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WO2019099836A1 - Formulation inhalée d'un inhibiteur moléculaire de la signalisation wnt/bêta-caténine pour le traitement de maladies pulmonaires interstitielles - Google Patents

Formulation inhalée d'un inhibiteur moléculaire de la signalisation wnt/bêta-caténine pour le traitement de maladies pulmonaires interstitielles Download PDF

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WO2019099836A1
WO2019099836A1 PCT/US2018/061531 US2018061531W WO2019099836A1 WO 2019099836 A1 WO2019099836 A1 WO 2019099836A1 US 2018061531 W US2018061531 W US 2018061531W WO 2019099836 A1 WO2019099836 A1 WO 2019099836A1
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Prior art keywords
inhibitor
beta
wnt
catenin
mmad
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Inventor
Ali P. LAM
Cara J. GOTTARDI
Manu Jain
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Northwestern University
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Northwestern University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • the present invention generally relates to methods, compositions, and devices for treating interstitial lung diseases.
  • the present invention relates to methods, compositions, and devices for treating interstitial lung diseases that involve administering an inhaled formulation of a molecular inhibitor of Wnt/beta-catenin signaling.
  • IPF Idiopathic Pulmonary Fibrosis
  • pulmonary fibrosis represents a significant unmet medical need and an area of market opportunity.
  • the methods, compositions, and devices utilize or include as a therapeutic agent an inhibitor of Wnt/beta-catenin signaling which may be administered via pulmonary delivery, for example, via an inhaled formulation of the inhibitor.
  • Suitable inhibitors of Wnt/beta-catenin signaling for the methods, compositions, and devices may include but are not limited to the compound (9E,lOE)-2,7- bis(((3R,5S)-3,5-dimethylpiperidin-l-yl)sulfonyl)anthracene-9,l0-dione dioxime which otherwise may be referred to as BC-2059 having a formula:
  • the disclosed inhibitor may be administered via pulmonary delivery and may be formulated as an inhaled formulation for delivery via an inhaler and/or a nebulizer.
  • devices for delivering an inhaled formulation of the inhibitor are contemplated herein.
  • Inhaled formulations of the inhibitor may include but are not limited to aerosol formulations.
  • the inhaled formulation comprises particles of the inhibitor having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or having a MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • FIG. 1 Lrp5 loss limits development of pulmonary fibrosis.
  • Total protein in bronchoalveolar lavage (BAL) fluid (B), total soluble collagen content (C) and COL1A1 and COL1A2 mRNA expression (D) were decreased in Lrp5-/- lungs compared with Lrp5+/+.
  • FIG. 1 Expression of Wnt/ -catenin pathway genes in peripheral blood mononuclear cells is associated with progression of IPF.
  • A. PBMCs from 74 subjects with IPF were analyzed for expression of Wnt pathway genes. Positive Cox score indicates higher expression correlated with rapid IPF progression, whereas lower expression indicates slower IPF progression.
  • D and E. A second cohort of IPF subjects confirmed inverse correlation of LRP5 with DLCO and direct correlation with Composite Physiology Index (CPI) 8 .
  • CPI Composite Physiology Index
  • FIG. 3 Intravenous BC-2059 reverses bleomycin-induced pulmonary fibrosis. BC-2059 was delivered twice weekly by tail vein injection in wild-type C56BL/6, starting on day 7 after intra-tracheal administration of one dose of bleomycin.
  • FIG. 4 Intranasal BC-2059 reverses bleomycin-induced pulmonary fibrosis. BC-2059 was inhaled twice weekly in wild-type C56BL/6, starting on day 7 after one of dose of intra-tracheally administered bleomycin.
  • Figure 6. Administration of a nebulized formulation of BC-2059 in a mouse model of pulmonary fibrosis.
  • Figure 7. C57BL/6 mice were given intratracheal bleomycin or saline to induce fibrosis or control state. Starting at day 7, each population of mice were given treatment with BC-2059 (IV or nebulized), vehicle, or pirfenidone gavage.
  • FIG. 8 Treatment with BC-2059 results in diminished histologic fibrosis in mice treated with bleomycin and is similar to pirfenidone. H&E staining of representative murine lungs treated with bleomycin with therapy of pirfenidone or BC- 2059 versus vehicle.
  • A IT bleomycin followed by vehicle.
  • B IT bleomycin followed by pirfenidone.
  • C IT bleomycin followed by BC-2059 IV.
  • FIG. 9 BC-2059 treatment after bleomycin injury results in diminished collagen content.
  • collagen content is similar to those treated with saline and significantly diminished from those treated with bleomycin followed by vehicle. ****p ⁇ 0.0001. n > 5 mice/group.
  • FIG. 10 Compliance, measured by Flexivent, is increased in mice treated with BC-2059 after bleomycin injury.
  • A In C57BL/6 mice treated with bleomycin followed by pirfenidone or IV BC-2059, there is significant improvement in lung compliance compared to those treated with vehicle only. **p ⁇ 0.01, ****p ⁇ 0.0001. n > 5 mice/group.
  • FIG. 11 Hydroxyproline content and compliance are improved in mice treated with nebulized BC-2059 after bleomycin injury.
  • A In C57BL/6 mice treated with bleomycin followed by pirfenidone or nebulized BC-2059, there is significant decrease in lung hydroxyproline compared to those treated with vehicle only.
  • B Nebulized BC-2059 also resulted in a significant difference in compliance in those treated with IT bleomycin. *p ⁇ 0.05, **p ⁇ 0.01. n > 4 mice/group.
