WO2016035023A1 - Combinaisons pharmaceutiques et leur utilisation - Google Patents

Combinaisons pharmaceutiques et leur utilisation Download PDF

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Publication number
WO2016035023A1
WO2016035023A1 PCT/IB2015/056662 IB2015056662W WO2016035023A1 WO 2016035023 A1 WO2016035023 A1 WO 2016035023A1 IB 2015056662 W IB2015056662 W IB 2015056662W WO 2016035023 A1 WO2016035023 A1 WO 2016035023A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
cancer
cgm097
nilotinib
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PCT/IB2015/056662
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English (en)
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Ravi Bhatia
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Novartis Ag
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Publication of WO2016035023A1 publication Critical patent/WO2016035023A1/fr

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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present disclosure relates to a pharmaceutical combination, e.g. a product, comprising a combination of an Mdm2 inhibitor and a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, respectively, which are jointly active in the treatment of proliferative diseases.
  • a pharmaceutical combination e.g. a product, comprising a combination of an Mdm2 inhibitor and a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, respectively, which are jointly active in the treatment of proliferative diseases.
  • the disclosure also relates to corresponding pharmaceutical formulations, uses, methods, combinations, data carrier and related disclosure embodiments.
  • the disclosure also relates to use of an Mdm2 inhibitor alone.
  • Chronic myelogenous leukemia is a clonal, multistep, multilineage myeloproliferative disorder.
  • the Philadelphia Chromosome is a hallmark for chronic myelogenous leukemia (CML) and carries a hybrid gene that contains N-terminal exons of the bcr gene and the major C- terminal part (exons 2-1 1 ) of the c-abl gene.
  • the gene product is a 210 kD protein (p210 BCR- ABL).
  • the leukemic cells are characterized by the presence of a BCR-ABL fusion gene as the sole detectable chromosomal abnormality (Goldman JM, Melo JV., N Engl J Med 349(15), 1451 [2003]).
  • the BCR-ABL encodes a chimeric oncoprotein (p210BCR-ABL) that displays constitutively elevated tyrosine kinase activity.
  • the Abl-part of the Bcr-Abl protein contains the abl-tyrosine kinase which is tightly regulated in the wild type c-abl, but constitutively activated in the Bcr-Abl fusion protein.
  • the Bcr-Abl fusion protein drives the pathogenesis of the disease (Lugo et al., Science 247, 1079 [1990]).
  • the elevated tyrosine kinase activity of the BCR-ABL oncoprotein causes biochemical changes that affect the growth factor dependence, turnover, and genomic stability of primitive CD34+ leukemic cells in chronic-phase patients (Holyoake et al., Leukemia16(4), 549 [2002]).
  • the protein p53 is a transcription factor that controls the expression of a multitude of target genes involved in DNA damage repair, apoptosis and cell cycle arrest, which are all important phenomena counteracting the malignant growth of tumors. p53 is thus critical for maintaining genetic stability and preventing tumor development.
  • the TP53 gene is one of the most frequently mutated genes in human cancers. It is reported that approximately half of all cancers have inactivated p53, caused by direct mutation. In cancers in which the p53 gene is not mutated, functional inactivation at the protein level has been demonstrated.
  • MDM2 Mae double minute 2
  • Mdm2 is therefore an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase, that leads to proteasomal degradation of p53, and an inhibitor of p53 transcriptional activation. This inhibitory mechanism is thought to be reversible provided p53 remains wild-type. Mdm2 inhibitors can limit the interaction between Mdm2 and p53 and thus allow the protein to exert again its effector functions. This way it can promote the beneficial effect of another compound that targets a possibly subordinate, interdependent or simply coexisting biochemical pathway.
  • TKIs tyrosine kinase inhibitors
  • TKIs are highly effective in treatment of CML, they do not eliminate the primitive, quiescent CML stem cells.
  • Small molecule tyrosine kinase inhibitors (TKIs) like for example imatinib mesylate, dasatinib or nilotinib are effective in the treatment of leukemia, but patients can develop resistance.
  • a specific TKI may even remain effective in some, but not all, patients that developed resistance to the other TKI.
