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

Absorption
Following once-daily dosing, the steady state of elafibranor and its major active metabolite, GFT1007, was achieved within seven and fourteen days, respectively. The mean (SD) Cmax at steady state was 802 (443) ng/mL for elafibranor and 2058 (459) ng/mL for GFT1007. The mean (SD) AUC was 3758 (1749) ng x h/mL for elafibranor and 11985 (7149) ng x h/mL for GFT1007. Following once-daily dosing of 80 mg in patients with PBC, the median time to peak plasma concentrations (Tmax) of elafibranor and GFT1007 was 1.25 hours (range: 0.5-2 hours). When administered with a high-fat and high-calorie meal, Tmax was delayed by 30 minutes for elafibranor and by 1-hour for GFT1007 compared to in fasted conditions. Under fed condition, mean Cmax and AUC of elafibranor decreased by 50% and 15% respectively and mean Cmax of GFT1007 decreased by 30%, but the AUC was not affected compared to fasted conditions. The difference was not clinically meaningful.

Route of Elimination
Following a single 120 mg oral dose (1.5 times the recommended dose) of 14C-radiolabelled elafibranor in healthy subjects, 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% was recovered in urine, primarily as glucuronide conjugate GFT3351 (11.8% of the administered dose). A negligible amount of unchanged elafibranor or GFT1007 was detectable in the urine. Biliary excretion of elafibranor in humans was suggested by the excretion of 60% of orally administered elafibranor in the bile of rats.

Volume of Distribution
The mean apparent volume of distribution (Vd/F) of elafibranor in healthy subjects was 4731 L, following a single dose of 80 mg under fasted conditions.

Clearance
The mean apparent total clearance (CL/F) of elafibranor was 50.0 L/h after a single 80 mg dose under fasted conditions.

Protein Binding
Elafibranor and GFT1007 were approximately 99.7% bound to plasma proteins, mostly to serum albumin.

Metabolism / Metabolites
Elafibranor is extensively metabolized to form a major active metabolite, GFT1007, the chemical structure of which has not yet been characterized. The mean systemic exposure (AUC) to GFT1007 was 3.2-fold higher than that of elafibranor at steady state. GFT3351, an acyl glucuronide conjugate, is a major inactive metabolite that consists of four stereoisomers. In vitro studies showed that elafibranor was metabolized by 15-ketoprostaglandin 13-Δ reductase (PTGR1), a cytosolic enzyme, to form GFT1007. Elafibranor was also metabolized by CYP2J2, UGT1A3, UGT1A4, and UGT2B7. GFT1007 was further metabolized by CYP2C8, UGT1A3, and UGT2B7.

Biological Half-Life
Following a single 80 mg dose under fasted conditions, median elimination half-life was 70.2 hours (range 37.1 to 92.2 hours) for elafibranor, and 15.4 hours (range 9.39 to 21.7 hours) for major active metabolite GFT1007.

Hepatotoxicity
In preregistration clinical trials, elafibranor was found to decrease both serum aminotransferase and alkaline phosphatase elevations in a high proportion of patients with PBC. In preliminary dose-finding studies in healthy volunteers, elevations of ALT and AST levels above 5 times the upper limit of normal (ULN) were found to be dose related and occurred in one-third of subjects exposed to doses above 120 mg daily. In contrast, in clinical trials of elafibranor in doses of 80 mg daily in patients with NASH and PBC, ALT elevations above 5 times ULN occurred in only 1% to 2% of patients, typically arising within the first few months of therapy and resolving spontaneously without drug interruption and without jaundice or symptoms. Careful assessment of cases with ALT elevations concluded that 3 were possibly due to drug induced injury, 2 among 138 patients with PBC and 1 among 1433 patients with NASH. Among patients with myalgia and CPK elevations during elafibranor therapy, one patient with preexisting cirrhosis who was also taking a statin, developed jaundice [5.5 mg/dL] with elevations in ALT [300 U/L] and AST [828 U/L] concurrent with rhabdomyolysis [CPK 12,647 U/L] and subsequently suffered hepatic decompensation. The incidence of gallstones and cholecystitis also may be increased with elafibranor therapy. Rare instances of drug induced liver injury are known to occur with other PPARα (fenofibrate, bezafibrate) and PPARγ (pioglitazone, rosiglitazone) agonists.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Elafibranor is well-tolerated in Phase II clinical trial; it does not cause weight gain or cardiac events but induces a mild, reversible increase in serum creatinine (effect size vs placebo: 4.31 ± 1.19 μmol/L, P<0.001) [2]
Unlike PPARγ-activating drugs (rosiglitazone, aleglitazar), Elafibranor does not affect heart weight or increase plasma adiponectin concentrations in db/db mice [3]
Long-term (12 months) administration of Elafibranor to cynomolgus monkeys shows no cardiac toxicity, haematological abnormalities, or bone marrow toxicity [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 and pluripotent medication for treatment of atherogenic dyslipidemia for an overweight patient with or without diabetes. It is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.
Elafibranor is an orally available peroxisome proliferator-activated receptor agonist that is used in combination with ursodeoxycholic acid to treat primary biliary cholangitis. Elafibranor therapy is associated with rare instances of worsening of liver enzymes during therapy but has not been convincingly linked to episodes of clinically apparent liver injury with jaundice.

