APOTEX ET AL. - EXHIBIT 1069
`Apotex Inc. et al. v. Novartis AG
`IPR2017-00854
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`THE USE GF GLUCGCGRTTCOTD RECEPTGR MGDULATQRS T9
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`POTENTTATE CHECKPGTNT TNHTBTTGRS
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`CRGSS—REFERENCE T0 RELATED APPLICATTGNS
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`[0001}
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`This application claims the benefit of, and priority to, US. Provisional Patent
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`Application Serial No. 62/302,106 filed March 1, 2016, and claims the benefit of, and priority to,
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`US Provisional Patent Application Serial No. 62/320,276 filed April 8, 2016, both of which
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`applications are hereby incorporated herein by reference in their entireties.
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`BACKGROUND
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`[0002} Cancer is a group of varied diseases characterized by uncontrolled growth and spread
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`of abnormal cells. The pathways regulating cell division and or cellular communication become
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`altered in cancer cells such that the effects of these regulatory mechanisms in controlling and
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`limiting cell growth fails or is bypassed. Through successive rounds of mutation and natural
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`selection, a group of abnormal cells, generally originating from a single mutant cell, accumulates
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`additional mutations that provide selective growth advantage over other cells, and thus evolves
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`into a cell type that predominates in the cell mass. As the cancer cells further evolve, some
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`become locally invasive and then metastasize to colonize tissues other than the cancer cell's
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`tissue of origin. This property along with the heterogeneity of the tumor cell population makes
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`cancer a particularly difficult disease to treat and eradicate.
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`[0003}
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`Traditional cancer therapies take advantage of the higher proliferative capacity of
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`cancer cells and their increased sensitivity to DNA damage: Ionizing radiation, including Ymrays
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`and X—rays, and cytotoxic agents, such as bleoniycin, cisnplatin, vinblastine, cyclophosphaniide,
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`5'~ fluorouracil, and inethotrexate rely upon a generalized damage to DNA, and destabilization of
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`chromosomal structure which eventually leads to destruction of cancer cells. These treatments
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`are particularly effective for those types of cancers that have defects in cell cycle checkpoint,
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`which limits the ability of these cells to repair damaged DNA before undergoing cell division.
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`The non~selective nature of these treatments, however, often results in severe and debilitating
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`side effects. The systemic use of these drugs may result in damage to normally healthy organs
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`and tissues, and compromise the longuterm health of the patient.
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`[0004} Recently, inimunotherapy targeting immune checkpoint signaling pathways has been
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`shown to be effective in treating cancer. These pathways suppress immune response and are
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`crucial for maintaining selfntolerance, modulating the duration and amplitude of physiological
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`immune responses in peripheral tissues, and, minimizing collateral tissue damage. It is believed
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`that tumor cells can activate the immune checkpoint signaling pathways to decrease the
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`effectiveness of the immune response against tumor tissues. Many of these immune checkpoint
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`signaling pathways are initiated by interactions between checkpoint proteins present on the
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`surface of the cells participating in the immune responses, e. g, '1" cells, and their ligands, thus
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`they can be readily blocked by agents or modulated by recombinant forms of the checkpoint
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`proteins or ligands or receptors. The agents blocking the immunosuppression pathway induced
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`by checkpoint proteins are commonly referred to as checkpoint inhibitors and a few have been
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`commercialized. Cytotoxic T—lymphocyte~associated antigen 4- (CTLA4) antibodies, blocking
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`the immunosuppression pathway by the checkpoint protein CTLA4, were the first of this class of
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`iinmunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Clinical
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`findings with blockers of additional immune—checkpoint proteins, such as programmed cell death
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`protein 1 (PD—l), indicate broad and diverse opportunities to enhance anti—tumor immunity with
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`the potential to produce durable clinical responses.