  • FIG. 12 Survival of mice after intratracheal bleomycin is improved by treatment with BC-2059, similar to pirfenidone.
  • A Only mice treated with intratracheal and no pirfenidone gavage or BC-2059 IV died prior to sacrifice.
  • B Mice treated with bleomycin died prior to sacrifice in both the vehicle and BC-2059 groups but BC-2059 increased time to death as well as number surviving.
  • the singular forms“a,”“an,” and“the” include plural forms unless the context clearly dictates otherwise.
  • the term“an inhibitor of Wnt/beta-catenin signaling” should be interpreted to mean“one or more inhibitors of Wnt/beta-catenin signaling” unless the context clearly dictates otherwise.
  • the term“plurality” means“two or more.”
  • the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.”
  • the terms “comprise” and “comprising” should be interpreted as being“open” transitional terms that permit the inclusion of additional components further to those components recited in the claims.
  • the terms“consist” and“consisting of’ should be interpreted as being“closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims.
  • the term“consisting essentially of’ should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter. [0025]
  • the phrase“such as” should be interpreted as“for example, including.”
  • a range includes each individual member.
  • a group having 1-3 members refers to groups having 1, 2, or 3 members.
  • a group having 6 members refers to groups having 1, 2, 3, 4, or 6 members, and so forth.
  • the modal verb“may” refers to the preferred use or selection of one or more options or choices among the several described embodiments or features contained within the same. Where no options or choices are disclosed regarding a particular embodiment or feature contained in the same, the modal verb “may” refers to an affirmative act regarding how to make or use and aspect of a described embodiment or feature contained in the same, or a definitive decision to use a specific skill regarding a described embodiment or feature contained in the same. In this latter context, the modal verb“may” has the same meaning and connotation as the auxiliary verb“can.” [0030] The disclosed methods and compositions relate to methods for treating a subject in need thereof.
  • a“subject in need thereof’ may include a subject having or at risk for developing an interstitial lung disease.
  • Interstitial lung diseases may include, but are not limited to, idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease, pulmonary fibrosis due to asbestos exposure, and pulmonary fibrosis due to autoimmune diseases.
  • IPF idiopathic pulmonary fibrosis
  • systemic sclerosis associated interstitial lung disease pulmonary fibrosis due to asbestos exposure
  • pulmonary fibrosis due to autoimmune diseases due to autoimmune diseases.
  • the disclosed methods and compositions may utilize and/or include pharmaceutical aerosol formulations of an active pharmaceutical ingredient for delivery directly to the lungs, /. ⁇ ? . , via pulmonary delivery.
  • an“aerosol” refers to a suspension of liquid droplets or fine solid particles in air or another gas.
  • the term“aerosol formulation” may refer to an aqueous composition, a dry powder composition, or a propellant-based composition, which can be aerosolized as described in more detail herein.
  • An aerosol formulation of the invention may be delivered to a subject in different ways, for example nasally or perorally, e.g. , by inhalation in order to delivery the aerosol formulation pulmonarily.
  • the aerosol formulations disclosed herein may be formulated with an active pharmaceutical ingredient alone, or in combination with one or more solvents, excipients, carriers, and/or propellants.
  • the amount of the active pharmaceutical ingredient in the aerosol formulation is from 5 to 500 micrograms, from 10 to 250 micrograms, from 15 to 150 micrograms or from 20 to 100 micrograms. In some embodiments, the amount of the active pharmaceutical ingredient in the aerosol formulation is 20, 40, 50, 100, 125, or 250 micrograms.
  • the step of administering the composition to the subject produces particles comprising an active pharmaceutical ingredient and having an average mean diameter in the range of 0.1 to 5 microns. In one embodiment, the step of administering the composition to the subject produces particles comprising an active pharmaceutical ingredient and having an average mean diameter in the range of 0.5 to 3 microns.
  • the aerosol formulation of the invention is adapted for once daily administration, twice daily administration, or thrice daily administration and, according to the methods described herein, the aerosol formulation is administered once a day, twice a day, or three times a day.
  • the aerosol formulation is a dry powder composition suitable for delivery by inhalation.
  • the dry powder comprises the active pharmaceutical ingredient in the form of microparticles or nanoparticles, optionally particles of a carrier, and optionally one or more excipients.
  • the microparticles or nanoparticles consist of particles of drug having mean diameters from about 0.1 to 5 microns.
  • the carrier may be selected from the group consisting of arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol, lysine, leucine, isoleucine, dipalmitylphosphatidylcholine, lecithin, polylactic acid, poly (lactic-co-glutamic) acid, and xylitol, and mixtures of any of the foregoing.
  • the amount of the active pharmaceutical ingredient in the aerosol formulation is from about 0.1% to 20% (w/w) based upon total weight of the composition. In particular, the amount may be from about 0.25% to 2% (w/w).
  • the amount the active pharmaceutical ingredient in the aerosol formulation is an amount effective to achieve a respirable dose of from 5 to 500 micrograms delivered to the lung. In one embodiment, the respirable dose is about 5, about 20, about 50, about 100 or about 250 micrograms. In one embodiment, the respirable dose is about 20 micrograms, to about 50 micrograms, or about 100 micrograms. In some embodiments, the amount is an amount effective to produce a concentration of the active pharmaceutical ingredient in the lung tissue of from 1 ng/g to 1 microgram (microgram)/g. In some embodiments, the concentration of active pharmaceutical ingredient in the lung tissue is from about 5-30 ng/g.
