WO2025255357A1 - Procédés de préparation et d'entretien de foies et de parties de ceux-ci pour une transplantation hépatique - Google Patents

Procédés de préparation et d'entretien de foies et de parties de ceux-ci pour une transplantation hépatique

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Publication number
WO2025255357A1
WO2025255357A1 PCT/US2025/032469 US2025032469W WO2025255357A1 WO 2025255357 A1 WO2025255357 A1 WO 2025255357A1 US 2025032469 W US2025032469 W US 2025032469W WO 2025255357 A1 WO2025255357 A1 WO 2025255357A1
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Prior art keywords
liver
pyrimidine
compound
perfusion
cyclohexenyl
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English (en)
Inventor
Onno C. MEIJER
Madeleine VAN DIJK
Tijmen MOLL
Marten ENGELSE
Maarten TUSHUIZEN
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Corcept Therapeutics Inc
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Corcept Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • Fatty liver disease is a common condition caused by the storage of extra fat in the liver. Fatty liver disease is due to an abnormal retention of lipid (fats) within hepatocytes. Liver disorders can be categorized in different groups of diseases, such as alcohol-induced fatty liver disease (AFLD), metabolic dysfunction-associated fatty liver disease (MAFLD, formerly NAFLD), metabolism associated steatohepatitis (MASH/NASH), drug-or alcohol-related liver disease, viral diseases, immune mediated liver diseases, metabolic liver diseases, and complications associated with hepatic insufficiency and/or liver transplantation.
  • AFLD alcohol-induced fatty liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • MASH/NASH metabolism associated steatohepatitis
  • drug-or alcohol-related liver disease such as alcohol-induced fatty liver disease (AFLD), metabolic dysfunction-associated fatty liver disease (MAFLD, formerly NAFLD), metabolism associated steatohepatitis (MASH/NASH), drug-or alcohol-
  • liver transplantation In humans, end-stage chronic liver disease or liver failure can be treated with a liver transplantation. Most transplanted livers are obtained from deceased liver donors. Liver disease-related mortality is rising globally, and the demand for suitable organs for transplantation is set to continue to increase. Up to 10,000 liver transplant operations are performed each year in the United States. Thus, there is great need for livers, or portions of livers, that can be used for liver transplantation. However, livers with substantial intra-cellular fat deposition (steatosis), or that exhibit insufficient lactate clearance, are typically not suitable for use in liver transplantation. [0003] In view of the unmet and growing need for livers and liver portions for transplantation, methods for increasing the liver donor pool are needed.
  • liver fat is believed to improve the suitability of the liver or liver portion for use in liver transplantation.
  • Such a reduction in liver fat is believed to increase the amount of time, following removal, that a liver or liver portion may be maintained in condition for use prior to its use in liver transplantation.
  • An increase in the level of triglycerides, or of free fatty acids, or of cholesterol in the perfusate perfusing the isolated liver or liver portion is an indication of fat reduction in the liver or liver portion. (In the following, for brevity, “liver” will refer both to an isolated liver and to an isolated portion of a liver.) It is believed that the additional triglycerides found in the perfusate derive from the liver.
  • the methods comprise perfusing a liver with a solution containing a pyrimidine cyclohexyl compound, such as, e.g., miricorilant (disclosed as Example 6, compound 3b of U.S. Patent 8,685,973), or a pyrimidine cyclohexenyl compound, such as CORT125385 (disclosed as Example 10 of U.S. Patent 11,542,238).
  • a pyrimidine cyclohexyl compound such as, e.g., miricorilant (disclosed as Example 6, compound 3b of U.S. Patent 8,685,973)
  • a pyrimidine cyclohexenyl compound such as CORT125385 (disclosed as Example 10 of U.S. Patent 11,542,238).
  • Applicant discloses herein methods and reagents for preparing a liver for transplantation, effective to reduce liver fat in a donor liver as compared to the initial level of fat in the liver.
  • the methods and reagents for preparing a liver for transplantation are believed to be able to reduce the level of triglycerides, or free fatty acids, or both, in the donor liver as compared to their initial levels.
  • An increase in cholesterol in the perfusate, or a reduction in cholesterol in a liver prior to transplantation may be an indication of the efficacy of the removal of triglycerides or free fatty acids from that liver.
  • the methods and reagents disclosed herein for treating and preparing livers prior to transplantation into a subject in need of a liver transplant may be effective to improve lactate clearance by the liver as compared to the initial level of lactate clearance in the liver.
  • improved lactate clearance may indicate improvement in the metabolism of the liver (e.g., by increased use of lactate as a source of energy, thereby reducing lactate in the perfusate), and may be an indication that a treated liver is suitable for use in transplantation into a subject in need of a liver transplant.
  • Methods and reagents disclosed herein may improve lactate clearance by an isolated liver as compared to the initial level of lactate clearance in that liver.
  • the pyrimidine cyclohexyl compound binds to the glucocorticoid receptor (GR) and is a pyrimidine cyclohexyl glucocorticoid receptor modulator (GRM) or a mixed GR agonist/antagonist.
  • GR glucocorticoid receptor
  • GAM pyrimidine cyclohexyl glucocorticoid receptor modulator
  • mixed GR agonist/antagonist are disclosed, for example, in U.S. Patent 8,685,973.
  • the pyrimidine cyclohexenyl compound binds to the GR and is a pyrimidine cyclohexenyl GRM or a mixed GR agonist/antagonist; such pyrimidine cyclohexenyl compounds are disclosed, for example, in U.S. Patent 11,542,238.