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`[0005} Glucocorticoid receptor (GR) mediated signaling pathways have dynamic biologic
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`effects involving different components of the immune system and their in vivo effects are
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`unpredictable. For exan'iple, glucocorticoids have been reported to have both
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`immunosuppressive effects
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`such as, suppression of proinilainmatory cytokines, promotion of
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`anti—inflammatory cytokines, inhibition of dendritic cells, suppression of natural killer cells,
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`promotion of T~regulatory cells, and induction of T cell apoptosis,
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`and immune-enhancing
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`effects. See l-linrichs J. lminunother. 2005: 28 (6): 517—524. The effects of GR mediated
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`sigi'ialing pathway on cancer cells is likewise elusive. On one hand, it is believed that activating
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`the GR signaling pathways induce apoptosis in certain types of cancer cells, for example,
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`malignant lymphoid cancers. See Schlossmacher, J. Endocrine. (2011). On the other hand, it
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`has also been reported that agents blocking the GR signaling pathway can potentiate
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`chemotherapy in killing cancer cells. See US. Pat. No. 9149485. This current invention uses a
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`novel combination therapy that targets both the checkpoint signaling pathway and GR signaling
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`pathway to treat patients suffering from a tumor load.
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`SUIWMARY
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`[00061
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`The cancer treatment method, disclosed herein includes administering to a patient
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`suffering from a tumor load a therapeutic amount of a checkpoint inhibitor and a selective
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`glucocorticoid receptor modulator (SGKM) in an amount effective to potentiate the activity of
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`the checkpoint inhibitor. The combination therapy of the checkpoint inhibitor and, SGRJNI
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`provides superior tumor load reduction compared to treatment with a checkpoint inhibitor alone.
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`[0007]
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`In some cases, the checkpoint inhibitor is an antibody against at least one checkpoint
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`protein, eg, I’D—l, C'I‘LAm4, 1’1)le or PDnLZ. In some cases, the checkpoint inhibitor is an
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`antibody that is effective against two or more of the checkpoint proteins selected from the group
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`of PD—lj C'I'LAnAL PDnLl and I’D—L2.
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`[0008]
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`In some cases, the checkpoint inhibitor is a small molecule, non~protein compound that
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`inhibits at least one checkpoint protein. In one embodiment, the checkpoint inhibitor is a small
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`molecule, non—protein compound that inhibits a checkpoint protein selected from the group
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`consisting of I’D—l, C'I'LA—AL PD—Ll and P1312.
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`[0009]
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`In one embodiment, the SGKM is mifepristone. In some cases, the SGRM is a
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`compound having a non—steroidal backbone. In some cases, the SGRM is a fused azadecalin.
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`[0010]
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`In some cases, the SGRI‘VI is CORT l25l34, i.e., (RHI~(4ufluorophenyl)~6—((l-n1ethyl—1H~
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`pyrazolu4—yl)sulfonyl)—4.,4a,iéflfl—hexahydroulI-I—pyrazolo[3,4uglisoquinolin-4a-yl)(4—
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`(trifluoromethyl)pyridin—2-yl)methanone, which has the following structure:
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`[0011}
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`In some cases, the SGRM is mifepristone.
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`[0012}
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`In some cases, the SGMVI is CORTl25281, i.e., ((4alL8aS)—l—(4—fluor‘opheiiyl)—6—((2u
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`methyl—2114,23 —triazol—4uyl)sulfonyl)~4,4a,5,6,7,8,8a,9uoctahydro— l H—pyrazololjizl—
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`glisoquinolin—zlauyl)(4—(trifluorometliyl)pyridinu2uyl)n1ethanone, which has the follmving
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`structure:
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`[0013}
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`In one embodiment, the cancer expresses the glucocorticoid receptor (GRl).
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`[0014}
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`In some cases, the cancer is a GR+ cancer and the cancer is selected from the group
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`consisting of breast cancer, prostate cancer, melanoma, sarcoma, renal cell cancer, head and neck
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`cancer, hepatocellular cancer, glioblastoma, cervical cancer, neuroendocrine cancer, bladder
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`cancer, prostate cancer, esophageal cancer, mesothelioma, lung cancer, ovarian cancer,
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`pancreatic cancer, gall bladder cancer, gastric cancer, endometrial cancer, and colon cancer.