  • a pharmaceutical combination comprising CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, is provided.
  • the combination provided is useful to treat CML.
  • the combination helps remove leukemia stem cells (LSC) and increases the possibility of treatment free remissions for CML patients.
  • LSC leukemia stem cells
  • a pharmaceutical combination comprising CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination according to any one of items 1 to 5 in the form or a kit of parts for the combined administration where the CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners are jointly active.
  • nilotinib or a pharmaceutically acceptable salt thereof.
  • CGM097, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer wherein the CGM097, or a pharmaceutically acceptable salt thereof, is to be administered simultaneously or sequentially to nilotinib, or a pharmaceutically acceptable salt thereof.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to item 13, wherein the cancer is leukemia.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, according to item 13 or 14, wherein the cancer is chronic myelogenous leukemia.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, according to any one of items 13 to 15, wherein the cancer is chronic myelogenous leukemia in a chronic phase or in a blast crisis phase.
  • CGM097, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to any one of items 13 to 16, wherein the cancer comprises functional p53 or p53 wt. 18.
  • Use of a data carrier comprising information about using CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, simultaneously or sequentially, and/or to instruct to administer CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, simultaneously or sequentially for the treatment of cancer.
  • a method of treating a patient suffering from cancer comprising administering to the patient either simultaneously or sequentially CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, wherein the amount of said CGM097 and nilotinib being such that the combination thereof is therapeutically effective in the treatment of the cancer.
  • cancer is chronic myelogenous leukemia in a chronic phase or in a blast crisis phase.
  • cancer comprises functional p53 or p53 wt.
  • a pharmaceutical combination comprising CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament or a pharmaceutical product for the treatment of cancer.
  • CGM097 or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, for combined use as a medicine.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer is leukemia.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to item 43, wherein the cancer is chronic myelogenous leukemia.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to item 44 or 45, wherein the cancer is chronic myelogenous leukemia in a chronic phase or in a blast crisis phase.
  • CGM097 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to any one of items 43 to 46, wherein the cancer comprises functional p53 or p53 wt.
  • Fig. 1 Effect of CGM097 on apoptosis and proliferation of CML chronic phase (CP) and normal cord blood CD34+ cells
  • the present disclosure provides a pharmaceutical combination comprising CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof. It was unexpectedly found that CGM097, or a pharmaceutically acceptable salt thereof, can have its antitumor effects significantly potentiated when combined with a nilotinib.
  • the combination induces a complementary set of anti-proliferative and apoptosis stimulating molecules, which result in strong increase of antineoplastic effect, while it also improves the compounds selectivity.
  • Combination partners when administered simultaneously or sequentially, cause increased apoptosis and markedly reduce proliferation relative to either single agent.
  • Such pronounced effect can for example be observed in vitro when a Mdm2 inhibitor of formula (S)-1 -(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4-methyl-3- oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino ⁇ -phenyl)-1 ,4-dihydro-2H-isoquinolin-3-one (CGM097) is combined with as low concentration of nilotinib.
  • the combination caused more profound proliferation regressions compared to the effect of the single compounds. Also effect of the combination on the colony forming cell frequency in CML chronic phase CD34+CD38+/- cells was evidently better compared to the effect of the single compounds.
  • CGM097 can be used in the same way also in a monotherapy.
  • the effects that CGM097 elicits on CD34+CD38- and CD34+CD38+ cells can be exploited in therapy.
  • nilotinib is 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl- 1 H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide and can be represented by the formula
  • Nilotinib can be obtained by the processes disclosed in WO/2004/005281
  • CGM097 as used herein is (S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4- ⁇ methyl-[4-(4- methyl-3-oxo-piperazin-1 -yl)-trans-cyclohexylmethyl]-amino ⁇ -phenyl)-1 ,4-dihydro-2H-isoquinolin- 3-one and can be depicted with the formula II:
  • CGM097 can be synthetized as explained in WO 201 1/076786.
  • CGM097 is a Mdm2 inhibitor.
