies in healthy volunteers, elevated ALT and AST levels exceeding the upper limit of normal (ULN) by more than 5 times were found to be dose-related, occurring in approximately one-third of subjects receiving daily doses exceeding 120 mg. In contrast, in clinical trials of elafibranor at a daily dose of 80 mg in patients with non-alcoholic steatohepatitis (NASH) and PBC, only 1% to 2% of patients experienced ALT elevations exceeding 5 times the ULN, typically occurring within the first few months of treatment and resolving spontaneously without interruption of treatment or the development of jaundice or other symptoms. Careful evaluation of the ALT elevation cases concluded that three cases were likely due to drug-induced damage: two out of 138 PBC patients and one out of 1433 NASH patients. Among patients who developed myalgia and elevated CPK during elafibranor treatment, one patient with a history of cirrhosis and concurrent statin therapy developed jaundice (5.5 mg/dL), elevated ALT (300 U/L) and AST (828 U/L), along with rhabdomyolysis (CPK 12,647 U/L), subsequently leading to hepatic decompensation. elafibranor treatment may also increase the incidence of gallstones and cholecystitis. Other PPARα (fenofibrate, bezafibrate) and PPARγ (pioglitazone, rosiglitazone) agonists are known to cause rare drug-induced liver injury. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Elafibranor was well tolerated in the Phase II clinical trial; it did not cause weight gain or cardiac events, but it did cause a slight, reversible increase in serum creatinine (effect size compared to placebo: 4.31 ± 1.19 μmol/L, P < 0.001) [2] Unlike PPARγ activators (rosiglitazone, agliflozin), Elafibranor did not affect heart weight or increase plasma adiponectin concentration in db/db mice [3] Long-term (12 months) administration of Elafibranor to cynomolgus monkeys did not show cardiotoxicity, hematological abnormalities or myelotoxicity [3]

[1]. Early investigational drugs targeting PPAR-α for the treatment of metabolic disease.Expert Opin Investig Drugs. 2015 May;24(5):611-21.

[2]. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.

[3]. The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects.Diab Vasc Dis Res. 2014 Nohttps://www.ncbi.nlm.nih.gov/pubmed/25212694.

Elafibranor (code name GFT505) is a multimodal, multi-effect drug for the treatment of atherogenic dyslipidemia in overweight patients with or without diabetes. It is an oral medication that acts on three subtypes of peroxisome proliferator-activated receptor (PPAR) (PPARα, PPARγ, and PPARδ), with a more significant effect on PPARα. As of February 2016, Elafibranor had completed eight clinical trials and was currently undergoing one Phase III clinical trial. Elafibranor is an oral peroxisome proliferator-activated receptor agonist used in combination with ursodeoxycholic acid for the treatment of primary biliary cholangitis. Rarely, elevated liver enzymes have been observed during Elafibranor treatment, but there is no conclusive evidence linking it to clinically significant liver damage with jaundice. Drug Indications It has been investigated for the treatment of atherosclerosis and type 2 diabetes.
Treatment of primary biliary cholangitis
Treatment of non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH)
Mechanism of Action
GFT505 is an oral medication that acts on three subtypes of PPAR (PPARα, PPARγ, PPARδ), preferentially acting on PPARα. Its mechanism of action is complex. It can differentially recruit cofactors to nuclear receptors, leading to differential regulation of gene expression and biological effects. Therefore, identifying and analyzing the activity of selective nuclear receptor modulators (SNuRMs) is an effective method for screening innovative drug candidates with higher efficacy and fewer side effects. These multifunctional molecules have significant positive effects on obesity, insulin resistance and diabetes, atherosclerosis, inflammation, and the lipid triad (increasing high-density lipoprotein cholesterol, decreasing triglycerides and low-density lipoprotein cholesterol).
Introduction: Fibrates have been used for many years to treat dyslipidemia and have recently been shown to have anti-inflammatory effects. These are relatively weak PPAR-α agonists and do have some adverse effects. Novel compounds, selective PPAR modulators (SPPARMs), with stronger PPAR-α agonist activity, are currently under development. These drugs may offer advantages in treating dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). This review focuses on PPAR-α agonists or SPPARMs under development and describes their preclinical and early-stage clinical studies. Information was derived from a search of published literature and recent conference abstracts. Ongoing clinical trials were searched using the Clinicaltrials.gov database. Expert opinion: New drugs are still needed to treat atherosclerotic dyslipidemia. The highly potent and selective PPAR-α agonist K-877 has shown beneficial effects on atherosclerotic dyslipidemia and avoids some of the adverse effects of fibrates. The dual PPAR-α/PPAR-δ agonist GFT-505 has shown promising results in improving atherosclerotic dyslipidemia and insulin resistance and appears to be a potential candidate for the treatment of NAFLD. Long-term trials are needed to evaluate the safety and efficacy of these new drugs for cardiovascular and hepatic outcomes. [1]