  • the concentration of active pharmaceutical ingredient in the lung tissue is about 5 ng/g, about 10 ng/g, about 15 ng/g about 20 ng/g, about 25 ng/g, about 30 ng/g, about 50 ng/g, about 60 ng/g, about 100 ng/g, or about 200 ng/g.
  • Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease, pulmonary fibrosis due to asbestos exposure, and pulmonary fibrosis due to autoimmune diseases.
  • the method and compositions utilize or include as a therapeutic agent an inhibitor of Wnt/beta-catenin signaling which may be administered by pulmonary administration via an inhaled formulation of the inhibitor.
  • the inhibitor utilized in the disclosed methods and compositions typically inhibits Wnt/beta-catenin signaling.
  • the molecule mechanisms of Wnt signaling are known in the art. ( See discussion in Example 1 below)
  • the Wnt-beta catenin signaling pathway otherwise may be referred to as the “canonical” Wnt pathway.
  • the inhibitor of Wnt/beta- catenin signaling may inhibit one or more biological activities of beta-catenin, which may include but are not limited to binding and/or interacting with the transducing beta-like protein a (TBL1).
  • Inhibitors of beta-catenin are known in the art including anthracene-9, 10- dione dioxime compounds and prodrugs thereof. (See, e.g., U.S. Patent No. 9,725,473 and U.S. Patent No. 9,238,030, the contents of which are incorporated herein by reference in their entireties).
  • the inhibitor of beta-catenin has a formula a formula I:
  • Ri, R , R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NR 1 R 2 and NR 3 R 4 can independently combine to form a 6- to l5-membered heterocycloalkyl which optionally is substituted at one or more positions with alkyl;
  • R 5 is selected from the group consisting of -P(0)(0H) 2 , -CHR 7 -0-P(0)(0H) 2 , -C(O)— R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 6 is selected from the group consisting of H, -P(0)(0H) 2 ; -CHR 7 -0-P(0)(0H) 2 , - C(0)-R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 7 is H or an optionally substituted lower alkyl
  • R 8 is a lower alkyl, -ORn, aryl, heteroaryl or heterocycloalkyl, wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR 9 R 10 and/or OR12;
  • Rg and Rio are independently selected from the group consisting of H, -P(0)(0H) 2 , and optionally substituted lower alkyl;
  • Rn is independently selected from the group consisting of lower alkyl, aryl, heteroaryl and heterocycloalkyl wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR9R10 and/or -OH; and
  • R12 is H or -P(0)(0H) 2 .
  • the inhibitor of beta-catenin has a formula:
  • BC-2059 or (9E,l0E)-2,7-bis(((3R,5S)-3,5- dimethylpiperidin- l-yl)sulfonyl)anthracene-9, lO-dione dioxime.
  • the disclosed methods and compositions may utilize and/or include inhaled formulations of the inhibitor of Wnt beta-catenin signaling that are delivered pulmonarily.
  • the inhaled formulation is administered via an inhaler and/or via a nebulizer system as known in the art.
  • a nebulizer system See, e.g., Qvar® brand inhaler, Flo vent HFA® brand inhaler, Advair® brand inhaler, Beclovent® brand inhaler, and dRapid® brand nebulizer system).
  • the inhaled formulation comprises particles of the inhibitor having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or having a MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • Suitable inhaled formulations of the inhibitor of Wnt/beta-catenin signaling may include but are not limited to aerosol formulations.
  • the aerosol formulation includes the inhibitor as an active pharmaceutical ingredient and a propellant (e.g., HFA (1, 1, 1, 2-tetrafluoroethane)) as components.
  • the aerosol formulation includes a solution of the inhibitor dissolved in the propellant, and preferably the aerosol formulation comprises liquid particles having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or having a MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • an aerosol formulation of the inhibitor may include additional components.
  • the aerosol formulation includes a solution of the inhibitor dissolved in the propellant as components, and the solution further comprises ethanol (e.g., as a co-solvent), where the ethanol is present in the solution at a concentration up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or within a concentration range bounded by any of these values.
  • the aerosol formulation may include a surfactant as an additional component (e.g. , a polyoxamer such as Poloxamer 188).
  • the aerosol formulation includes solid particles of the inhibitor as an active pharmaceutical ingredient suspended in a propellant as components.
  • the particles Preferably, the particles have a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or having a MMAD within a range bounded by any of these values.
  • the aerosol formulation comprises a carrier for the inhibitor (e.g. , a sugar or sugar alcohol carrier such as sorbitol, lactose, or mannitol).
  • the inhibitor is administered as a powder formulation.
  • the powder comprises particles of the inhibitor having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm.
  • MMAD mass median aerodynamic diameter
  • Embodiment 1 A method for treating an interstitial lung disease in a subject in need thereof, the method comprising administering to the subject an inhibitor of Wnt/beta-catenin signaling.
  • Embodiment 2. The method of embodiment 1, wherein the interstitial lung disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), systemic sclerosis associated interstitial lung disease, pulmonary fibrosis due to asbestos exposure, and pulmonary fibrosis due to autoimmune diseases.
  • IPF idiopathic pulmonary fibrosis
  • systemic sclerosis associated interstitial lung disease pulmonary fibrosis due to asbestos exposure
  • pulmonary fibrosis due to autoimmune diseases idiopathic pulmonary fibrosis due to autoimmune diseases.
  • Embodiment 3 The method of embodiment 1 or 2, wherein the inhibitor of Wnt/beta-catenin signaling inhibits biological activity of a member of the Wnt/beta- catenin signaling pathway such as beta-catenin.
  • Embodiment 4 The method of any of the foregoing embodiments, wherein the inhibitor inhibits binding of transducing beta-like protein a (TBL1) and beta-catenin.