  • Leukemia is a type of blood cancer that begins in the bone marrow and refers to irregularities in proliferation of leukocyte progenitors or leukocytes (white blood cells). Leukemia leads to an uncontrolled increase in the number of white blood cells, which eventually prevents maturation of leukocytes and prevents platelets from being made. Leukemia can be classified in Acute lymphocytic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML) and Hairy cell leukemia.
  • ALL Acute lymphocytic leukemia
  • AML Acute myelogenous leukemia
  • CLL Chronic lymphocytic leukemia
  • CML Chronic myelogenous leukemia
  • CML Chronic myelogenous leukemia
  • Ph Philadelphia
  • MDM2/p53 ratio e.g. due to mutations, polymorphisms or molecular defects in the affected cells, can be found in many proliferative diseases.
  • MDM2 is capable to inhibit the activity of the tumor suppressor protein p53, thus leading to loss of p53's tumor suppressor activity and inhibiting regulatory mechanisms that impede cells from uncontrolled proliferation.
  • CML chronic phase
  • CP chronic phase
  • AP accelerated phase
  • BC blast crisis
  • BM bone marrow
  • TKIs Tyrosine kinase inhibitors
  • CD34 is a cell-surface protein expressed by haematopoietic stem cells, haematopoietic progenitor cells and endothelial cells, which is used as a marker to isolate human haematopoietic progenitor cells or if in leukemia patient, leukemia stem cells.
  • CD34+ fraction is still a very heterogeneous population, which can be further enriched by limiting to, for example, a CD34+CD38- subset (which is still not entirely uniform).
  • CML LSC Helping to target and help eradicate CML LSC can aid in treating leukemia, particularly if the antiproliferative effect or triggered apoptosis is selectively imposed only on the CML LSC while growth of normal stem/progenitor cells is kept intact.
  • CGM097 alone can do that, but the effect is even potentiated when used in combination with nilotinib.
  • CGM097, alone or in combination be used in the treatment of cancer.
  • the cancer is leukemia, particularly chronic myelogenous leukemia.
  • the present disclosure embodiments also include pharmaceutically acceptable salts of the compounds useful according to the disclosure described herein.
  • pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the
  • non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the salt is sulphate salt, or bisulphate salt.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present disclosure relates to a pharmaceutical combination, especially a pharmaceutical combination product, comprising the mentioned combination partners and at least one pharmaceutically acceptable carrier.
  • “Pharmaceutical combination” refers to use, application or formulations of the separate partners with or without instructions for combined use or to combination products.
  • the combination partners may thus administered entirely separately or be entirely separate pharmaceutical dosage forms.
  • the combination partners may be pharmaceutical compositions that are also sold independently of each other and where just instructions for their combined use are provided in the package equipment, e.g. leaflet or the like, or in other information e.g. provided to physicians and medical staff (e.g. oral communications, communications in writing or the like), for simultaneous or sequential use for being jointly active, especially as defined below.
  • the effect is synergistic.
  • co-administration or “combined administration” or “combined use” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration and/or at the same time.
  • pharmaceutical combination thus means a pharmaceutical product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients (which may also be combined).
  • fixed combination means that the active ingredients, i.e. CGM097 and nilotinib, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the active ingredients are present in one dosage form, e.g. in one tablet or in one capsule.
  • non-fixed combination means that the active ingredients are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • non-fixed combination thus defines especially administration, use, composition or formulation in the sense that the combination partners CGM097 and nilotinib as defined herein can be dosed independently of each other or by use of different fixed combinations with distinguished amounts of the combination partners, i.e.
  • the combination partners may also be used as entirely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other and just instructions of the possibility of their combined use is or are provided in the package equipment, e.g. leaflet or the like, or in other information e.g. provided to physicians and medical staff.
  • the independent formulations or the parts of the formulation, product, or composition can then, e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners (i) and (ii), thus being jointly active.
  • the ratio of the total amounts of the combination partner (i) to the combination partner (ii) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • the dose of one of the combination partner can be lower than the amount administered when the compound is used alone (e.g., not in a combination). It is also contemplated to be able to reduce the dose of both compounds in the pharmaceutical combination. This has the benefit of limiting or reducing side effects and improved flexibility in deciding on a treatment plan. The advantage of reducing the dose is even better when a further co-agent is involved.