  • the pyrimidine cyclohexyl compound, or the pyrimidine cyclohexenyl compound is present in the perfusate at initial concentrations of between about 0.1 micromolar ( M) and about 100 M, or between about 0.5 M and about 20 M, or between about 1 M and about 10 M.
  • the initial concentration of the pyrimidine cyclohexyl compound or of the pyrimidine cyclohexenyl compound is about 5 M.
  • the liver is placed in the perfusion machine, and is allowed to stabilize while being perfused with a perfusate solution lacking pyrimidine cyclohexyl or pyrimidine cyclohexenyl compounds. Perfusion of the liver with a perfusion solution containing a pyrimidine cyclohexyl compound or a pyrimidine cyclohexenyl compound, or both (“compound-containing perfusate”) may be initiated at any suitable time after placement of the liver in the perfusion machine.
  • Perfusion of the liver with a compound-containing perfusate is typically begun upon metabolic stabilization of the liver in the perfusion machine.
  • the pyrimidine cyclohexyl compound or the pyrimidine cyclohexenyl compound may be included in the perfusate prior to initiating perfusion of the liver; or the pyrimidine cyclohexyl compound or the pyrimidine cyclohexenyl compound may be added to the perfusate upon initiation, or soon after initiation, of perfusion of the liver.
  • further pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound may be added to the perfusate during perfusion of the liver.
  • Such further pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound may be added to the perfusate once, or twice, or more times after initiation of perfusion with compound-containing perfusate.
  • Such further addition of the pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound may be in varying amounts, and at varying time intervals (e.g., at 3 hours, or 3 hour and 6 hours, or 3, 6, and 9 hours) following initiation of perfusion with the compound-containing perfusate, or the further amounts of the pyrimidine cyclohexyl compound or the pyrimidine cyclohexenyl compound may be continuously added to the compound- containing perfusate during perfusion of the liver.
  • the methods and reagents disclosed herein provide improved methods of maintaining a liver, e.g., between the time of its removal from the donor until it is transplanted into the transplant recipient.
  • the methods and reagents disclosed herein provide improved methods of preparing a liver, for transplantation into a recipient.
  • the methods and reagents disclosed herein provide methods and reagents for improving the usefulness of a donor liver for liver transplantation.
  • the methods and reagents disclosed herein provide improved methods for increasing the suitability of a donor liver for use in liver transplantation.
  • the methods and reagents disclosed herein are believed to be able to reduce triglyceride levels in a liver, where the liver would otherwise not be suitable for use in liver transplantation due to excess triglyceride levels in the liver, thereby improving the suitability of that liver for use in liver transplantation.
  • novel methods and novel reagents disclosed herein include disclosure of novel uses, and novel uses of compounds in the manufacture of novel reagents for use in treating livers for transplantation. It will be understood that all such discussion and disclosure of these novel methods and novel reagents apply equally to uses of the novel compound-containing perfusates, including the use of a perfusate comprising a pyrimidine cyclohexyl compound, the use of a perfusate comprising a pyrimidine cyclohexenyl compound, and the use of a perfusate comprising both a pyrimidine cyclohexyl compound and pyrimidine cyclohexenyl compound, in the treatment of a liver for transplantation.
  • FIG.1A provides a schematic diagram representing an exemplary machine for normothermic machine perfusion of a liver. Pyrimidine cyclohexyl- and pyrimidine cyclohexenyl-containing perfusates as disclosed herein may be used to maintain livers prior to liver transplantation, and to prepare them for such transplantation into a recipient.
  • FIG.1B provides an example of a schematic timeline for the treatment of a liver after it has been removed from the donor and prior to transplantation.
  • FIG.2B shows shows hematocrit (Hct) and chemistry (levels of sodium, potassium,chloride, glucose, and lactose) of the perfusate perfusing donor liver LD-24, and in the bile produced by the liver.
  • FIG.2C shows improvement of lactate clearance in 2 out of 4 cases from the perfusate bathing and perfusing a donor liver when miricorilant (5 M) is included in the perfusion reagent.
  • FIG.3A1 presents perfusate triglyceride, cholesterol, and free fatty acids for the donor livers LD-24 LD-26, LD29, and LD-30.
  • FIG.3A2 presents liver triglyceride, cholesterol, and free fatty acids for the liver LD-30, and includes comparative graphs with data from donor livers LD-24, LD-26, LD-29, and LD-30. Triglyceride measurements were based on free glycerol.
  • FIG.3E shows cholesterol measured over time in the perfusate during perfusion of donor liver LD-24 with a miricorilant-containing perfusate. A single measurement of the top layer was made at the end timepoint.
  • FIG.4 shows increased lipid levels in the perfusate bathing both livers treated with the pyrimdine cyclohexenyl compound CORT125385 in the perfusate. The left-most graph shows triglyceride, the middle graph shows total cholesterol, and the right-most graph shows free fatty acid levels for the two livers. DETAILED DESCRIPTION INTRODUCTION [0024] Liver disease can be a serious health threat.
  • liver transplant Patients suffering from a liver disorder such as, e.g., a fatty liver disease, hepatitis, liver failure, liver cancer, cirrhosis, or other liver disorder may be in need of a liver transplant.
  • a liver transplant requires that a liver, or a portion of a liver, be obtained from a donor, and then maintained in a healthy state from the time it was removed from the donor until the time it is surgically placed in the recipient. (As noted above, “liver” will be understood to refer both to a liver, and to a portion of a liver.)
  • livers for transplantation are stored on ice, or in a cold chamber or bath for up to about 12 hours.
  • donor livers may be maintained, prior to transplantation into the recipient, in a machine designed to provide the liver with temperature near body temperature, with sufficient oxygenation to maintain liver health, and other characteristics that those livers require for near-physiologic metabolic activity.
