Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)

Harrison, Stephen A.; Thang, Carole; Bolze, Sébastien; DeWitt, Sheila; Hallakou‐Bozec, Sophie; Dubourg, Julie; Bédossa, Pierre; Cusi, Kenneth; Ratziu, Vlad; Grouin, Jean‐Marie; Fouqueray, Pascale

doi:10.1016/j.jhep.2023.02.004

Cited by 32 publications

(14 citation statements)

References 61 publications

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“…According to the preliminary results reported at AASLD 2022 meeting, this drug can reduce the liver fat content in 40% of patients and improve at least 1 fibrosis stage in 30-50% of treated patients. In this trial, up to 30% of patients showed NASH resolution after 36 weeks of treatment with a good safety profile since it lacks the PPAR-gamma side effects of glitazones [71]. The phase 3 trial has not started yet.…”

Section: Other Metabolic Treatmentsmentioning

confidence: 99%

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

et al. 2023

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Metabolic dysfunction–associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.

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Section: Other Metabolic Treatmentsmentioning

confidence: 99%

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

et al. 2023

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“…MSDC-0160 and MSDC-0602 were developed with this in mind, and display significant antidiabetic benefits despite little-to-no PPARg activation [22], [23], [24], [25], [26], [27] . Along these lines, PXL065, which is a stabilized Renantiomer of pioglitazone shown to inhibit the MPC but not bind PPARg, is also in development for MASLD [28] , [29] . MPC inhibitors without an impact on PPARg would likely make for better insulin-sensitizing compounds while avoiding unwanted side effects.…”

Section: Amentioning

confidence: 99%

Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex

Hadfield,

Walker,

Arnatt

et al. 2024

Preprint

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The mitochondrial pyruvate carrier (MPC) plays a role in numerous diseases including neurodegeneration, metabolically dependent cancers, and the development of insulin resistance. Several previous studies in genetic mouse models or with existing inhibitors suggest that inhibition of the MPC could be used as a viable therapeutic strategy in these diseases. However, the MPC structure is unknown, making it difficult to screen for and develop therapeutically viable inhibitors. Currently known MPC inhibitors would make for poor drugs due to their poor pharmacokinetic properties, or in the case of the thiazolidinediones (TZDs), off-target specificity for peroxisome-proliferator activated receptor gamma (PPARgamma) leads to unwanted side effects. In this study, we develop several structural models for the MPC heterodimer complex and investigate the chemical interactions required for the binding of these known inhibitors to MPC and PPARgamma. Based on these models, the MPC most likely takes on outward-facing (OF) and inward-facing (IF) conformations during pyruvate transport, and inhibitors likely plug the carrier to inhibit pyruvate transport. Although some chemical interactions are similar between MPC and PPARgamma binding, there is likely enough difference to reduce PPARgamma specificity for future development of novel, more specific MPC inhibitors.

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“…45 The pharmacological inhibition of MPC in the liver is also relevant to new therapeutic strategies for NASH. 18,21 The liver is essential for lipid metabolism and it has been shown that hepatocyte-specific MPC2 deletion and pharmacological inhibition of MPC with MSDC-0602K in a mouse model of NASH reduced liver injury, fibrosis and hepatic stellate cells activation. 17 In MPC1 KO mice, protection was shown against NASH development after a long-term high fat diet.…”

Section: Metabolic Consequences Of Mpc Deletion or Pharmacological In...mentioning

confidence: 99%

“…MSDC‐0602 K has been considered in clinical trials for the treatment of NASH 18,19 and MSDC‐0160 for Alzheimer's disease 96 . Additionally, a deuterium‐modified (R)‐pioglitazone which lacks in vitro activity for PPARγ is in clinical trials for the treatment of NASH 21 . However, pioglitazone did not inhibit MPC transport in human MPC proteoliposomes to more than 50% of control even at a high concentration of 100 μM 15 .…”

Section: The Various Mpc Inhibitors and Their Proposed Therapeutic Usesmentioning

confidence: 99%

“…14,15 Despite its name, the MPC is unrelated to SLC25 members and was assigned to a new protein family, named SLC54. 16 Given its central role in metabolism, MPC has been proposed as a pharmacological target for different pathologies, including diabetes, non-alcoholic steatohepatitis (NASH), [17][18][19][20][21] neurodegenerative disorders, [22][23][24] and specific cancers. [25][26][27] An increasing number of studies have been addressing the physiological consequences of MPC inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition

Tavoulari,

Sichrovsky,

Kunji

2023

Acta Physiologica

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The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non‐alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero‐dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.

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Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)

Cited by 32 publications

References 61 publications

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment

Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex

Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition

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