  • either one or both of the compounds of the present pharmaceutical combination can be used in subtherapeutical dose.
  • nilotinib since it was observed in in vitro experiments that nilotinib can almost double the antiproliferative effect of CGM097 already at low amounts, it is expected that doses of nilotinib that otherwise would not be sufficient to elicit full therapeutic effect, could be in fact used for the treatment of the cancer disease when combined with CGM097 of the present disclosure. The same may be true also for CGM097.
  • the combination partners CGM097 and nilotinib in any disclosure embodiment are preferably formulated or used to be jointly (prophylactically or especially therapeutically) active.
  • the term "jointly (therapeutically) active” may mean that the compounds may be given separately or sequentially (in a chronically staggered manner, especially a sequence-specific manner) in such time intervals that they preferably, in the warm-blooded animal, especially human, to be treated, and still show a (preferably synergistic) interaction (joint therapeutic effect).
  • a joint therapeutic effect can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals, but this is not to exclude the case where the compounds are jointly active although they are not present in blood simultaneously.
  • the present disclosure thus pertains to a combination product for simultaneous or sequential use, such as a combined preparation or a pharmaceutical fixed combination, or a combination of such preparation and combination.
  • the compounds useful according to the disclosure may be manufactured and/or formulated by the same or different manufacturers.
  • the combination partners may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the disclosure and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of a physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the disclosure and the other therapeutic agent.
  • data carrier comprising information about using CGM097, or a pharmaceutically acceptable salt thereof, and nilotinib, or a pharmaceutically acceptable salt thereof, simultaneously or sequentially, is provided.
  • the data carrier for example in a form of a product information leaflet or a label, packaging, brochure or web page instruction can be used to instruct to administer CGM097 and nilotinib, or their salts, simultaneously or sequentially for the treatment of cancer.
  • the data carrier is particularly useful in the event the two partners of the combination are not formulated together, and supplied or sold separately. Each of the partners can be supplied with the data carrier, or even have the data carrier detached or provided separately, that informs or instructs about the possibility to use the combination partner in a pharmaceutical combination of the present disclosure.
  • the data carrier can be used for the same purpose also in fixed combinations or situations, where both partners are supplied or sold together.
  • any of the above pharmaceutical combination, use, administration, composition, method, product or formulation involve further administering one or more other (e.g. third) co-agents, especially a chemotherapeutic agent.
  • the disclosure relates in a further embodiment to a pharmaceutical combination, particularly a pharmaceutical composition or a product comprising a therapeutically effective amount of CGM097 and nilotinib, or a pharmaceutically acceptable salt thereof, respectively.
  • the combination partners forming a corresponding combination according to the disclosure may be mixed to form a fixed pharmaceutical composition or they may be administered separately or pairwise (i.e. before, simultaneously with or after the other drug substance(s)).
  • a combination product according to the disclosure can besides or in addition be administered especially for cancer therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumour regression, or even chemo- preventive therapy, for example in patients at risk.
  • combination products according to the disclosure may be used in combination with other tumour treatment approaches, including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids or hormones.
  • the pharmaceutical combination is useful in the treatment of one or more of the diseases which respond to an inhibition of Mdm2 or tyrosine kinase activity, especially a neoplastic or tumor disease, especially solid tumor, more especially those cancers in which Mdm2 or tyrosine kinase are implicated, such as benign or malignant tumors, a sarcoma, such as liposarcoma, rhabdomyosarcoma or bone cancer, e.g.
  • osteosarcomas a carcinoma, such as of the brain, kidney, liver, adrenal gland, bladder, breast, gastric, ovary, colon, rectum, pro-state, pancreas, lung, vagina or thyroid, a glioblastoma, a multiple myeloma, a gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the head and neck, a melanoma, a prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, a leukemia or a lymphoma, such as of B- or T-cell origin, and metastases in other organs.
  • a carcinoma such as of the brain, kidney, liver, adrenal gland, bladder, breast, gastric, ovary, colon, rectum, pro-state, pancreas, lung, vagina or thyroid
  • a glioblastoma a multiple myeloma
  • the combination product of the present disclosure is especially appropriate for treatment a patient suffering from a proliferative disorder, in particular leukemia.