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Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with liver inflammation. Despite its global pandemic status, no anti-NASH drugs have been approved. This is partly due to the lack of effective tools for evaluating the efficacy of potential candidates, which has slowed the drug development process. This study describes the construction and application of a novel preclinical model of NASH using hepatocytes derived from human skin precursors. Exposing these cells to adipogenic factors (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) induced a typical non-alcoholic steatohepatitis (NASH) response, characterized by intracellular lipid accumulation, regulation of NASH-specific gene expression, enhanced caspase-3/7 activity, and expression and/or secretion of inflammatory markers (including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL-1α, IL-6, and IL-11). Transcriptomic analysis validated the human relevance of the proposed NASH model, revealing shared genes and gene classes between the in vitro system and NASH patients. Testing elafibranor (a promising anti-NASH compound currently undergoing phase III clinical trials) demonstrated the potential of this in vitro model. Elafibranor alleviated key features of NASH in vitro and significantly reduced lipid load and the expression and secretion of inflammatory chemokines responsible for recruiting immune cells in vivo. This reduction in inflammatory response was mediated by NFκB. In summary, this human-related in vitro system has proven to be a sensitive test tool for studying novel anti-NASH compounds. [4] Elafibranor (GFT505) is a dual PPAR-α/δ agonist and an investigational drug targeting the liver. [1][3] It is currently undergoing a Phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH). [4] Elafibranor has anti-diabetic effects in a type 2 diabetes model and can improve atherosclerotic dyslipidemia and insulin resistance, making it a potential candidate drug for the treatment of NAFLD/NASH. [1][3] Its mechanism of action involves the regulation of lipid metabolism, glucose homeostasis and inflammation, and its anti-inflammatory effect is achieved by inhibiting the NFκB pathway. [2][3][4]
In clinical trials, Elafibranor 120 mg/d showed superior efficacy compared to 80 mg/d; the pre-specified primary endpoint was not met in the intention-to-treat population, but post-hoc analysis showed significant benefit in specific patient subgroups.[2]
Pharmacodynamics
Elafibranor inhibits bile acid synthesis. Studies have also shown that it improves insulin sensitivity, glucose homeostasis, and lipid metabolism. In patients with primary biliary cholangitis (PBC), elafibranor reduced the average level of alkaline phosphatase (ALP). In vitro PPAR function assays showed that both elafibranor and GFT1007 activated PPARα (EC50 of 46 nM and 14 nM, respectively, and Emax of 56% and 61%, respectively, relative to the reference agonist). Elafibranor and GFT1007 exhibit approximately 3 to 8 times greater activation potency for PPAR-α than for PPAR-γ and PPAR-δ, respectively. Elafibranor is a dual agonist of peroxisome proliferator-activated receptor (PPAR) α and β/δ, acting by inhibiting bile acid synthesis. On June 10, 2024, Elafibranor received accelerated approval from the FDA for the treatment of primary biliary cholangitis (PBC). It also received EMA approval on September 23, 2024. Elafibranor is a peroxisome proliferator-activated receptor agonist. Its mechanism of action is as a peroxisome proliferator-activated receptor agonist and a cytochrome P450 3A4 inducer. Elafibranor is an orally bioavailable peroxisome proliferator-activated receptor (PPAR)-α (PPARα) and -δ (PPARδ) agonist that reduces bile acid activity. After oral administration, elafibranor and its main active metabolite GFT1007 target, bind to, and activate PPARα and PPARδ in the liver. This induces the expression of fibroblast growth factor 21 (FGF21) and downregulates CYP7A1 (a key enzyme responsible for the synthesis of bile acids from cholesterol). By reducing CYP7A1 expression, bile acid synthesis is reduced. This reduces bile toxicity and decreases inflammation and scarring associated with primary biliary cholangitis (PBC). Elafibranor is a small molecule drug, currently in Phase IV clinical trials (covering all indications), and was first approved in 2024 for cholangitis, with six other investigational indications.

C22H24O4S

384.49

384.139

C, 68.73; H, 6.29; O, 16.64; S, 8.34

824932-88-9

Elafibranor;923978-27-2

Typically exists as solids at room temperature

1.2±0.1 g/cm3

569.0±50.0 °C at 760 mmHg

297.9±30.1 °C

0.0±1.6 mmHg at 25°C

1.606

5.63

CC1=CC(=CC(=C1OC(C)(C)C(=O)O)C)C=CC(=O)C2=CC=C(C=C2)SC

(E/Z)-GFT505; (E/Z)-Elafibranor

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)