  • Embodiment 5 The method of any of the foregoing embodiment, wherein the inhibitor has a formula I
  • Ri, R , R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NR 1 R 2 and NR 3 R 4 can independently combine to form a 6- to l5-membered heterocycloalkyl which optionally is substituted at one or more positions with alkyl;
  • R 5 is selected from the group consisting of -P(0)(0H) 2 , -CHR 7 -0-P(0)(0H) 2 , -C(O)— R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 6 is selected from the group consisting of H, -P(0)(0H) 2 ; -CHR 7 -0-P(0)(0H) 2 , - C(0)-R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 7 is H or an optionally substituted lower alkyl
  • R 8 is a lower alkyl, -ORn, aryl, heteroaryl or heterocycloalkyl, wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR 9 R 10 and/or OR12;
  • Rg and Rio are independently selected from the group consisting of H, -P(0)(0H) 2 , and optionally substituted lower alkyl;
  • R 11 is independently selected from the group consisting of lower alkyl, aryl, heteroaryl and heterocycloalkyl wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR 9 R 10 and/or -OH; and
  • R 12 is H or -P(0)(0H) 2 .
  • Embodiment 6 The method of any of the foregoing embodiments, wherein the inhibitor has a formula:
  • Embodiment 7 The method of any of the foregoing embodiments, wherein the inhibitor is administered pulmonarily for example via inhalation.
  • Embodiment 8 The method of embodiment 7, wherein the inhibitor is administered as an aerosol formulation.
  • Embodiment 9 The method of embodiment 8, wherein the aerosol formulation comprises the inhibitor and a propellant.
  • Embodiment 10 The method of embodiment 9, wherein the aerosol formulation comprises a solution of the inhibitor dissolved in the propellant.
  • Embodiment 11 The method of embodiment 10, wherein the solution comprises ethanol at a concentration up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or within a concentration range bounded by any of these values.
  • Embodiment 12 The method of any of embodiments 10 or 11, wherein the solution of the inhibitor further comprises a surfactant.
  • Embodiment 13 The method of any of embodiments 8-12, wherein the aerosol formulation comprises liquid particles having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm.
  • MMAD mass median aerodynamic diameter
  • Embodiment 14 The method of embodiment 9, wherein the aerosol formulation comprises a suspension of solid particles of the inhibitor in the propellant.
  • Embodiment 15 The method of embodiment 14, wherein the particles have a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm.
  • MMAD mass median aerodynamic diameter
  • Embodiment 16 The method of any of embodiments 8-15, wherein the aerosol formulation comprises a carrier for the inhibitor.
  • Embodiment 17 The method of embodiment 8, wherein the inhibitor is administered as a powder.
  • Embodiment 18 The method of embodiment 17, wherein the powder comprises particles of the inhibitor having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm.
  • MMAD mass median aerodynamic diameter
  • Embodiment 19 The method of any of the foregoing embodiments, wherein the inhibitor is administered via an inhaler or a nebulizer.
  • Embodiment 20 A pharmaceutical composition comprising an aerosol formulation of an inhibitor of Wnt/beta-catenin signaling, the composition comprising particles of the inhibitor having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm.
  • MMAD mass median aerodynamic diameter
  • Embodiment 21 A device for administering an aerosolized formulation of an inhibitor of Wnt/beta-catenin signaling, optionally wherein the device is an inhaler or a nebulizer.
  • Embodiment 22 The device of embodiment 21, wherein the inhibitor of Wnt/beta-catenin signaling inhibits biological activity of a member of the Wnt/beta- catenin signaling pathway such as beta-catenin.
  • Embodiment 23 The device of embodiment 21 or 22, wherein the inhibitor inhibits binding of transducing beta-like protein a (TBL1) and beta-catenin.
  • TBL1 transducing beta-like protein a
  • Embodiment 24 The device of any of embodiments 21-23, wherein the inhibitor has a formula I
  • Ri, R , R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NR 1 R 2 and NR 3 R 4 can independently combine to form a 6- to l5-membered heterocycloalkyl which optionally is substituted at one or more positions with alkyl;
  • R 5 is selected from the group consisting of -P(0)(0H) 2 , -CHR 7 -0-P(0)(0H) 2 , -C(O)— R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 6 is selected from the group consisting of H, -P(0)(0H) 2 ; -CHR 7 -0-P(0)(0H) 2 , - C(0)-R 8 , and -CHR 7 -0-C(0)-R 8 ,
  • R 7 is H or an optionally substituted lower alkyl
  • R 8 is a lower alkyl, -ORn, aryl, heteroaryl or heterocycloalkyl, wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR 9 R 10 and/or OR12;
  • Rg and Rio are independently selected from the group consisting of H, -P(0)(0H) 2 , and optionally substituted lower alkyl;
  • Rn is independently selected from the group consisting of lower alkyl, aryl, heteroaryl and heterocycloalkyl wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with -NR9R10 and/or -OH; and
  • R12 is H or -P(0)(OH) 2 .
  • Embodiment 25 The device of any of embodiments 21-24, wherein the inhibitor has a formula:
  • BC-2059 or (9E,l0E)-2,7-bis(((3R,5S)-3,5-dimethylpiperidin-l- yl)sulfonyl)anthracene-9, lO-dione dioxime.
  • Embodiment 26 The device of any of claims 21-25, wherein the device is an inhaler or a nebulizer.
  • Embodiment 27 The device of any of embodiments 21-26, wherein the device comprises the inhibitor and a propellant.
  • Embodiment 28 The device of embodiment 27, wherein the device comprises a solution of the inhibitor dissolved in the propellant.