  • the cancer that can be treated by the pharmaceutical combination is CML.
  • the cancer is in CML chronic phase.
  • the CML is in blast crisis phase.
  • the cancer comprises functional p53 or p53 wt.
  • therapeutically effective refers in relation to an amount to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or a- meliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the present disclosure that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by Mdm2 and/or mediated by tyrosine kinase activity, or (ii) characterized by activity (normal or abnormal) of Mdm2 and/or tyrosine kinase (TK); or (2) reducing or inhibiting the activity of Mdm2 and/or of TK; or (3) reducing or inhibiting the expression of Mdm2 and/or TK.
  • a "subtherapeutic" dose as used herein describes the dose that does not lead to clinically satisfactory effect.
  • the TK is BCR-ABL, or abl-tyrosine kinase.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans
  • the subject is a primate.
  • the subject is a human.
  • CGM097 of the pharmaceutical combination can be administered in unit dosage of about 1- 5000 mg of active ingredient for a subject of about 50-70 kg, or about 1 mg - 3g or about 200- 1200 mg, or about 250-1000 mg, or about 300-800 mg, once or twice a day.
  • the therapeutically effective dosage of the compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • Nilotinib can be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained in the larger mammal, e.g. humans, at a daily dosage of nilotinib: 300 mg twice daily in newly diagnosed patients with CML in the chronic phase, or 400 mg twice daily in patients with chronic or accelerated (blast) phase CML. Treatment should be continued as long as the patient continues to benefit. For a dose of 300 mg twice daily, 150 mg hard capsules can be
  • the dosage of the active ingredient to be applied to a warm-blooded animal depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. Also amount and frequency of simultaneous or sequential administration of drugs is the combination is to be considered.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the pharmaceutical combination product according to the disclosure (as fixed combination, or as kit, e.g. as combination of a fixed combination and individual formulations for one or both combination partners or as kit of individual formulations of the combination partners) comprises the combination of the present disclosure and one or more pharmaceutically acceptable carrier materials (carriers, excipients).
  • carriers, excipients for particular routes of administration such as oral
  • combination products of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the combination products and/or their combination partners can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more commonly known carriers, e.g. one or more carriers selected from the group consisting of a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) Lubricants, e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) Binders, e.g.
  • Diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • Lubricants e.g. , silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • Binders e.g.
  • Disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavors and sweeteners.
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration especially include an effective amount of one or more or in case of fixed combination formulations each of the combination partners (active ingredients) in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient(s) in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • Parenteral compositions and other can be prepared by known methods in the art.
  • Example 1 Effect of CGM097 on apoptosis and proliferation of CML chronic phase (CP) and normal cord blood CD34+ cells
  • CD34+ cells were labeled with CFSE, were incubated in SFM supplemented with low
  • CGM097 had similar effects on CML and normal cells when used alone, it showed relatively increased efficacy towards CML CD34+ cells in combination with Nilotinib (Fig.1 ).
  • CD34+ cells were labeled with CFSE.
  • CD34+CD38+/- cells with narrow and uniform CFSE labeling were selected by flow cytometry and incubated in SFM supplemented with low concentration of growth factors for 72 hrs. Cells were treated with the compounds. Cells were analyzed for apoptosis after labeling with Annexin V and DAPI, and for proliferation based on reduction of CFSE fluorescence intensity.
  • CGM097 showed increased efficacy towards CML CD34+CD38- cells compared to CD34+CD38+ cells
  • Example 3 Effect of CGM097 on colony forming cell frequency of CML chronic phase CP and normal cord blood CD34+ cells
  • CD34+ cells were treated as shown in Fig. 3 and plated in methylcellulose progenitor culture and assessed for the presence of CFU-GM, and BFU-E colonies after 14 days culture. Although CGM097 had similar effects on CML and normal cells when used alone, it showed relatively increased efficacy towards CML CD34+ cells in combination with Nilotinib.