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`[0015}
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`In one embodiment, the checkpoint inhibitor and SGKM are conadministered. In a
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`preferred embodiment, the SGRIVI is COR’I‘125134 and the checkpoint inhibitor is an antibody
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`against I’Dnl.
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`[0016}
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`In some embodiments, provided herein is a SGRM for use in combination with a
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`checkpoint inhibitor in a method of treating a patient hosting a tumor load, the method
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`comprising administering to a patient suffering from a tumor load a therapeutic amount of a
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`checkpoint inhibitor and a selective glucocorticoid receptor modulator (SGRIVI) in an, amount
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`effective to potentiate the activity of the checkpoint inhibitor, In additi on, all the related
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`embodiments described above are also included in these embodiments of the disclosure.
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`BRIEF DESCRIPTEGN OF THE DRAW/INGS
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`[0017}
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`F1G. 1 shows the tumor growth data from three (3) groups of mice that were treated
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`with l) anti—PDml vehicle (PBS; lOml/kg); i. p. twice a week and the CORT125134 vehicle 13.0.
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`(10% DMSO, 0. 1% Tween 80 and 89.9% HPMC (0.5%); lOml/kg) daily; 2) the mouse anti PDnl
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`antibody (clone RPh/ll—M, lOmg/kg) i. p. twice a week; and 3) the mouse anti PD—l antibody
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`(clone RPMlnlil; lOmg/kg) i. p. twice a week and CORN/”35134 (a SGRM) (3 Omg/kg) orally on
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`a daily basis, respectively. The result shows that the combination of anti PDnl and,
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`COR’1‘125134 is superior to both the anti PD—l group and the vehicle group in reducing tumor
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`growth.
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`[0018}
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`FIG. 2 shows the mean tumor volume for each group of ten mice plotted against the
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`number of days of tumor growth since initiation of the treatment. Group 1 mice were dosed with
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`the anti—PD-l vehicle and the (301117125281 vehicle; Group 11 mice were dosed with mouse anti
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`PD~1 antibody; and Group III mice were dosed with mouse anti PD—l antibody and
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`CORT125281. The combination of anti PD~1 and CORT 12528] is superior to both the anti PD—l
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`group and the vehicle group in reducing tumor growth.
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`[0019}
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`FIG. 3 shows the mean tumor volume for each group often mice plotted against the
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`number of days of tumor growth since initiation of the treatment. Group I mice were dosed with
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`the anti—CTl..-A4 vehicle and the CORT125134 vehicle; Group II mice were dosed with the
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`mouse anti C "ELA4 antibody; Group III mice were dosed with mouse anti CTLA4 antibody and
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`CORT125134; Group IV mice were dosed with mouse anti CTLA4 antibody and COR.T1.25281.
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`The combination of anti CTlA4 with CORT125134 and the combination of anti CTLA4 with
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`CORTlZSZSl were each superior to both the anti CTLA4 group and the vehicle group in
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`reducing tumor growth.
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`A.
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`INTRODUCTION
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`DETAILED DESCRIPTIGN
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`[0020}
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`This method disclosed herein can be used to treat a patient hosting a tumor load by
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`administering at least one SGRl‘vl and at least one checkpoint inhibitor, The checkpoint inhibitor
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`is administered in an amount that is effective to treat the cancer when administered alone or in
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`combination with a SGRh/l. The SGRM is administered in an amount that is effective to
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`potentiate the checkpoint inhibitor’s activity of blocking the checkpoint signaling pathways. In
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`some cases, the tumor load is caused by a checkpoint inhibitor sensitive cancer.
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`B.