  • Embodiment 29 The device of embodiment 28, wherein the solution comprises ethanol at a concentration up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or within a concentration range bounded by any of these values.
  • Embodiment 30 The device of any of embodiment 28 or 29, wherein the solution of the inhibitor further comprises a surfactant.
  • Embodiment 31 The device of any of embodiments 21-30, wherein the device delivers an aerosol formulation comprising liquid particles having a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or an MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • Embodiment 32 The device of embodiment 31, wherein the aerosol formulation comprises a suspension of solid particles of the inhibitor in the propellant.
  • Embodiment 33 The device of embodiment 32, wherein the particles have a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or an MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • Embodiment 34 The device of any of embodiments 21-33, wherein the device comprises a carrier for the inhibitor.
  • Embodiment 35 The device of embodiment 34, wherein the device delivers the inhibitor as a powder.
  • Embodiment 36 The device of embodiment 35, wherein the powder comprises particles of the inhibitor have a mass median aerodynamic diameter (MMAD) of less than about 5, 4, 3, 2, 1, 0.5, 0.2, or 0.1 pm or an MMAD within a range bounded by any of these values.
  • MMAD mass median aerodynamic diameter
  • Example 1 Chronic intrapulmonary delivery of a novel small molecule
  • Idiopathic pulmonary fibrosis is a devastating, progressive disease with no known cure and no treatment that convincingly alters the disease course or significantly improves mortality.
  • the objective of this proposal is the development of nebulized delivery of the small molecule inhibitor of Wnt/beta-catenin signaling, BC- 2059, for Idiopathic Pulmonary Fibrosis.
  • BC-2059 has favorable pharmacokinetics and safety data with intravenous administration, which provides support for short-term use.
  • intravenous administration is undesirable for patients.
  • Nebulization of BC-2059 would achieve high local levels of the drug, while minimizing off-target side effects in other critical organs, which is key for the chronic treatment of patients with pulmonary fibrosis.
  • a respiratory formulation of BC-2059 will be optimized to generate particle sizes ⁇ 3 pm to allow for maximal distribution into the alveolar spaces.
  • the efficacy and pharmacodynamics of nebulized administration of BC-2059 will be determined in vivo using two mouse models of chronic pulmonary fibrosis, using intratracheally administered asbestos and repetitive intratracheal administration of bleomycin, both of which create non-resolving fibrosis.
  • Nebulized BC-2059 will be administered after the establishment of pulmonary fibrosis, in order to determine whether the drug improves the resolution of fibrosis, which would increase its translational potential and make a clinically meaningful impact for patients.
  • the overall goal for this Phase 1 application is the generation of high quality pre-clinical data that will provide a highly compelling rationale for clinical trials for the treatment of IPF and potentially other fibrotic lung diseases.
  • the goal of this proposal is the development of nebulized delivery of the small molecule inhibitor of Wnt/beta-catenin signaling, BC-2059, for Idiopathic Pulmonary Fibrosis.
  • This approach would achieve high local levels of the drug, while minimizing off-target side effects in other critical organs, for the chronic treatment of patients with pulmonary fibrosis.
  • the findings from these studies will provide a highly compelling rationale for clinical trials using nebulized BC-2059 for the treatment of IPF and potentially other fibrotic lung diseases.
  • Lam et al “Beta-catenin TCFsignaling promotes the survival and differentiation of alveolar epithelial cells,” J Biol Chem 2010;285(5):3157-67; Lam et al“Wnt co-receptor Lrp5 is a driver of idiopathic pulmonary fibrosis,” Am J Respir Crit Care Med 2014; 190(2): 185-95. PMID: 249; Sennello et al , “Lrp5 beta-catenin signaling controls lung macrophage differentiation and inhibits resolution of fibrosis.
  • SSc-ILD Systemic Sclerosis
  • adiponectin which is a negative regulator of tissue fibrosis, inhibits phosphorylation of the Wnt co-receptor Lrp6 and negatively regulates Wnt/ beta - catenin signaling.
  • Our data suggest a tissue-context dependent relationship of Wnt/ beta - catenin signaling in fibrosis and adipogenesis.
  • the technology relates to a respiratory formulation of BC-2059 that will allow for maximal distribution into the alveolar spaces to achieve high drug levels at the site of injury/aberrant repair, while avoiding toxic systemic levels and side effects in the chronic treatment of pulmonary fibrosis.
  • Idiopathic pulmonary fibrosis is a devastating, progressive disease with no known cure and no treatment that convincingly alters the disease course or improves mortality.
  • pulmonary fibrosis represents a significant unmet medical need.
  • the pathophysiology is incompletely understood, pulmonary fibrosis is the result of dysregulated repair after tissue injury.
  • Work from our group and others have demonstrated that the Wnt/ -catenin pathway is aberrantly activated in pulmonary fibrosis, including IPF and systemic sclerosis associated interstitial lung disease (SSc- ILD) 1 7 .
  • monocyte derived alveolar macrophages are required for the development of pulmonary fibrosis in the bleomycin lung model 9 and that sustained b-catenin signaling in alveolar macrophages promotes the persistence of lung fibrosis 10 .
  • Wnt/ -catenin signaling we have also recently shown that monocyte derived alveolar macrophages are required for the development of pulmonary fibrosis in the bleomycin lung model 9 and that sustained b-catenin signaling in alveolar macrophages promotes the persistence of lung fibrosis 10 .
  • BC -2059 is a novel small molecule inhibitor of beta-catenin signaling through disruption of Transducin beta-like protein 1 (TBLP/beta-catenin binding.