  • livers may remain metabolically active at lower temperatures, or with low oxygenation, etc., it is better to maintain isolated livers in conditions closely approximating the conditions found in a living body than to maintain them in sub-optimal conditions.
  • NMP nonormothermic machine perfusion
  • NMP normothermic machine perfusion
  • Livers with much more fat content than that may be rejected for use in transplantation on the basis of fat content alone.
  • Steatotic livers defined as having intrahepatic triglyceride levels of at least 5% to 10% of liver weight, or as having 5% or more hepatocytes that contain lipid vacuoles, are typically not considered suitable for transplantation.
  • liver transplantation surgery it is believed that such perfusion would improve the condition of such marginal livers so that they would be suitable for use in liver transplantation surgery, and thus to increase the number of livers suitable for use in liver transplantation that are available to treat patients in need of liver transplants. Such increased numbers of suitable livers could be used to treat patients able to benefit from liver transplantation surgery but who might otherwise not have had a liver available to them for transplantation.
  • Donor livers are rare and are a scarce yet critical resource in the treatment of patients with advanced liver disease. Such patients typically have few other treatment options for their potentially fatal conditions.
  • reagents and methods disclosed herein may allow the use of livers that otherwise would not be suitable for transplantation, and so would be discarded and the potential recipient denied the opportunity for transplantation surgery, or the transplant surgery for that potential recipient delayed until a different donor liver would be obtained.
  • delay of such surgery could have dire consequences, and might preclude any surgery if the patient’s health continues to decline.
  • the present methods and reagents are believed to be useful by increasing the donor pool to meet the needs of patients suffering from liver disease and in need of a liver transplant.
  • Applicant discloses herein methods and reagents for preparing a liver for use in a liver transplant.
  • Applicant discloses herein methods and reagents for improving the length of time a liver may be maintained prior to its use in a liver transplant, as compared to the length of time that liver could be maintained, without use of the present methods and reagents, in a machine or container for storage (or maintenance) prior to transplantation.
  • Applicant discloses herein methods and reagents for reducing liver fat levels in a liver for use in a liver transplant, as compared to the initial fat levels in the liver at the time of placement of that liver in a machine or container for storage (or maintenance) prior to transplantation.
  • lactate clearance may be improved in livers for transplantation, as compared to the initial level of lactate clearance in the liver (see, e.g., Fig.2C).
  • Applicant provides improved methods and reagents for use in maintaining livers prior to transplantation, and for use in NMP.
  • the novel reagents disclosed herein include solutions containing a pyrimidine cyclohexyl compound, such as, e.g., miricorilant, or a pyrimidine cyclohexenyl compound, such as, e.g., CORT125385.
  • the novel reagents disclosed herein are compatible with, and supportive of, the maintenance of livers ex vivo for many hours.
  • the novel reagents disclosed herein may include other components, such as, e.g., salts, buffers, and red blood cells.
  • the novel methods disclosed herein include perfusing a liver with such a reagent. [0031] .
  • Applicant discloses herein methods for decreasing levels of liver fat in a liver prior to transplantation of said liver into a recipient, said liver having an initial level of liver fat, the method comprising: Perfusing said liver with a solution comprising a pyrimidine cyclohexyl or a pyrimidine cyclohexenyl compound for a period of time, Whereby the level of liver fat in the liver is decreased as compared to said initial level of liver fat.
  • Liver fat may be, or may include, triglycerides, free fatty acids, and other lipids and lipid-soluble compounds.
  • the liver may be perfused for as long as needed; e.g., for up to a day, or up to two days, or up to a week.
  • the period of time may be any suitable time, including periods of time of between about one hour and about twelve hours, or about a day, or about two days, or longer.
  • further pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound may be added to the perfusate after initiation of perfusion with compound-containing perfusate.
  • Such further addition of the pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound to the perfusion solution may be in varying amounts, and at varying time intervals (e.g., at 3 hours, or 3 hour and 6 hours, or 3, 6, and 9 hours).
  • these reagents may be used to decrease liver fat levels in a liver after removal of that liver from the liver donor, as compared to the fat levels in the liver prior to placement of the liver in a container or machine for maintenance of a liver prior to transplantation.
  • the reagent comprises a pyrimidine cyclohexyl compound such as, e.g., miricorilant, or a pyrimidine cyclohexenyl compound, such as, e.g., CORT125385.
  • Liver fat may be, or may include, triglycerides, free fatty acids, and other lipids and lipid-soluble compounds.
  • the reagent includes between about 0.1 micromolar ( M) and about 100 M, or between about 0.5 M and about 20 M of the pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound, or between about 1 M and about 10 M of the pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound. In embodiments, the reagent includes about 5 M of the pyrimidine cyclohexyl compound or pyrimidine cyclohexenyl compound.
  • pyrimidine cyclohexyl and pyrimidine cyclohexenyl compounds suitable for the methods and uses disclosed herein bind to GR, and modulate GR as GRMs or mixed GR agonist/antagonists.
  • Pyrimidine cyclohexyl compounds suitable for the methods and uses disclosed herein are disclosed in U.S. Patent 8,685,973.
  • the pyrimidine cyclohexyl compound is miricorilant, (E)-6-(4- Phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione, which has the structure (Example 6, compound 3b of U.S. Patent 8,685,973, hereby incorporated by reference in its entirety).
  • Pyrimidine cyclohexenyl compounds suitable for the methods and uses disclosed herein are disclosed in U.S. Patent 11,542,238.
  • the pyrimidine cyclohexenyl compound is CORT125385, 5-benzyl-6-(4'-chloro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'- biphenyl]-4-yl)pyrimidine-2,4(1H,3H)-dione, which is disclosed as Example 10 of U.S. Patent 11,542,238, and which has the structure .
