Classifications

• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• ⁇ -Guanidinopropionic acid also referred to as guanidinopropionic acid, beta- guanidinopropionic acid or, N-(aminoiminomethyl)-beta-alanine is a creatine analog.
• acidic guanidine derivatives such as ⁇ -GPA can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Accordingly, it is sometimes used as a dietary supplement in diabetic patients to regulate blood sugar levels.
• the invention features methods of treating cancer by administering about 1 ,500 mg to about 4,000 mg of ⁇ -GPA twice daily.
• the inventors have discovered that this dosing regimen surprisingly results in higher than expected levels of systemically circulating ⁇ -GPA.
• the invention features a method of treating cancer (e.g., gastrointestinal cancer such as colon cancer or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, adenocarcinoma of the esophagogastric junction, and melanoma) in a subject in need thereof.
• cancer e.g., gastrointestinal cancer such as colon cancer or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, adenocarcinoma of the esophagogastric junction, and melanoma
• This method includes administering about 1 ,500 mg to about 4,000 mg (e.g., about 1 ,500 mg to about 2,000 mg, about 1 ,750 mg to about 2,250 mg, about 2,000 mg to about 2,500 mg, about 2,250 mg to about 2,750 mg, about 2,400 mg to about 2,800 mg, about 2,700 mg to about 3,000 mg, about 2,750 mg to about 3,250 mg, about 3,100 mg to about 3,400 mg, about 3,200 mg to about 3,600 mg) of ⁇ -GPA, or a pharmaceutically acceptable salt thereof to the subject twice per day.
• the method includes administering between about 2,400 mg and about 3,600 mg of ⁇ -GPA, or a pharmaceutically acceptable salt thereof to the subject twice per day.
• the method includes administering about 2,400 mg of ⁇ -GPA, or a pharmaceutically acceptable salt thereof to the subject twice per day. In some embodiments of any of the foregoing methods, the method includes administering about 3,600 mg of ⁇ -GPA, or a pharmaceutically acceptable salt thereof to the subject twice per day.
• the method further includes administering one or more further anti-cancer therapies (e.g., radiation therapy, surgery, and/or one or more therapeutic agents).
• the one or more further anti-cancer therapies includes folinic acid, fluorouracil, irinotecan, and/or oxaliplatin.
• the one or more further anti-cancer therapies includes FOLFIRI, i.e. , folinic acid, fluorouracil, and irinotecan.
• the one or more therapeutic agents is cyclocreatine, a RNAi agent, a nucleic acid, a vector, 5-fluorouracil, oxaliplatin, irinotecan, capecitabine, gemcitabine, cetuximab, taxol, avast!
• folinic acid leucovorin
• regorafenib zaltrap
• topoisomerase I inhibitors etirinotecan pegol, tivantinib, sonolisib, sorafenib, linifanib, kinase inhibitors, telatinib, BMS-908662 (i.e., methyl N-[6-[2-(5-chloro-2- methylphenyl)-1-hydroxy-3-oxoisoindol-1-yl]-1H-benzimidazol-2-yl]carbamate), robatumumab, and/or IGF1-R inhibitors.
• the cancer is metastatic cancer (e.g., metastatic gastrointestinal cancer such as metastatic colon cancer or metastatic gastric cancer, metastatic pancreatic cancer, metastatic liver cancer, metastatic breast cancer, metastatic prostate cancer, metastatic lung cancer, metastatic adenocarcinoma of the esophagogastric junction, or metastatic melanoma).
• metastatic cancer e.g., metastatic gastrointestinal cancer such as metastatic colon cancer or metastatic gastric cancer, metastatic pancreatic cancer, metastatic liver cancer, metastatic breast cancer, metastatic prostate cancer, metastatic lung cancer, metastatic adenocarcinoma of the esophagogastric junction, or metastatic melanoma.
• the cancer is gastrointestinal cancer (e.g., colorectal cancer, gastric cancer, or adenocarcinoma of the esophagogastric junction).
• gastrointestinal cancer e.g., colorectal cancer, gastric cancer, or adenocarcinoma of the esophagogastric junction.
• the cancer expresses CKB.
• the subject is identified to have, or to be at risk of having, metastatic cancer (e.g., on the basis of the expression level of CKB being above a predetermined reference value).
• the cancer is resistant to one or more therapeutic agents. In some embodiments of any of the foregoing methods, the cancer progressed on or after treatment with one or more anti-cancer therapies.
• the ⁇ -GPA, or a pharmaceutically acceptable salt thereof is the succinate salt of ⁇ -GPA (e.g., the 2:1 succinate salt of ⁇ -GPA).
• the term “about” represents a value that is in the range of ⁇ 10% of the value that follows the term “about.”
• administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.
• bronchial including by bronchial instillation
• a “drug resistant” cancer is meant a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein).
• failed to respond to a prior therapy or “refractory to a prior therapy,” refers to a cancer that progressed despite treatment with the therapy.
• metastatic tumor refers to a tumor or cancer in which the cancer cells forming the tumor have a high potential to or have begun to, metastasize, or spread from one location to another location or locations within a subject, via the lymphatic system or via hematogenous spread, for example, creating secondary tumors within the subject. Such metastatic behavior may be indicative of malignant tumors. In some cases, metastatic behavior may be associated with an increase in cell migration and/or invasion behavior of the tumor cells.