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Drug Indication
Investigated for use/treatment in atherosclerosis and diabetes mellitus type 2.
Treatment of primary biliary cholangitis
Treatment of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH)

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Mechanism of Action
GFT505 is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. It has a sophisticated mechanism of action. It is able to differentially recruit cofactors to the nuclear receptor, which subsequently lead to differential regulation of genes and biological effect. Therefore, the ability to identify and profile the activity of selective nuclear receptor modulator (SNuRMs) is a powerful approach to select innovative drug candidates with improved efficacy and diminished side effects. These pluripotent and multimodal molecules have significant positive effects on obesity, insulin-resistance and diabetes, atherosclerosis, inflammation, and the lipid triad (increasing of HDL cholesterol, lowering of triglycerides and LDL cholesterol).\n

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\nIntroduction: The fibrates have been used for many years to treat dyslipidemias and have also recently been shown to have anti-inflammatory effects. They are relatively weak PPAR-α agonists and do have some adverse effects. Novel compounds are in development, which are selective PPAR modulators (SPPARMs) and have more potent PPAR-α agonist activity. These may prove to have advantages in the treatment of dyslipidemia, insulin resistance and non-alcoholic fatty liver disease (NAFLD).\n\nAreas covered: This review focuses on PPAR-α agonists or SPPARMs in development describing the preclinical and early clinical studies. The information was obtained by searching the published literature and abstracts from recent meetings. Ongoing clinical trials were identified using the Clinicaltrial.gov database.\n\nExpert opinion: There is still a need for new drugs to treat atherogenic dyslipidemia. The highly potent and selective PPAR-α agonist K-877 has shown beneficial effects on atherogenic dyslipidemia and absence of some adverse effects seen with fibrates. The dual PPAR-α/PPAR-δ agonist GFT-505 has shown favorable results in improving atherogenic dyslipidemia and insulin resistance and appears to be a potential candidate for the treatment of NAFLD. Long-term trials are needed to assess the safety and efficacy of these new agents for cardiovascular and liver outcomes.[1]

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\n\n\nNon-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Despite its pandemic proportions, no anti-NASH drugs have been approved yet. This is partially because drug development is decelerated due to the lack of adequate tools to assess the efficacy of potential new drug candidates. The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors. Exposure of these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) resulted in a characteristic NASH response, as indicated by intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the expression and/or secretion of inflammatory markers, including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11. The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and the identification of the same gene classes between the in vitro system and patients suffering from NASH. The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response was NFκB-mediated. In summary, this human-relevant, in vitro system proved to be a sensitive testing tool for the investigation of novel anti-NASH compounds.[4]

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Elafibranor (GFT505) is a dual PPAR-α/δ agonist and liver-targeted investigational drug [1][3]
It is being evaluated in clinical Phase III trials for the treatment of non-alcoholic steatohepatitis (NASH) [4]
Elafibranor exerts anti-diabetic effects in type 2 diabetes models and improves atherogenic dyslipidemia and insulin resistance, making it a potential candidate for NAFLD/NASH treatment [1][3]
Its mechanism of action involves modulation of lipid metabolism, glucose homeostasis, and inflammation, with anti-inflammatory effects mediated via NFκB pathway inhibition [2][3][4]
In clinical trials, Elafibranor 120 mg/d shows better efficacy than 80 mg/d; the predefined primary outcome is not met in intention-to-treat population, but post-hoc analyses demonstrate significant benefits in specific patient subgroups [2]

Pharmacodynamics
Elafibranor inhibits bile acid synthesis. It was also shown to improve insulin sensitivity, glucose homeostasis, and lipid metabolism. In patients with PBC, elafibranor reduced the mean levels of alkaline phosphatase (ALP). An in vitro PPAR functional assay showed that both elafibranor and GFT1007 produced activation of PPARalpha (EC50 = 46 nM and 14 nM, respectively, and Emax = 56% and 61%, respectively, relative to reference agonists). The potency of elafibranor and GFT1007 for PPAR-alpha activation exceeded the respective potencies for PPAR-gamma and PPAR-delta activation by approximately 3- to 8-fold.

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR) α and β/δ agonist that works to inhibit bile acid synthesis. On June 10, 2024, elafibranor was granted accelerated approval by the FDA for the treatment of primary biliary cholangitis (PBC). The drug was also approved by the EMA on September 23, 2024.
Elafibranor is a Peroxisome Proliferator-activated Receptor Agonist. The mechanism of action of elafibranor is as a Peroxisome Proliferator-activated Receptor Agonist, and Cytochrome P450 3A4 Inducer.
Elafibranor is an orally bioavailable agonist of peroxisome proliferator-activated receptor (PPAR)-alpha (PPARa) and -delta (PPARd), with bile acids reducing activity. Upon oral administration, elafibranor, and its main active metabolite GFT1007, target, bind to and activate PPARa and PPARd in the liver. This induces the expression of fibroblast growth factor 21 (FGF21) and downregulates CYP7A1, the key enzyme responsible for the synthesis of bile acids from cholesterol. By reducing CYP7A1 expression, bile acid synthesis is reduced. This leads to reduced bile toxicity, and reduced inflammation and scarring associated with primary biliary cholangitis (PBC).
ELAFIBRANOR is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for cholangitis and has 6 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

88.9

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。