  • CORT125385 has two enantiomers: (R)-5-benzyl-6-(4'-chloro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)pyrimidine-2,4(1H,3H)-dione, which has the structure 5-benzyl-6-(4'-chloro-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)pyrimidine- 2,4(1H,3H)-dione, which has the enantiomers may be used in the practice of the methods and uses disclosed herein.
  • the term “perfusate” refers to a reagent as described herein when used to perfuse a liver.
  • the initial concentration of the pyrimidine cyclohexyl compound or the pyrimidine cyclohexenyl compound is about 5 M.
  • such compound levels are the initial levels of the pyrimidine cyclohexyl or the pyrimidine cyclohexenyl compound in the reagent; it will be understood that the level of the pyrimidine cyclohexyl compound (e.g., miricorilant) or the pyrimidine cyclohexenyl compound (e.g., CORT125385) may be reduced over time during use (e.g., during perfusion of a liver).
  • pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound in order to maintain the pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound levels over time during perfusion of a liver with a compound-containing perfusate, further pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound may be added to the perfusate during perfusion of the liver with a compound-containing perfusate.
  • Such addition may be in varying amounts at varying intervals following initiation of perfusion with a compound-containing perfusate, or the further amounts of the pyrimidine cyclohexyl or the pyrimidine cyclohexenyl compound may be continuously added to the perfusate during perfusion of the liver with compound-containing perfusate.
  • Such further addition of the pyrimidine cyclohexyl or the pyrimidine cyclohexenyl compound may be effective to replace pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound lost or metabolized during perfusion, and may be effective to maintain the concentration of the pyrimidine cyclohexyl or the pyrimidine cyclohexenyl compound in the compound-containing perfusate during perfusion of the liver.
  • Such maintained concentration of the pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound may be, e.g., between about 1 M to about 10 M, and may be about 5 M.
  • the reagent comprises a pyrimidine cyclohexyl compound, a pyrimidine cyclohexenyl compound, or both, and red blood cells.
  • the reagents as disclosed herein may include leukocytes, may include thrombocytes, and may include both leukocytes (e.g., up to about 1x 10 6 /L) and thrombocytes (e.g., up to about 10x10 9 /L).
  • leukocytes e.g., up to about 1x 10 6 /L
  • thrombocytes e.g., up to about 10x10 9 /L
  • other compounds and medications may be included in the reagents.
  • the perfusing step in the methods disclosed herein may include perfusion of the liver with a compound-containing perfusate for a period of time, where the period of time may be between about 15 minutes to about 12 hours, inclusive, and may continue for longer periods of time. In embodiments of the methods, the perfusing step continues for at least three hours. In embodiments of the methods, the perfusing step continues for at least six hours. In embodiments of the methods, the perfusing step continues for at least nine hours. In embodiments of the methods, the perfusing step continues for at least 12 hours.
  • Perfusion may comprise perfusion of the liver with a compound-containing perfusate at a perfusion rate of between about 0.5 liter per minute (L/min) to about 5 L/min, inclusive. In embodiments, the perfusion rate is selected from 1 L/min, 2 L/min, 3 L/min, 4 L/min, and 5 L/min.
  • Liver fat may comprise many components, including triglycerides, free fatty acids, and lipid soluble compounds such as cholesterol.
  • the amount of liver fat is decreased by at least about 10%, or by at least about 15% as compared to said initial amount of liver fat, after about 3 hours of perfusion, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver. In further embodiments of the methods disclosed herein, the amount of liver fat is decreased by at least about 20%, or by at least about 30%, as compared to said initial amount of liver fat, after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver.
  • Such reductions in liver fat may be reductions in triglyceride levels, where liver triglyceride levels are decreased by at least about 10%, or by at least about 15%, or by at least about 20%, or by at least about 30%, after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver.
  • Such reductions in liver fat may be reductions in free fatty acid levels, where liver free fatty acid levels are decreased by at least about 10%, or by at least about 15%, or by at least about 20%, or by at least about 30%, after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver.
  • Reductions in cholesterol levels, where liver cholesterol levels are decreased by at least about 10%, or by at least about 15%, or by at least about 20%, or by at least about 30%, after at least about 3 hours of perfusion of the liver may provide an indirect measure of the efficacy of the perfusion in removing liver fat.
  • An indication of decreased liver fat, and of decreased liver triglyceride, free fatty acid, and cholesterol levels is an increase in the level of fat, or of triglyceride, or of free fatty acid, or of cholesterol, in the perfusate which is perfusing the liver. Such levels increase over time during perfusion of a liver with reagents as disclosed herein.
  • Changes of these levels in the perfusate over time during perfusion of a liver with a reagent disclosed herein provide indications of changes over time of liver fat, triglyceride, free fatty acid, and cholesterol levels in the liver, and may be used to track such changes, and to determine when, and if, a particular liver is suitable for use in transplantation.
  • the amount of triglyceride in the perfusate is increased by at least about 10% (where % indicates weight percent) as compared to said initial amount of triglyceride in the perfusate after about 3 hours of perfusion, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • the amount of triglyceride in the perfusate is increased by at least about 15% as compared to said initial amount of triglyceride in the perfusate after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver. In further embodiments of the methods disclosed herein, the amount of triglyceride in the perfusate is increased by at least about 20%, or by at least about 30%, as compared to said initial amount of triglyceride in the perfusate after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver.