  • CD34+CD38-/+ cells were treated as shown in Fig. 4 and plated in methylcellulose progenitor culture and assessed for the presence of CFU-GM, and BFU-E colonies after 14 days culture.
  • CGM097 showed efficacy towards both CML CD34+CD38+ and CD34+CD38- cells, which was increased in combination with Nilotinib.
  • Example 5 Effect of CGM097 on apoptosis and proliferation of CML BC CD34+ cells
  • CD34+ cells from CML blast crisis phase were labeled with CFSE, cultured with low concentration of growth factors for 72 hrs, treated with compounds and analyzed for apoptosis with Annexin V and DAPI labeling and proliferation by reduction in CFSE fluorescence.
  • CGM097 demonstrated efficacy against CML BC CD34+ cells which was increased in combination with Nilotinib.
  • CGM097 to target CML stem/progenitor cells by itself or in combination with nilotinib was evaluated.
  • Normal or CML CD34+ cells were treated with CGM097, nilotinib or the combination for 72 hours.
  • Treatment with CGM097 (1 , 2 ⁇ ) by itself did not result in significant increase in apoptosis in either chronic phase (CP) CML and normal CD34+ cells.
  • CP chronic phase
  • CGM097 with nilotinib (1 ⁇ ) resulted in significantly increased apoptosis of CML progenitors compared to untreated controls, or cells treated with nilotinib or CGM097 alone (p ⁇ 0.001 ), and resulted in significantly enhanced targeting of CML compared to normal CD34+ cells (p ⁇ 0.001 ) (see Table 1 ).
  • the CGM097 and nilotinib combination also resulted in significant reduction in the colony forming cell (CFC) capacity of CML CD34+ cells (p ⁇ 0.01 ) but not normal CD34+ cells.
  • CFC colony forming cell
  • CGM097 in combination with nilotinib significantly enhanced apoptosis of CML CD34+38- stem/primitive progenitor cells compared to untreated cells or cells treated with nilotinib or CGM097 alone (p ⁇ 0.001 ) and resulted in significantly enhanced targeting of CML compared to normal CD34+38- cells (p ⁇ 0.001 ) (Table 1 ).
  • Treatment with the combination of CGM097 and nilotinib (1 ⁇ ) significantly increased apoptosis (p 0.001) and reduced CFC frequency (p ⁇ 0.001) in CML blast crisis (BC) CD34+ cells (Table 1).
  • CGM097 showed greater selectivity for CML CP compared with normal CD34+ cells, compared to Nutlin- 3, another HDM2 inhibitor undergoing clinical testing, and in combination with nilotinib showed greater efficacy against CML BC CD34+ cells (p ⁇ 0.01).
  • CGM097 treatment resulted in enhanced expression of mRNA and protein for several p53 target genes including PUMA, PIG3, P21 , HDM2, DR5 and BAX in BC CML CD34+ cells.
  • CML blast crisis (BC) leukemia stem cells (LSC) engrafted in NSG mice to test the effects of in vivo treatment with CGM097 with or without nilotinib.
  • the results indicate that the HDM2-p53 inhibitor, CGM097 in combination with nilotinib is effective in inducing apoptosis and inhibiting growth of primitive CML chronic phase and blast crisis stem/progenitor cells.
  • CGM097 treatment induced significantly less apoptosis and growth inhibition in normal stem/progenitor cells, and can selectively target CML LSC in combination with nilotinib.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne une combinaison pharmaceutique, par exemple un produit, comprenant une combinaison de CGM097 et de nilotinib, ou leur sel pharmaceutiquement acceptable, respectivement, qui sont conjointement actifs dans le traitement de maladies prolifératives. L'invention porte en outre sur des formulations pharmaceutiques, des utilisations, des procédés, des combinaisons et des vecteurs de données correspondants, ainsi que sur des modes de réalisation de l'invention afférents.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005281A1 (fr) 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005281A1 (fr) 2002-07-05 2004-01-15 Novartis Ag Inhibiteurs de tyrosine kinases
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées
US20130281473A1 (en) * 2009-12-22 2013-10-24 Novartis Ag Substituted isoquinolinones and quinazolinones

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