  • BC-2059 acts downstream in the Wnt signaling cascade, whereby it does not disrupt the cell-cell adhesive function of beta- catenin or interfere with the stem cell maintenance function of beta-catenin in the intestinal crypts, both of which are critical functions of beta-catenin required for tissue homeostasis and are key in preventing off-target side effects.
  • TBLP/beta-catenin binding TBLP/beta-catenin binding.
  • BC-2059 acts downstream in the Wnt signaling cascade, whereby it does not disrupt the cell-cell adhesive function of beta- catenin or interfere with the stem cell maintenance function of beta-catenin in the intestinal crypts, both of which are critical functions of beta-catenin required for tissue homeostasis and are key in preventing off-target side effects.
  • Beta Cat Pharmaceuticals has demonstrated that BC-2059 is highly potent in patient cancer cells ex vivo and in mouse tumorigenesis models. Further pre-clinical studies in rodents, dogs, and minipigs show favorable pharmacokinetics and safety data with intravenous administration, which provides support for short-term use. However, in a chronic disease, such as IPF, which requires prolonged treatment, intravenous administration is undesirable for patients. Thus, we propose a direct intra-pulmonary delivery approach for BC-2059 via nebulization that limits systemic side effects in the treatment of pulmonary fibrosis.
  • Phase I objectives Based on our preliminary studies in which intravenously and intranasally administered BC-2059 decreased pulmonary fibrosis in the bleomycin model, we propose to determine whether nebulized BC-2059 improves established fibrosis using two robust mouse models of chronic pulmonary fibrosis and to determine if there are off target effects of nebulized BC-2059 in other organs.
  • the overall goal for Phase 1 is the generation of high quality pre-clinical data that will provide a highly compelling rationale for clinical trials for the treatment of IPF and potentially other fibrotic lung diseases, such as SSc-ILD.
  • Specific Aim 1 To optimize the nebulized formulation of BC-2059 for the chronic treatment of pulmonary fibrosis. We will optimize a respiratory formulation of BC-2059 that will generate particle sizes ⁇ 3 pm to allow for maximal distribution into the alveolar spaces. This approach will achieve high drug levels at the site of injury/aberrant repair, while avoiding toxic systemic levels and side effects in the chronic treatment of pulmonary fibrosis.
  • Specific Aim 2 To determine the efficacy and pharmacodynamics of nebulized administration of BC-2059. compared to intravenous administration, in the chronic treatment of pulmonary fibrosis.
  • IPF Idiopathic Pulmonary Fibrosis
  • the Wnt/ -catenin signaling pathway is one of a number of core embryonic signaling pathways that is crucial for tissue development and homeostasis after injury 17 21 . This is a key pathway in driving cellular differentiation; early loss of Wnt/ -catenin signaling results in aberrant lung development and embryonic death 17 ’ 18 , while in adult tissues, Wnt/ -catenin is critical in maintaining self-renewal of hematopoietic stem cells and gut epithelial cells 19 ’ 20 .
  • the Wnt/ -catenin pathway has been extensively targeted for cancer 22 .
  • BC-2059 is a novel small molecule inhibitor of beta-catenin signaling through disruption of Transducin beta-like protein 1 (TBLl)/beta-catenin binding 23 .
  • TBLl Transducin beta-like protein 1
  • BC-2059 inhibits the activation of beta-catenin-target genes by limiting recruitment of the scaffold coactivator protein, TBL1.
  • this drug avoids targeting upstream pathway components used in other signaling pathways, such as Axin in Smad/TGFb-signaling ’ or the pleiotropic kinase, GSK3b, in insulin and other signaling pathways 26 .
  • beta-catenin s important role in the maintenance of cell-cell adhesion 27 or interfere with the stem cell maintenance function of beta-catenin in the intestinal crypts, both of which are critical functions of beta-catenin required for tissue homeostasis and are key in avoiding to prevent off-target side effects.
  • BC- 2059 is highly potent in patient cancer cells ex vivo and in mouse tumorigenesis models ’ . Further pre-clinical studies in rodents, dogs, and minipigs show favorable pharmacokinetics with intravenous administration, which provides support for limited use such as in cancer. BC-2059 is due to begin phase 1 clinical trials in the near future in cancer patients. However, in a chronic disease, such as IPF, intravenous administration may be suboptimal for patients who require continuing treatment, both from a tolerability and adherence perspective. Particularly, long term use of systemic beta-catenin signaling inhibitors may promote bone loss, through antagonizing specification of bone-forming osteoblasts.
  • BC-2059 is formulated currently as a nanosuspension (l50nm particles) with 0.625% poloxamer 188/10% sorbitol in 5% dextrose vehicle and has poor oral bioavailability, necessitating intravenous infusion.
  • nebulization is an ideal approach for the lung, since this would achieve high drug levels at the site of injury/aberrant repair for the chronic treatment of pulmonary fibrosis.
  • Drugs that resolve or hasten resolution of established fibrosis may offer greater translational potential. Studies that administer a drug prior to or at the time of onset of injury do not reflect the“real world” clinical situation, in which patients present for treatment after fibrosis has been established for years. Thus, we will test whether treatment with nebulized BC-2059 after the establishment of pulmonary fibrosis improves the resolution of fibrosis, which is clinically important for patients.
  • systemic beta-catenin signaling inhibitors may promote bone loss through antagonizing specification of bone-forming osteoblasts and result in clinically significant osteoporosis, which is a concern for the Wnt/ -catenin inhibitors that are currently in development and especially relevant in IPF patients, who are typically in their seventh decade of life29,30.