  • the amounts of fatty acids in the perfusate are increased by at least about 10% (where % indicates weight percent) as compared to said initial amounts of fatty acids in the perfusate after about 3 hours of perfusion, or after about 6 hours , or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • the amounts of fatty acids in the perfusate are increased by at least about 15% as compared to said initial amounts of fatty acids in the perfusate after about 3 hours of perfusion, or after about 6 hours of perfusion of the liver.
  • the amounts of fatty acids in the perfusate are increased by at least about 20%, or by at least about 30%, as compared to said initial amounts of fatty acids in the perfusate after about 3 hours of perfusion, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • detectable amounts of triglyceride are observed in the perfusate after about one hour, or after about 2 hours, or after about 3 hours, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • detectable amounts of fatty acids are observed in the perfusate after about one hour, or after about 2 hours, or after about 3 hours, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • detectable amounts of cholesterol are observed in the perfusate after about one hour, or after about 2 hours, or after about 3 hours, or after about 6 hours, or after about 8 hours, or after about 10 hours, or after about 12 hours, or after about 15 hours, or after about 18 hours, or after about 24 hours, or more, of perfusion of the liver.
  • the salt composition, pH, and osmolarity of the perfusate are all similar to the corresponding salt composition, pH, and osmolarity of normal human blood, and are all compatible with the physiological maintenance of mammalian tissue.
  • reagents disclosed herein may comprise between about 135 and about 150 millimolar (mM) sodium; between about 3 and about 6 mM potassium; between about 120 and about 160 mM chloride, or other halide; between about 10 and about 50 mM buffer, such as a carbonate, or phosphate, or other buffer (e.g., 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), or tris(hydroxymethyl)aminomethane (TRIS) or other physiologically acceptable buffer); and may include an antioxidant such as, e.g., butylated hydroxytoluene (BHT), buylated hydroxyanisole (BHA), tert-butyl hydroquinone (TBHQ), a tocopherol, or other physiologically acceptable antioxidant.
  • BHT butylated hydroxytoluene
  • BHA buylated hydroxyanisole
  • TBHQ tert-butyl hydroquinone
  • perfusates for use in perfusing livers may include glucose, for example, may include between about 2 mM to about 50 mM glucose, or about 3 mM to about 8 mM glucose, or between about 4 mM to about 6 mM glucose.
  • An exemplary infusion solution may contain sodium taurocholate (e.g., 5.6 grams (g) dissolved in 27 ml NaCl, to a final volume 30 ml); may contain Flolan ® (available from GlaxoSmithKline, Durham, North Carolina, USA, at a level of, e.g., 0.25 mg in 30 ml); may contain heparin (e.g., 25,000 units); may contain aminoplasmal with 10% glucose (e.g., 375 ml aminoplasmal mixed with 125 ml of 40% glucose; these components may be combined to provide 500 ml aminoplasmal with 10% glucose) for infusion at an infusion rate of about 1 ml/hour into a perfusate bathing a liver.
  • sodium taurocholate e.g., 5.6 grams (g) dissolved in 27 ml NaCl, to a final volume 30 ml
  • Flolan ® available from GlaxoSmithKline, Durham, North Carolina, USA, at a level of
  • the perfusate will typically be provided with, e.g., nitrogen, oxygen, carbon dioxide, and/or other gases, where provision of such gas or gases may be effected by bubbling gas through the liquid perfusate, by using a membrane oxygenator, or by otherwise contacting the liquid perfusate with the gas or gasses.
  • reagents disclosed herein may have a pH of between about pH 7.0 to about pH 7.8, preferably between about pH 7.3 to about pH 7.5, or between about pH 7.35 to about pH 7.45 when in use in perfusing a liver (where about, as used here, indicates ⁇ 0.1 pH).
  • the perfusate pH is initially set at pH 7.35 to about 7.45, as a healthy liver should be able to restore the perfusate pH by itself to about pH 7.4.
  • the perfusate (and liver perfused by the perfusate) will typically be maintained at a physiological temperature of about 35° C to about 38° C, or preferably about 36° C to about 37° C.
  • a compound is substituted with "an" alkyl or aryl
  • the compound is optionally substituted with at least one alkyl and/or at least one aryl, wherein each alkyl and/or aryl is optionally different.
  • a compound is substituted with "a” substituent group
  • the compound is substituted with at least one substituent group, wherein each substituent group is optionally different.
  • the term “soon after” refers to a time within fifteen minutes, or within half an hour, or within an hour of the referred-to event.
  • liver refers to a whole liver, and also includes reference to a portion of a liver.
  • references to a liver and to a portion of a liver include reference to isolated livers and to isolated liver portions, e.g., to a liver, or a portion thereof, that has been removed from a donor in preparation for its transplantation to a recipient. Livers for transplantation, and portions of such livers, must be isolated (i.e., removed from the donor) prior to use in a liver transplantation procedure.
  • donor and “liver donor” refer to a mammal, typically a human, that is or will be having their liver, or a portion thereof, removed for use in liver transplantation.
  • Fatty liver disease refers to a mammal, typically a human, that is or will be receiving, or has received, a liver via liver transplantation.
  • FLD Fatty liver disease
  • FLD also known as hepatosteatosis
  • FLD includes, e.g., alcoholic fatty liver disease, and nonalcoholic fatty liver disease.
  • Fatty liver disease may be, e.g., macrovesicular steatosis or microvesicular steatosis.
  • the term “reagent” refers to a composition for use in one or more of preparing a liver for transplantation into a recipient; maintaining a liver prior to transplantation into a recipient; reducing triglyceride levels, or fatty acid levels, or both in a liver for liver transplantation. Use of a reagent in the perfusion of an isolated liver may result in improving lactate clearance in that liver for liver transplantation; and other uses related to liver transplantation.