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`DEFl Nl'l'lON S
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`[0021} As used herein, the term “subject” or patient” refers to a human or non—human
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`organism. Thus, the methods and compositions described herein are applicable to both human
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`and veterinary disease. In certain embodiments, subjects are “patients,” i.e., living humans that
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`are receiving medical care for a disease or condition, This includes persons with no defined
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`illness who are being investigated for signs of pathology. Preferred are subjects who have an
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`existing diagnosis of a particular cancer which is being targeted by the compositions and,
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`methods of the present invention. In some cases, a subject may suffer from one or more types of
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`cancer simultaneously, at least one of which is targeted by the compositions and methods of the
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`present invention. Preferred cancers for treatment with the compositions described herein
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`include, but are not limited to prostate cancer, renal carcinoma, melanoma, pancreatic cancer,
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`cervical cancer, ovarian cancer, colon cancer, head & neck cancer, lung cancer, sarcoma, breast
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`cancer, hepatocellular tumor, glioblastoma, neuroendocrine turn or, bladder cancer
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`gall bladder
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`cancer, gastric cancer, , endometrial cancer, and mesothelioma.
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`[0022] As used herein, the term ”tumor load” or “tumor burden” generally refers to the number
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`of cancer cells, the size of a tumor, or the amount of cancer in the body in a subject at any given
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`time. Tumor load can be detected by e. g measuring the expression of tumor specific genetic
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`markers and measuring tumor size by a number of well~known, biochemical or imaging methods
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`disclosed herein, infra.
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`[0023}
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`The term “immune response” refers to the action of, for example, lymphocytes, antigen
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`presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the
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`above cells or the liver (including antibodies, cytolrines, and complement) that results in
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`selective damage to, destruction of, or elimination from the human body of invading pathogens,
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`cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or
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`pathological inflammation, normal human cells or tissues
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`[0024} As used herein, the term “checkpoint inhibitor sensitive cancer” refers to a cancer that
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`is responsive to checkpoint inhibitors. Administration of one or more checkpoint inhibitors to
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`patients having such a tumor would cause a reduction in the tumor load or other desired
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`beneficial clinical outcome related to cancer improvement.
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`{0025] As used herein, the term “effective amount” or “therapeutic amount” refers to an
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`amount of a pharmacological agent effective to treat, eliminate, or mitigate at least one symptom
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`of the disease being treated. In some cases, “therapeutically effective amount” or “effective
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`amount” can refer to an amount of a functional agent or of a pharmaceutical composition useful
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`for exhibiting a detectable therapeutic or inhibitmy effect. The effect can be detected by any
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`assay method known in the art. The effective amount can be an amount effective to invoke an
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`antitumor response. The effective amount can be an amount effective to evoke a humoral and/or
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`cellular immune response in the recipient subj ect leading to growth inhibition or death of target
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`cells. For the purpose of this disclosure, the therapeutic amount of the checkpoint inhibitor is an
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`amount that would reduce tumor load or bring about other desired beneficial clinical outcomes
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`related to cancer improvement.
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`[0026] As used herein, the phrase “an amount effective to potentiate” refers to the amount of
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`of a pharmacological agent effective to enhance the activity of another therapeutic agent in
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`treating, eliminating, or mitigating at least one symptom of the disease being treated. The agent
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`used to potentiate the activity of another can be effective or non—effective in treating, eliminating,
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`or mitigating the symptom of the disease itself In some cases, the potentiating agent is not
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`effective, and the effect of potentiation can be sh own by the increased degree in relieving the
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`symptom resulting from treatment by the combination of the two agents as compared to the
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`treatment with the therapeutic agent alone. In some cases, the potentiating agent itself is
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`effective in treating the symptoms, and the potentiating effect can be shown by a synergistic
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`effect between the potentiating agent and the therapeutic agent. For the purpose of this
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`disclosure, the SGRM acts as a potentiating agent to potentiate the activity of checkpoint
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`inhibitors in treating cancer, regardless whether the SGRM would be effective in treating the
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`cancer if administered alone.