  • Wnt/ -catenin inhibitors that are currently in development and especially relevant in IPF patients, who are typically in their seventh decade of life29,30.
  • LRP5 is expressed in the normal adult mouse lung; no gross abnormalities are observed in Lrp5-/- lungs, likely as a result of continued signaling through its paralog, LRP631. Twenty-one days after intratracheal administration of bleomycin, mice lacking Lrp5 showed a marked attenuation of tissue injury and matrix deposition compared to Lrp5+/+ littermates (Fig. I) 8 .
  • Wnt pathway genes are associated with IPF progression.
  • PBMC peripheral blood mononuclear cells
  • Wnt signaling as one of the top 2 over-represented pathways associated with worsened prognosis, whereby positive regulators such as the Wnt co-receptors LRP5 and LRP6 were independently associated with disease progression (Fig. 2) 8 .
  • Inhibition of Wnt/beta-catenin signaling by BC-2059 reverses bleomycin- induced pulmonary fibrosis.
  • BC-2059 is a novel small molecule inhibitor of beta-catenin signaling through disruption of Transducin beta-like protein 1 (TBLl)/beta-catenin binding 23 .
  • BC- 2059 acts at the most downstream step of the Wnt signaling cascade, inhibiting the activation of beta-catenin target genes by limiting recruitment of the scaffold co-activator protein, TBL1.
  • wild-type mice received intravenous BC-2059 by tail vein injection on day 7 after intratracheal administration of bleomycin. On day twenty-one after bleomycin, wild- type mice that were treated with intravenous BC-2059 demonstrated improvement in fibrosis, with significantly reduced deposition of collagen and improved lung compliance (Fig. 3).
  • ethanol can be used as a co-solvent up to 10% within inhalation formulations.
  • the lipophilicity (LogP estimated at 3.3) of BC-2059 makes it amenable to solubility increase from a co-solvent like EtOH.
  • the existing formulation of BC-2059 25 mg/mL in Poloxamer 188 and sorbitol will also be evaluated for nebulization.
  • the formulation(s) developed within the chemistry testing will be tested within a rodent nose only inhalation exposure chamber (Fig. 5), using both commercially available air jet nebulizer and vibrating mesh nebulizer.
  • the formulations will be evaluated based on the following key parameters: aerosol concentration, particle size distribution, and aerosol concentration repeatability.
  • the aerosol concentration will be measured by filter sample collection and analysis with the developed extraction procedure.
  • the target will be to have a range of aerosol concentrations based on a range of different concentrations in the formulations. All developed aerosols will be evaluated for at least 60 minutes (expected length of an exposure) to ensure that the aerosols are stable over this duration and reflect sufficient concentration repeatability (typically ⁇ 20%) for use in in vivo exposures.
  • the particle size distribution will be measured via cascade impaction. Cascade impactor analysis is the standard method used to characterize the particle size distribution of aerosols.
  • the target will be to have a particle size distribution of 1 - 3.5 pm MMAD; this target particle size range has been previously found to be highly respirable in rats 33 .
  • Specific Aim 2 To determine the efficacy and pharmacodynamics of nebulized administration of BC-2059, compared to intravenous administration, in the chronic treatment of pulmonary fibrosis
  • BC-2059 in vivo using two mouse models of chronic pulmonary fibrosis.
  • We will intratracheally administer one dose of asbestos or repetitively administer intratracheal bleomycin every two weeks; both models create persistent fibrosis.
  • We will administer nebulized BC-2059 or vehicle (5% dextrose) daily after the establishment of pulmonary fibrosis (starting on day 21), in order to determine whether the drug improves the resolution of established fibrosis, which is clinically important for patients.
  • Lam AP Herazo- Maya JD, Sennello JA, et al. Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014;190:185-95.
  • Idiopathic Pulmonary Fibrosis IPF: Genetic Factors, Pathogenesis and Emerging Treatments. New York, USA: Nova Science Publisher; 2016.
  • Example 2 Ultrasonic Nebulized Form of BC-2059 Administered in a Mouse Model of Pulmonary Fibrosis
  • Wnt/ -catenin pathway is pathogenic in multiple forms of pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • BC-2059 binds transducing b-like proteinl (TBL1), displacing b-catenin and leading to its degradation.
  • TBL1 transducing b-like proteinl
  • BC-2059 is highly potent in cancer cells ex vivo and mouse tumorigenesis models.4,5 Pre-clinical studies in rodents, dogs, and minipigs show favorable pharmacokinetics and safety data with intravenous administration, providing support for short-term use. However, prolonged systemic therapy would be required for chronic diseases, such as IPF, with resultant undesirable adverse effects. Delivery of BC- 2059 directly intra-pulmonary could limit adverse effects in those requiring long-term therapy.
  • Activation of canonical Wnt ⁇ -catenin signaling occurs through binding of a Wnt ligand to cell-surface receptor, Frizzled, and a co-receptor, Lrp5 or 6. This results in inactivation of the b-catenin destruction complex, allowing b-catenin to dock with its scaffolding co-activator.
  • Transducin beta-like proteinl (TBL-l) to translocate into the nucleus and bind its downstream targets, such as transcription T-cell factor (TCF), leading to transcription of target genes.
  • TBL1 and b-catenin This allows for blockade of canonical Wnt ⁇ -catenin signaling in a distant, downstream fashion, avoiding the adverse affects of interfering with proximal steps in the pathway.
  • Figure 7 illustrates the bleomycin-induced model for fibrosis.