  • perfusate and “perfusion solution” refer to a solution for perfusing a liver.
  • a reagent containing a pyrimidine cyclohexyl compound as disclosed herein is a perfusate, and is a perfusion solution, when used to perfuse a liver.
  • a liver may be perfused a) when placed in a perfusate (e.g., a reagent containing miricorilant), b) when a perfusate is pumped into a vein or artery of the liver, or both a) and b).
  • perfusate may be introduced into a liver via the hepatic artery or portal vein (or both) and may exit the liver via the hepatic veins (also termed portal veins, which connect with the inferior vena cava).
  • Perfusate exiting the liver may be recycled back into the liver again, or, in some cases, may be discarded and fresh perfusate introduced into the liver. In embodiments, some of the perfusate exiting the liver may be discarded and some recycled back into the liver again, while some fresh perfusate is also introduced into the liver as needed.
  • gelofusine refers to Gelofusine ® and related plasma substitutes and plasma volume expanders.
  • the commercial product gelofusine ® is a water-based 4% (w/v) succinylated gelatin solution containing sodium chloride (where w/v means weight per volume); 1 L of gelofusine contains: 40 grams (g) of succinylated gelatin, 154 mmol/L sodium, 120 mmol/L chloride, water for injection, and sodium hydroxide for pH adjustment.
  • GR glucocorticoid receptor
  • the term “glucocorticoid receptor” (“GR”) refers to the type II GR, an intracellular receptor which specifically binds to cortisol and/or cortisol analogs such as dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol.
  • TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.
  • GRMs can combine agonist and antagonist characteristics, based on different readouts for GR activity.
  • the term "compound” is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety (“compound”) may exist in a free species form, in which it is not associated with other molecules.
  • Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, in combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pyrimidine cyclohexyl compound refers to a compound, and salts thereof, as described and disclosed in U.S. Patent 8,685,973, the entire contents of which patent is hereby incorporated by reference in its entirety.
  • the pyrimidine cyclohexyl compound is selected from the group consisting of: .
  • the pyrimidine cyclohexenyl compound suitable for use in the methods and uses disclosed herein is selected from the group consisting of the compounds disclosed in US 11,542,238, hereby incorporated by reference in its entirety.
  • the pyrimidine cyclohexenyl compound may be selected from the group consisting of the compounds claimed in any of the claims of US 11,542,238.
  • the pyrimidine cyclohexenyl compound suitable for use in the methods and uses disclosed herein may be, for example, a compound claimed in US 11,542,238.
  • the pyrimidine cyclohexenyl compound is the compound CORT125385 which is claimed in claim 24 of US11,542,238, having the chemical name 5-benzyl-6-(4'-chloro- 2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)pyrimidine-2,4(1H,3H)-dione, and having the structure (the racemic mixture), and its enantiomers claimed in claims 31 and 32 of that patent:
  • metabolic stabilization e.g., as referring to a liver placed in a perfusion machine, refers to the adjustment of the liver to the conditions in the perfusion machine, while being perfused with a standard perfusate, in which, after a period of time, the conditions of the liver become reasonably constant as indicated by analytes or metabolites measured in the perfusate.
  • Clinical phase refers to the initial time period during which an isolated liver or liver portion, placed in a perfusion machine, is considered to be suitable for use for transplantation into a recipient in need of a liver transplant (see Fig. 1B).
  • An isolated liver or liver portion typically achieves metabolic stabilization in the clinical phase during perfusion; although the examples discussed in the present application are from livers that were declined for use in transplantation, perfusion with compound-containing perfusate may begin during the clinical phase, and livers treated with compound-containing perfusate may be used for transplantation.
  • the liver or portion thereof may be perfused with the perfusate via a vein or artery as well (e.g., tubing containing the perfusate may be connected to the hepatic artery and portal vein for fluid flow into the liver, with perfusate exiting via the hepatic veins (also termed portal veins, which connect with the inferior vena cava).
  • the perfusate includes red blood cells; preferred perfusates do not include, or include only a minimal amount of, white blood cells (WBCs).
  • WBCs white blood cells
  • FIG.1A provides a schematic illustration of a system for perfusing a liver according to the methods disclosed herein.
  • the perfusate enters the reservoir from above and leaves at the bottom, and so is in constant movement.
  • a tube that has the blood parameter sensor and the sampling port connects to tubing that goes from the oxygenator directly to the reservoir.
  • Perfusate enters the liver from the reservoir (e.g., via “arterial tubing” connected to the hepatic artery and portal vein).
  • lipid layer is indicative of increased lipid or lipid soluble components (e.g., triglyceride, cholesterol, and/or fatty acids) in the perfusate, and that such a lipid layer is indicative of decreased amounts of lipids and lipid soluble compounds in the liver.
  • the perfusate consisted of Gelofusine ® as the perfusate base with packed red blood cells (RBCs; the packed RBCs are similar to the regular RBCs used for transfusions).
  • RBCs red blood cells
  • perfusates may also include human serum human serum albumin, and other physiologically acceptable components.
  • Standard RBCs were used in the perfusate; such RBCs contain less than 10 6 /unit leukocytes (where a unit is about 280 mL) and less than 10 10 /L thrombocytes.
  • the RBCs may be matched packed cells, and need not be obtained from the liver donor.
  • perfluorocarbon synthetic artificial blood formulations may be included in the perfusate to provide or enhance oxygenation.
  • the perfusate included the following: 0.5 L + liver volume Gelofusine ® , 2.5 RBC bags, 10k U heparin, 10% Calcium gluconate, and 5 M Miricorilant.
  • the perfusate included heparin, bile salts such as sodium taurocholate, epoprostanol, insulin and Aminoplasmal with 10% glucose.