• cancers that can be defined as metastatic include but are not limited to non-small cell lung cancer (e.g., non-squamous non-small cell lung cancer), breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medulloblastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, multiple myeloma, leukemia, intraepithelial neoplasms, liver cancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer.
• non-small cell lung cancer e.g., non-squamous non-small cell lung cancer
• breast cancer ovarian
• compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
• oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
• a “pharmaceutically acceptable excipient,” as used herein, refers any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject.
• Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, d is integrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
• Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.
• the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
• These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
• the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art.
• subject refers to a human or non-human animal (e.g., a mammal such as a non-human primate, horse, cow, or dog).
• treatment refers to any administration of a substance (e.g., provided compositions) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
• a substance e.g., provided compositions
• such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
• treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
• the invention features methods of treating cancer by administering about 2,000 mg to about 4,000 mg of ⁇ -GPA twice daily.
• the inventors have discovered that this dosing regimen surprisingly results in higher than expected levels of circulating ⁇ -GPA.
• ⁇ -GPA ⁇ -GPA has the structure: ⁇ -GPA is zwitterionic and highly soluble in water (> 50 mg/ml_), but has low solubility in organic solvents.
• ⁇ -GPA possesses a basic guanidino group, and is thus capable of forming both 1 :1 ( ⁇ - GPA:acid) and 2:1 ( ⁇ -GPA:acid) salts with diacids.
• a “2:1 salt” of ⁇ -GPA with a diacid refers to a salt including two molecules of ⁇ -GPA and one molecule of the diacid, e.g., a “2:1 succinate salt” includes two molecules of ⁇ -GPA and one molecule of succinic acid.
• Treatment Methods ⁇ -GPA has recently been found to be effective for the suppression of metastasis.
• the mechanism of action has been hypothesized as inhibition of creatine transport and/or creatine kinase.
• the phosphocreatine system promotes metastasis by enhancing the survival of disseminated cancer cells in the liver by acting as an energetic store for ATP generation to endure hepatic hypoxia. Inhibition of creatine transport into cancer cells limits the amount of phosphocreatine available to use in the production of ATP. Inhibition of creatine kinase inhibits the production of ATP through conversion of phosphocreatine to creatine.
• Typical vascularized tumors that can be treated with the methods of the invention include solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients.
• Exemplary solid tumors include, but are not limited to, carcinomas of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, glioblastomas, neuroblastomas, Kaposi's sarcoma, and sarcomas.
• Treating cancer can result in a reduction in size or volume of a tumor.
• tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment.
• Size of a tumor may be measured by any reproducible means of measurement.
• the size of a tumor may be measured as a diameter of the tumor.
• Treating cancer may further result in a decrease in number of tumors.
• tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
• Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
• Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
• the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
• the number of metastatic nodules may be measured by any reproducible means of measurement.
• the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
• Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
• the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
• An increase in average survival time of a population may be measured by any reproducible means.
• An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
• An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
• Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
• the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
• a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention.
• a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a method of the invention.
• composition refers to the combination of an active agent with a excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
• a “pharmaceutically acceptable excipient,” after administered to or upon a subject, does not cause undesirable physiological effects.
• the excipient in the pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient and can be capable of stabilizing it.
• One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound.
• examples of a pharmaceutically acceptable excipient include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
• the pharmaceutical compositions of the present invention additionally include a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
• a pharmaceutically acceptable excipient includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
• Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
• compositions in any of the forms described above, can be used for treating cancer, or any other disease or condition described herein.
• An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
• a pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally.
• parenteral refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
• a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
• fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
• Other commonly used surfactants such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.
• a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
• the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
• Subjects were administered RGX-202 (a highly compressible salt form of ⁇ -GPA) in a regimen of 600 mg BID, 1 ,200 mg BID, 2,400 mg BID, or 3,600 mg BID, and plasma samples were taken from the subjects and tested using the protocol described below for levels of ⁇ -GPA over the course of 24 hours after administration.
• RGX-202 a highly compressible salt form of ⁇ -GPA
• Subjects with advanced gastrointestinal tumors were administered multiple doses of orally administered RGX-202 as a monotherapy or in combination with irinotecan, folinic acid, and fluorouracil.
• RGX-202 was administered orally twice or three times daily on days 1-28 of each 28-day cycle. The dose regimen was dependent on the cohort in which the patient was enrolled.
• RGX-202 was administered in the same way as described for the monotherapy arm in combination with FOLFIRI.
• results The subjects did not exhibit dose limiting toxicity. Objective monotherapy (RGX-202) and combination therapy (RGX-202 +FOLFIRI) activities were observed. Of the 7 subjects who received the combination therapy, 6 subjects showed stable disease (as described by RECIST 1.1 guidelines) after 40 weeks of treatment (e.g., doses of RGX-202 > 1 ,800 mg BID). Of the 10 subjects who received the monotherapy, one subject exhibited a partial response (at a dose of 3,600 mg BID after 40 weeks), and three exhibited stable disease (at doses of 1 ,200 mg BID, 2,400 mg BID, and 3,600 mg BID).

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