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`in some embodiments, a potentiatin g effect of lO‘F/éi to lOOO‘F/éi can
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`be achieved. In some embodiments, the SGRM is administered at an amount that renders the
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`tumor sensitive to the checkpoint inhibitor, i.e., a showing of a reduction of tumor load or other
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`related clinical benefit that would not otherwise appear when the tumor is treated with the
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`checkpoint inhibitor in the absence of the SGRM.
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`[0027} As used herein, the term “combination therapy” refers to the administration of at least
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`two pharmaceutical agents to a sub} ect to treat a disease. The two agents may be administered
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`simultaneously, or sequentially in any order during the entire or portions of the treatment period.
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`The two agents may be administered following the same or different dosing regimens. In some
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`cases, one agent is administered following a scheduled regimen while the other agent is
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`administered intermittently. In some cases, both agents are administered intermittently. In some
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`embodiments, the one pharmaceutical agent, e.g., a SGRM, is administered every day, and the
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`other pharmaceutical agent, eg, a checkpoint inhibitor, is administered weekly or biweekly.
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`{00238} As used herein, the terms “administer,” “administering,” “administered” or
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`“administration” refer to providing a compound or a composition (eg one described herein), to
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`a sub} ect or. patient.
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`[0029] As used herein, the term “co~administer” refers to administer two compositions
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`simultaneously or within a short time of each other, e.g., within about within 0.5, l, 2, 4, 6, 8, IO,
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`12, l6, 20, or 24 hours of each other.
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`[0030} As used herein, the term “compound" is used to denote a molecular moiety of unique,
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`identifiable chemical structure. A molecular moiety ("compound”) may exist in a free species
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`form, in which it is not associated with other molecules. A compound may also exist as part of a
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`larger aggregate, in which it is associated with other moleculets), but nevertheless retains its
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`chemical identity. A solvate, in which the molecular moiety of defined chemical structure
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`(”compound”) is associated with a molecule(s) ofa solvent, is an example of such an associated
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`form. A hydrate is a solvate in which the associated solvent is water. The recitation of a
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`”compound” refers to the molecular moiety itself (of the recited structure), regardless whether it
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`exists in a free form or an associated form.
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`[0031} As used herein, the term “small molecule, nonmprotein compound” refers to a low
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`molecular weight organic compound, which typically has a molecular weight of less than 900
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`daltons
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`[0032} As used herein, the term "pharmaceutically acceptable carrier” is intended to include
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`any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and
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`absorption delaying agents, and the like, compatible with pharmaceutical administration. The
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`use of such media and agents for pharmaceutically active substances is well known in the art.
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`Except insofar as any conventional media or agent is incompatible with the active compound,
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`use thereof in the compositions is contemplated Supplementary active compounds can also be
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`incorporated into the compositions.
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`[0033} As used herein, the term “checkpoint protein” refers to a protein that is present on the
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`surface of certain types of cells, eg. T cells and certain tumor cells, and can induce checkpoint
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`signaling pathways and result in suppression of immune responses Commonly known
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`checkpoint proteins include CTLA4, PD—l, PDULI, LAG3, 1374-13, Bil-14, Tlh/B, CD160,
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`CD244, VISTA, TlGlT, and BTLA. (Pardoll, 2012, Nature Reviews Cancer 12:252—264; Baksh,
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`2015, Semin Oncol. 2015 lun;42(3):363—77). Among these, CTLA4, l’Dnl and Pl)le are most
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`well studied, and therapies targeting these proteins are more clinically advanced than therapies
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`targeting other checkpoint proteins.
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`[0034} As used herein, the term “P’Dnl” refers to Programmed Cell Death Protein 1 (also
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`known as CD279), a cell surface membrane protein of the immunoglobulin superfamily.