  • Such perfusates as described herein, without added pyrimidine cyclohexyl or pyrimidine cyclohexenyl compound, are standard perfusates.
  • liver enzymes e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)
  • other analytes were measured.
  • liver enzyme levels including alanine aminotransferase (ALT), aspartate aminotransfersase (AST), alkaline phosphatase (AP), and/or glutamyl transpeptidase (GGT)).
  • liver proteins including haptoglobin, total bilirubin, alpha-2-microglobulin, resistin, cleaved or intact cytokeratin-18
  • haptoglobin including haptoglobin, total bilirubin, alpha-2-microglobulin, resistin, cleaved or intact cytokeratin-18
  • serum glucose and insulin resistance parameters Since the level of ALT activity is frequently increased in NASH patients (Angulo and Lindor, Best Pract Res Clin Gastroenterol, 2002, 16(5):797-810), this criterion was considered a surrogate marker for assessing liver injury.
  • Livers were obtained from livers donated for transplant that were subsequently deemed unsuitable for use in transplantation into a liver transplant recipient.
  • livers for transplantation were placed in a perfusate lacking pyrimidine cyclohexyls, and maintained for several hours, until such time as that liver was deemed unsuitable for transplantation (e.g., by rising lactate levels rendering the liver unsuitable), at which time the perfusate was changed to one including the pyrimidine cyclohexyl compound miricorilant at a concentration of 5 M. Samples of the perfusate and from the liver itself were obtained at this time. The livers were treated with miricorilant-containing perfusate, and samples of the perfusate and liver were obtained at multiple timepoints during perfusion. Note that the “clinical phase” illustrated in Fig.1B is optional.
  • Characteristics of the donors from whom these livers were obtained are presented in the following Table: TABLE 2 [0088] As illustrated in Fig. 2A, blood pH rose, bile pH fell, while blood and bile gas (CO 2 and bicarbonate levels) measurements remained fairly constant over time during ten hours of perfusion of a liver (where “blood” indicates the perfusate).
  • these measurements are of interest since the bile pH, lactate and glucose levels provide indications regarding the quality of the bile, and thus the functioning of the liver. While the titles refer to gases, these graphs include measures of the partial pressure of CO2 gas (pCO2 in mmHg) and also include measurements of the compound bicarbonate in solution in the perfusate/bile (HCO3-). [0089] As illustrated in Fig.
  • lactate clearance was improved following inclusion of 5 M miricorilant in the perfusate; in two instances immediate improvement was observed; in two other instances, beneficial effects may have been delayed. Insufficent lactate clearance can be a reason to decline a donor liver. Renewed lactate clearance as shown in the figure is important because it indicates that the liver is utilizing the lactate and turning it into energy to use for its metabolic processes.
  • Renewed lactate generation very shortly after miricorilant administration indicates that miricorilant acts on the liver to stimulate or restore liver defatting processes that need energy. Improved lactate clearance may be an indication that the condition of a prospective donor liver is improving, and may suggest that the prospective donor liver may be suitable for transplantation.
  • lactate levels in the perfusate perfusing the donor liver LD- 24 (which was insufficient at the start of miricorilant treatment) decreased over time during perfusion with a perfusate containing 5 M miricorilant. Lactate levels in the perfusate perfusing the donor liver LD-26 first increased, then decreased over time during perfusion with a perfusate containing 5 M miricorilant.
  • Lactate levels in the perfusate perfusing donor liver LD-29 decreased over time during perfusion with a perfusate containing 5 M miricorilant. Lactate levels in the perfusate perfusing donor liver LD-30 (a steatotic liver) first increased, remained steady for about 3 hours, then decreased during perfusion with a perfusate containing 5 M miricorilant.
  • FIG.3A shows that donor liver perfusion with a perfusion reagent containing 5 M miricorilant increased lipid levels in the perfusate in 2 of 4 livers. Lipid levels measured included the levels of triglyceride, cholesterol, and fatty acids shown in the figure.
  • FIG.3B is an image showing the lipid layer formed at the surface of the miricorilant- containing perfusate perfusing donor liver LD-24. Such lipid layers are not typically seen on the surfaces of perfusates lacking miricorilant during perfusion of livers.
  • FIGs.3C, 3D, and 3E show the levels of triglycerides, free fatty acids, and cholesterol levels measured over time during perfusion of donor liver LD-24 with a miricorilant-containing perfusate. Triglyceride, free fatty acids, and cholesterol levels measured in the perfusate are shown. [0094] Triglyceride levels in the perfusate at six hours of perfusion were enriched as compared to the initial triglyceride levels in the perfusate during perfusion with a perfusate containing 5 M miricorilant.
  • lipid levels in the perfusate may increase over time during perfusion of a liver with a miricorilant-containing perfusate.
  • lipids in a distinct layer on top of the perfusate reservoir were enriched when measured after six hours of perfusion. It is believed that the source of the lipids that make up such increased lipid levels was the donor liver itself.
  • Such increases in lipid levels are thus believed to be due to transfer of the lipids from the donor liver to the miricorilant-containing perfusate and to a layer that may form on top of the miricorilant-containing perfusate. (Such a layer may appear thicker, and appear to be more yellow, than the perfusate below the upper layer; it may resemble the sort of separation that may be seen when mixing water and oil.)
  • perfusion of a donor liver with a miricorilant-containing perfusate can be effective to reduce lipid levels in that donor liver, or in portions of that donor liver, and to improve lactate clearance by the liver.