  • C57BL/6 mice were given intratracheal bleomycin or saline to induce fibrosis or control state. Starting at day 7, each population of mice were given treatment with BC-2059 (IV or nebulized), vehicle, or pirfenidone gavage.
  • Figure 8 illustrates that treatment with BC-2059 results in diminished histologic fibrosis in mice treated with bleomycin and is similar to pirfenidone via H&E staining of representative murine lungs treated with bleomycin with therapy of pirfenidone or BC- 2059 versus vehicle.
  • Figure 10 illustrates that compliance, measured by Flexivent, is increased in mice treated with BC-2059 after bleomycin injury. In C57BL/6 mice treated with bleomycin followed by pirfenidone or IV BC-2059, there is significant improvement in lung compliance compared to those treated with vehicle only.
  • Figure 11 illustrates that hydroxyproline content and compliance are improved in mice treated with nebulized BC-2059 after bleomycin injury.
  • nebulized BC-2059 In C57BL/6 mice treated with bleomycin followed by pirfenidone or nebulized BC-2059, there is significant decrease in lung hydroxyproline compared to those treated with vehicle only. Nebulized BC-2059 also resulted in a significant difference in compliance in those treated with IT bleomycin.
  • Figure 12 illustrates that survival of mice after intratracheal bleomycin is improved by treatment with BC-2059, similar to pirfenidone. Only mice treated with intratracheal and no pirfenidone gavage or BC-2059 IV died prior to sacrifice. Mice treated with bleomycin died prior to sacrifice in both the vehicle and BC-2059 groups but BC-2059 increased time to death as well as number surviving.
  • Treatment with BC-2059 does not affect survival in mice treated with IT saline and may be beneficial in those treated with bleomycin.
  • Lam AP Herazo- Maya JD, Sennello JA, et al. Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med20l4;l90:l85-95.
  • Beta-catenin inhibitor BC2059 is efficacious as monotherapy or in combination with proteasome inhibitor bortezomib in multiple myeloma. Mol Cancer Ther 2017.

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Abstract

L'invention concerne des méthodes et des compositions pour traiter des maladies pulmonaires interstitielles. La méthode et les compositions utilisent ou comprennent en tant qu'agent thérapeutique un inhibiteur de la signalisation Wnt/bêta-caténine qui peut être administré par l'intermédiaire d'une formulation inhalée de l'inhibiteur. Des inhibiteurs appropriés de la signalisation Wnt/bêta-caténine peuvent comprendre, sans y être limités, le composé (9E,10E)-2,7-bis(((3R,5S)-3,5- diméthylpiperidin-l-yl)sulfonyl)anthracène-9,10-dione dioxime qui peut autrement être appelé BC-2059.
PCT/US2018/061531 2017-11-16 2018-11-16 Formulation inhalée d'un inhibiteur moléculaire de la signalisation wnt/bêta-caténine pour le traitement de maladies pulmonaires interstitielles Ceased WO2019099836A1 (fr)

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US20220098173A1 (en) * 2020-09-29 2022-03-31 Iterion Therapeutics, Inc. Crystalline form of tegavivint, method of preparation, and use thereof
WO2022115434A1 (fr) * 2020-11-24 2022-06-02 Iterion Therapeutics, Inc. Formulations lyophilisées de tegavivint
US11964054B2 (en) 2020-11-24 2024-04-23 Iterion Therapeutics, Inc. Formulations of tegavivint
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WO2014061827A1 (fr) * 2012-10-19 2014-04-24 Hiroyuki Kouji Traitement de la fibrose pulmonaire à l'aide d'un inhibiteur de la cbp/caténine
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CN112752574A (zh) * 2018-06-01 2021-05-04 伊特里恩治疗有限公司 特加维因和相关化合物的制剂
US11266637B2 (en) * 2018-06-01 2022-03-08 Iterion Therapeutics, Inc. Formulations of tegavivint and related compounds
EP3810118A4 (fr) * 2018-06-01 2022-03-30 Iterion Therapeutics, Inc. Formulations de tegavivint et composés apparentés
US12246010B2 (en) * 2018-06-01 2025-03-11 Iterion Therapeutics, Inc. Formulations of tegavivint and related compounds
US20220098173A1 (en) * 2020-09-29 2022-03-31 Iterion Therapeutics, Inc. Crystalline form of tegavivint, method of preparation, and use thereof
US12297185B2 (en) * 2020-09-29 2025-05-13 Iterion Therapeutics, Inc. Crystalline form of tegavivint, method of preparation, and use thereof
US11602501B2 (en) 2020-11-24 2023-03-14 Iterion Therapeutics, Inc. Lyophilized formulations of tegavivint
US11793759B2 (en) 2020-11-24 2023-10-24 Iterion Therapeutics, Inc. Lyophilized formulations of tegavivint
US11964054B2 (en) 2020-11-24 2024-04-23 Iterion Therapeutics, Inc. Formulations of tegavivint
US12208166B2 (en) 2020-11-24 2025-01-28 Iterion Therapeutics, Inc. Lyophilized formulations of tegavivint
US11571388B2 (en) 2020-11-24 2023-02-07 Iterion Therapeutics, Inc. Lyophilized formulations of tegavivint
WO2022115434A1 (fr) * 2020-11-24 2022-06-02 Iterion Therapeutics, Inc. Formulations lyophilisées de tegavivint
US12491162B2 (en) 2020-11-24 2025-12-09 Iterion Therapeutics Inc. Formulations of tegavivint
WO2024206100A3 (fr) * 2023-03-24 2024-12-26 Ohio State Innovation Foundation Agents de dégradation de la protéine 1 de type transducine bêta

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