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`l’Dnl is
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`expressed by B cells, T cells and NK. cells. The major role of PDml is to limit the activity of T
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`cells in peripheral tissues during inflammation in response to infection, as well as to limit
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`autoimmunity. PD-l expression is induced on activated T cells and binding of PD—l to one of its
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`endogenous ligands acts to inhibit T cell activation by inhibiting stimulatory kinases, PD~1 also
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`acts to inhibit the TCR “stop signal”. PD~1 is highly expressed on Treg cells (regulatory T cells)
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`and may increase their proliferation in the presence of ligand (Pardoll, 2012, Nature Reviews
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`Cancer 12252264),
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`[0035] As used herein, the term “PD~L1” refers to Programmed Cell Death 1 ligand l (also
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`known as CD274 and B7—H1), a ligand for PDml. PD—Ll is found on activated T cells, B cells,
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`myeloid cells, i'nacrophages, and tumor cells~ Although there are two endogenous ligands for
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`PD—l, PD—Ll and PD—LZ, anti—tumor therapies have focused on anti-PDJJ. The complex of
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`PD~l and PD—Ll inhibits proliferation of CD8+ T cells and reduces the immune response
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`(Topalian et al, 2012., N. Engl J. filed. 366:2443—54; Brahmer et a1, 2012, N. Engl J. .Med.
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`366:2455-65),
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`[0036} As used herein, the term “CTLA4” refers to Cytotoxic T~lymphoeyte antigen 4 (also
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`known as CD152), a member of the inununovlobulin su )erfamil ' that is ex ressed exclusively
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`on T cells. CTLA4 acts to inhibit T cell activation and is reported to inhibit helper T cell activity
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`and enhance regulatory T cell immunosuppressive activity. Although the precise mechanism of
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`action of CTL4—A remains under investigation, it has been suggested that it inhibits T cell
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`activation by outcompeting CD28 in binding to CD80 and CD86 on antigen presenting cells, as
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`well as actively delivering inhibitor signals to the T cell (Pardoll, 2012, Nature Reviews Cancer
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`12:252—264).
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`[0037} As used herein, the term “checkpoint inhibitor” refers to any molecules, including
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`antibodies and small molecules, that block the immunosuppression pathway induced by one or
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`more checkpoint proteins.
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`[0038] As used herein, the term "antibody” as used, herein also includes a full—length antibody
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`as well as an “antigenmbinding portion” of an antibody. The term “antigen—binding portion", as
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`used herein, refers to one or more fragments of an antibody that retain the ability to specifically
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`bind to an antigen (e. g, PDml). Examples of binding fragments encompassed within the term
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`"antigen—binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment
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`consisting of the VL, VH, CL and CH1 domains; (ii) a F(abi)2 fragment, a. bivalent fragment
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`comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Pd
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`fragment consisting of the VH and CHl domains; (iv) a Fv fragment consisting of the VL and
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`VH domains of a single arm of an antibody, (v) a dAb fragment, (Ward et al., (1989) Nature
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`341544646), which consists of a. VH domain; and (vi) an isolated complementarity determining
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`region (CDR). Furthermore, although the two domains of the Fv fragment, VI... and VH, are
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`coded for by separate genes, they can be joined, using recombinant methods, by a synthetic
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`linker that enables them to be made as a single protein chain in which the VI... and VH regions
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`pair to form monovalent molecules (known as single chain Fv (scFv); see e. g Bird et al. (1988)
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`Science 242:423—426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 856879-5883;
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`and Osbourn et a1. 1998, Nature Biotechnology 16: 778). Such single chain antibodies are also
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`intended to be encom passed within the term “ai'itigen-binding portion" of an antibody. Any VH
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`and VL sequences of specific scFv can be linked to human immunoglobulin constant region
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`cDNA or genomic sequences, in order to generate expression vectors encoding complete lgG
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`molecules or other isotypes. Vl-l and VI can also be used in the generation of Fab, F v or other
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`fragments of immunoglobulins using either protein chemistry or recombinant DNA technology.