  • This Example discusses results from the preparation and maintenance of a liver for later use in a liver transplantation surgical procedure in which the pyrimidine cyclohexenyl compound CORT125385 was included in the perfusate. This compound was added to the perfusate perfusing the livers as a racemic mixture including both enantiomers of CORT125385. Similar to the perfusate used with miricorilant, the perfusate to which CORT125385 was added was as described in Table 1 above, with 5 M CORT125385 instead of 5 M miricorilant.
  • CORT125385 was added to the perfusate upon metabolic stabilization of the liver and then every 3 hours thereafter.
  • an infusion solution containing bile salts, epoprostenol, heparin, insulin, and aminoplasmal with 10% glucose was continuously added to the perfusate during perfusion.
  • Perfusate samples were taken from oxygenated blood before it entered the hepatic artery.
  • CORT125385 was added to the perfusate upon metabolic stabilization of the liver and then every 3 hours thereafter.
  • Two livers were treated with CORT125385, from liver donors identified as LD-36 and LD-37.
  • Liver LD-36 weighed 2.48 kilograms (kg) and was obtained from a man who was 67 years old at the time of circulatory death; his body mass index (BMI) was 34.
  • BMI body mass index
  • the liver was declined for transfusion due to steatosis. It received 12 hours of CORT125385 perfusion out of a total of 15 hours perfusion time. This liver was maintained on ice for approximately one and one half hours after preparation for perfusion but before starting perfusion.
  • Liver LD-37 weighed 2.2 kg and was obtained from a male who was 73 years old at the time of brain death; his body mass index (BMI) was 26. The liver was declined for transfusion due to greater than 50% steatosis; at that time preparation for NMP was begun. The liver received 12 hours of perfusion.
  • BMI body mass index
  • perfusate lipid levels in both livers treated with CORT 125385 increased over time during perfusion with perfusate including 5 M CORT 125385.
  • Perfusate triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA) levels increased in both livers during perfusion.
  • perfusion of isolated livers with the pyrimidine cyclohexenyl compound CORT125385 increased perfusate lipid levels (e.g., TG, TC, and FFA).
  • perfusate lipid levels e.g., TG, TC, and FFA.

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Abstract

La demanderesse divulgue des procédés et des réactifs pour le traitement de foies isolés, ou de parties de foie isolées, avant la transplantation chez un sujet ayant besoin d'une transplantation hépatique, l'objectif étant de préparer et maintenir ces foies isolés et parties isolées en vue d'une transplantation hépatique, et de réduire la graisse hépatique dans ces foies. Les procédés comprennent la perfusion d'un foie isolé ou d'une partie hépatique isolée avec une solution contenant un composé de pyrimidine cyclohexyle (par exemple, le miricorilant) ou un composé de pyrimidine cyclohexényle (par exemple, CORT125385). Les réactifs destinés aux utilisations et procédés de l'invention contiennent un composé de pyrimidine cyclohexyle ou un composé de pyrimidine cyclohexényle. La perfusion avec des réactifs contenant du miricorilant a amélioré la réduction du lactate. La perfusion de foies isolés avec ces réactifs a augmenté les niveaux de lipides dans le perfusat par rapport aux niveaux initiaux. Il est supposé que l'amélioration de la réduction du lactate et l'accroissement des niveaux de lipides dans le perfusat indiquent une réduction des niveaux de graisse dans le foie isolé, et une aptitude améliorée de ces foies pour une transplantation.
PCT/US2025/032469 2024-06-06 2025-06-05 Procédés de préparation et d'entretien de foies et de parties de ceux-ci pour une transplantation hépatique Pending WO2025255357A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130072486A1 (en) * 2011-03-18 2013-03-21 Corcept Therapeutics, Inc. Pyrimidine cyclohexyl glucocorticoid receptor modulators
WO2016061195A1 (fr) * 2014-10-15 2016-04-21 Corcept Therapeutics, Inc. Traitement de la stéatose hépatique à l'aide d'antagonistes des récepteurs des glucocorticoïdes et des minéralocorticoïdes
WO2018236749A2 (fr) * 2017-06-20 2018-12-27 Corcept Therapeutics, Inc. Méthodes de traitement des tumeurs neuro-épithéliales à l'aide de modulateurs sélectifs du récepteur de glucocorticoïdes
WO2019236487A1 (fr) * 2018-06-04 2019-12-12 Corcept Therapeutics Incorporated Modulateurs de récepteurs de glucocorticoïdes de type pyrimidine cyclohexényle
WO2021226260A1 (fr) * 2020-05-06 2021-11-11 Corcept Therapeutics Incorporated Polymorphes des modulateurs des récepteurs de glucocorticoïdes de type pyrimidine cyclohexyle

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130072486A1 (en) * 2011-03-18 2013-03-21 Corcept Therapeutics, Inc. Pyrimidine cyclohexyl glucocorticoid receptor modulators
WO2016061195A1 (fr) * 2014-10-15 2016-04-21 Corcept Therapeutics, Inc. Traitement de la stéatose hépatique à l'aide d'antagonistes des récepteurs des glucocorticoïdes et des minéralocorticoïdes
WO2018236749A2 (fr) * 2017-06-20 2018-12-27 Corcept Therapeutics, Inc. Méthodes de traitement des tumeurs neuro-épithéliales à l'aide de modulateurs sélectifs du récepteur de glucocorticoïdes
WO2019236487A1 (fr) * 2018-06-04 2019-12-12 Corcept Therapeutics Incorporated Modulateurs de récepteurs de glucocorticoïdes de type pyrimidine cyclohexényle
WO2021226260A1 (fr) * 2020-05-06 2021-11-11 Corcept Therapeutics Incorporated Polymorphes des modulateurs des récepteurs de glucocorticoïdes de type pyrimidine cyclohexyle

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