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`Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are
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`bivalent, bispecific antibodies in which VH and VL domains are expressed on a single
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`polypeptide chain, but using a linker that is too short to allow for pairing between the two
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`domains on the same chain, thereby forcing the domains to pair with complementary domains of
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`another chain and creating two antigen binding sites (see e.g., Holliger, P, et al. ( 1993) Proc.
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`Natl. Acad. Sci, USA 90:6444—6448; Poljak, R. J., et al. (1994) Structure 11121—1123).
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`[0039} Antibodies may be polyclonal or monoclonal; xenogeneic, allogeneic, or syngeneic; or
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`modified forms thereof, e. g. humanized, chimeric, etc. Antibodies of the invention bind
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`specifically or substantially specifically to one or more checkpoint proteins. The term
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`"monoclonal antibodies" refer to a population of antibody molecules that contain only one
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`species of an antigen binding site capable of irnmunoreacting with a particular epitope of an
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`antigen, whereas the term ”polyclonal antibodies“ and ”polyclonal antibody composition" refer
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`to a population of antibody molecules that contain multiple species of antigen binding sites
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`capable of interacting with a particular antigen. A monoclonal antibody composition typically
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`displays a single binding affinity for a particular antigen with which it imi‘nunoreacts
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`[0040} As used herein, the term “antibody effective against a checkpoint protein” refers to an
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`antibody that can bind to the checkpoint protein and antagonize the checkpoint protein’s function
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`in suppressing immune response. For example, an antibody against PD—l refers to an antibody
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`that can bind to PDvl and block the PD—l ’s inhibitory function on the immune response, through
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`e.g,, blocking the interactions between PD-l and PD—Ll. In some cases, an antibody can be
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`against two checkpoint proteins, i,e., having the ability of binding to two checkpoint proteins and
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`inhibiting their function,
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`[0041} As used herein, the term “Glucocorticoid receptor” (“GR”) refers to a family of
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`ii'rtracellular receptors which specifically bind to cortisol and/or cortisol analogs The
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`glucocorticoid receptor is also referred to as the cortisol receptor. The term includes isoforms of
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`GR, recombinant GR and mutated GR~ “Glucocorticoid receptor” (“GR”) refers to the type II
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`GR which specifically binds to cortisol and/or cortisol analogs such as dexainethasone (See, eg
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`Turner & Muller, .l h/lol Endocrinol October 1, 2005 35 283—292.).
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`[0028]
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`“Glucocorticoid receptor modulator” (“GRl‘s/l”) also known and described in the
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`scientific and patent literature as a glucocorticoid receptor antagonist refers to any compound
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`which inhibits any biological response associated with the binding of GR to an agonist. For
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`example, a GR agonist, such as dexamethasone, increases the activity of tyrosine
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`aminotransferase (TAT) in HepG2 cells (a human liver hepatocellular carcinoma cell line;
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`ECACC, UK). Accordingly, GR modulators of the present invention can be identified by
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`measuring the ability of the compound to inhibit the effect of dexamethasone. TAT activity can
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`be measured as outlined in the literature by A. Ali er 51]., J. Med. Chem, 2004, 47, 244lm2452.
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`A modulator is a compound with an lex, (half maximal inhibition concentration) of less than 10
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`micromolar. See Example 1, infm.
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`{00423} As used herein, the term “selective glucocorticoid receptor modulator” refers to any
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`composition or compound which inhibits any biological response associated with the binding of
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`a GR to an agonist. By “selective,” the drug preferentially binds to the GR rather than other
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`nuclear receptors, such as the progesterone receptor (PR), the inineralocorticoid receptor (IVER) or
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`the androgen receptor (AR). It is preferred that the selective glucocorticoid receptor antagonist
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`bind GR with an affinity that is 10x greater (1/le the Kd value) than its affinity to the MR, AR
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`or PR, both the IVER and PR, both the MR and AR, both the AR and PR, or to the l‘va, AR, and
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`lO
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`l5
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`PR.
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`In a more preferred embodiment, the selective glucocorticoid receptor antagonist binds GR
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`with an affinity that is 100x greater (l/l 00th the K;- value) than its affinity to the MR, AR, 0]” PR,
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`both the MR and PR, both the MR and AR, both the AR and PR, or to the MR, AR, and PR. In
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`another embodiment, the selective glucocorticoid receptor antagonist binds GR with an affinity
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`20
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`that is lOOOx greater (1/1000L11 the K0; value) than its affinity to the MR, AR, or PR, both the MR
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`and PR, both the MR and AR, both the AR and PR, or to the MIR, AR, and PR.
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`[0043} As used herein, the term "composition” is intended to encompass a. product comprising
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`the specified ingredients such as the said compounds, their tautorneric forms, their derivatives,
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`their analogues, their stereoisomers, their polymorphs, their pl'iarmaceutically acceptable salts,
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`esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and
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`pharmaceutical ly acceptable compositions in specified amounts, as well as any product which
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`results, directly or indirectly, from combination of the specified ingredients in the specified
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`amounts. Such term in relation to a pharmaceutical composition is intended to encompass a
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`product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier,
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`as well as any product which results, directly or indirectly, in combination, coniplexation or
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`aggregation of any two or more of the ingredients, or from dissociation of one or more of the
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`ingredients, or from other types of reactions or interactions of one or more of the ingredients.
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`Accordingly, the pharmaceutical compositions of the present invention are meant to encompass
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`any composition made by admixing compounds of the present invention and their
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`pharmaceutically acceptable carriers.
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`[0044] As used herein, the phrase “not otherwise indicated for treatment with a glucocorticoid
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`receptor modulator” refers to refers to a patient that is not suffering from any condition
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`recognized by the medical community to be effectively treatable with glucocorticoid receptor
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`antagonists, with the exception of hepatic steatosis. Conditions known in the art and accepted by
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`the medical community to be effectively treatable with glucocorticoid receptor antagonists
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`include: psychosis associated with interferonnd therapy, psychotic major depression, dementia,
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`stress disorders, autoimmune disease, neural injuries, and Cushing’s syndrome,
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`{@045}
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`In some embodiments, the term “consisting essentially of ’ refers to a composition in a
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`formulation whose only active ingredient is the indicated active ingredient, however, other
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`compounds may be included which are for stabilizing, preserving, etc: the formulation, but are
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`not involved directly in the therapeutic effect of the indicated active ingredient. In some
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`embodiments, the term “consisting essentially of’ can refer to compositions which contain the
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`active ingredient and components which facilitate the release of the active in gredient, For
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`example, the composition can contain one or more components that provide extended release of
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`the active ingredient over time to the subj ect. In some embodiments, the term “consisting” refers
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`to a composition, which contains the active ingredient and a pharma ceutically acceptable carrier
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`or excipient.
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`[0046}
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`The term “steroidal backhone” in the context of glucocorticoid receptor antagonists
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`containing such refers to glucocorticoid receptor antagonists that contain modifications of the
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`basic structure of cortisol, an endogenous steroidal glucocorticoid receptor ligand. The basic
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`structure of a steroidal backbone is provided as Formula I:
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`Formula I: Steroidal Backbone
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`The two most commonly known classes of structural modifications of the cortisol steroid
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`backbone to create glucocorticoid antagonists include modifications of the 11" 33 hydroxy group
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`and modification of the 17— 3 side chain (See, 8 g Lefebvre (1989) J. Steroid, Biochem. 33: 557—
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`L!)
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`563)
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`[0047} As used herein, the phrase “nonnsteroidal backbone” in the context of SGRMs refers to
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`SGRMS that do not share structural homology to, or are not modifications of, cortisol with its
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`steroid, backbone containing seventeen carbo