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WO2025172573A1 - Combinaisons d'inhibiteurs de par2 et d'inhibiteurs de points de contrôle immunitaires pour le traitement du cancer - Google Patents

Combinaisons d'inhibiteurs de par2 et d'inhibiteurs de points de contrôle immunitaires pour le traitement du cancer

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Publication number
WO2025172573A1
WO2025172573A1 PCT/EP2025/054098 EP2025054098W WO2025172573A1 WO 2025172573 A1 WO2025172573 A1 WO 2025172573A1 EP 2025054098 W EP2025054098 W EP 2025054098W WO 2025172573 A1 WO2025172573 A1 WO 2025172573A1
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Prior art keywords
inhibitor
cancer
carbonyl
use according
par2
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Thibaut BRUGAT
John Stagg
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Domain Therapeutics SA
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Domain Therapeutics SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a protease-activated receptor-2 (PAR2) inhibitor in combination with an immune checkpoint inhibitor for use in the treatment of cancer via a specific administration/dosage regimen, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier (e.g., 3 to 7 days earlier) than the administration of the immune checkpoint inhibitor.
  • PAR2 protease-activated receptor-2
  • protease-activated receptors (PARs) family The protease-activated receptors (PARs) family
  • G Protein-Coupled Receptors form the largest family of human membrane proteins ( ⁇ 800 members) and are involved in many physiological processes. Compounds targeting GPCRs also represent approximately 27% of the global market for therapeutic drugs (Hauser et al., Nat. Rev. Drug Discov., 2017, 16(12):829-842).
  • proteases also called proteinases
  • proteases also called proteinases
  • PARs Protease-Activated Receptors
  • the PARs family is composed of four members (PAR-1 , PAR-2, PAR-3 and PAR-4) and belongs to the class A GPCR-receptor sub-family (Marcfarlane et al., Pharmacological Reviews, 2001 , 475(7357):519-23).
  • PAR-2 is activated by several host and pathogen-derived serine proteases such as trypsin, mast cell tryptase, kallikreins and members of the coagulation cascade TF-FVIla and FVa-FXa. These proteases cleave at R 34 J,S 35 LIGKV and unmask the tethered ligand SLIGKV in humans. Artificially, in vitro, synthetic peptides corresponding to the TL (SLIGKV) can activate the receptor without cleavage. Activation of PAR-2 induces several signalling cascades involving a number of G proteins such as G q , G, and G12/13.
  • G proteins such as G q , G, and G12/13.
  • PAR-2 is involved in the function of the cardiovascular system. Indeed, its activation can induce the relaxation or contraction of some vessels such as pulmonary arteries, coronary and intramyocardial arteries, therefore regulating the blood flow. It also controls inflammation and repair of the endothelium which influences vascular permeability.
  • PAR-2 is involved in airways function since it is expressed by epithelial and endothelial cells in the lungs. Its activation has been shown to regulate bronchodilatation or bronchoconstriction (depending on the experimental system used), ion transport in the airway epithelium, proliferation and activation of airway smooth muscle cells and lung fibroblasts. PAR-2 can thus regulate airway resistance, lung inflammation and lung fibrosis.
  • PAR-2 expression has been detected in keratinocytes, microvasculature and immune cells. Its activation has been involved in skin pigmentation, skin inflammation, and wound healing.
  • PAR-2 expression has been detected in immune cells such as macrophages where it influences cell maturation and cytokine secretion, thereby regulating inflammation.
  • the expression of PAR-2 on other cells of the tumor microenvironment can also control the immune response to cancer cells, fibrosis, as well as angiogenesis and cancer-induced pain (Mubbach et al., Mol cancer, 2016, 15(1):54; Uusitalo-Jarvinen et al., Arieriocler Thromb Vase Biol, 2007, 27(6): 1456-62; D’Andrea et al., Am J Pathol, 2001 , 158(6):2031-41 ; Graf et al., Sci Immunol, 2019, 4(39):eaaw8405; Qian at al., Oncol Lett, 2018, 16(2): 1513-20; Tu et al., J Neurosci, 2021 , 41 (1):193-210).
  • PAR2 loss of function mutation or inhibition of one of its ligands led to reduced infiltration of immune-suppressive Tumor Associated Macrophages and regulatory T cells while increasing cytotoxic T cells in the tumor in several syngeneic mouse models; this unleashed the anti-tumoral immune response and increased the potency of immune-checkpoint inhibitors currently used in the clinic (Graf et al., Sci Immunol, 2019, 4(39):eaaw8405).
  • PAR-2 therefore constitutes a promising therapeutic target in oncology and immuno-oncology.
  • the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • FIG. 1 B is a diagram showing the progression free survival rate in MC38 bearing wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD1 or isotype control (Iso).
  • Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • C Mean tumor growth.
  • Fig. 1C is a diagram showing mean MC38 tumor volume changes in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). 10 mice per group were treated.
  • FIG. 1 D is a set of diagrams showing MC38 tumor volume changes in each wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 16 (D16).
  • FIG. 1 E is a diagram showing individual MC38 tumor volume in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso) at day 16 (last day at which all mice were still alive in every group). Average tumor volume (mm 2 ) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • FIG. 2 Influence of pharmacological inhibition of PAR2 on anti-tumor efficacy of anti-PD1 according to the timing of administration.
  • FIG. 2A is a schematic diagram showing the design of the experiment performed to determine the effect of pharmacological PAR2 inhibition on the anti-tumor efficacy of immune checkpoint inhibitors according to timing of administration.
  • MC38 cells were subcutaneously injected into groups of 15 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage for 21 days.
  • Fig. 2B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated.
  • Fig. 2C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD 1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated. Average tumor volume (mm 3 ) and SD bars were plotted for each group.
  • 2E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm 3 ) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups (taking all groups into account), p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****. (F) Progression-free survival. Fig.
  • FIG. 2F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117.
  • start of 1-117 treatment compared to anti-PD1 therapy is indicated.
  • Log-rank (Mantel-Cox) test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • G Mean tumor growth.
  • Fig. 2G is a diagram showing mean MC38 tumor volume changes in mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117.
  • start of 1-117 treatment compared to anti-PD 1 therapy is indicated.
  • Fig. 2H is a diagram showing individual MC38 tumor volume in mice treated with anti-PD1 or a combination of both anti-PD 1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm 3 ) and SD bars were also plotted for each group. Mann-Whitney test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • Fig. 3B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1, 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start and end days of 1-117 treatment are indicated.
  • FIG. 3D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 18 (D18).
  • 3F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of anti-PD1 and 1-117.
  • start and end days of 1-117 treatment are indicated.
  • Log-rank (Mantel-Cox) test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • G Mean tumor growth.
  • Fig. 3G is a diagram showing mean MC38 tumor volume changes in mice treated with anti- PD1 or a combination of anti-PD1 and 1-117.
  • start and end days of 1-117 treatment are indicated.
  • FIG. 4A is a schematic diagram showing the design of the experiment performed to determine the effect of priming doses of Compound 207 on the anti-tumor efficacy of immune checkpoint inhibitors.
  • MC38 cells were subcutaneously injected into groups of 12 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation.
  • the PAR2 inhibitor Compound 207 (207) or vehicle were given once a day by oral gavage from day 2 post tumor inoculation to day 6.
  • Compound 207 was given at a 30mg/kg dose.
  • Fig. 4B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207.
  • doses of Compound 207 used are indicated.
  • FIG. 4C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. Average tumor volume (mm 2 ) and SD bars were plotted for each group.
  • Fig. 4D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 25 (D25). Fig.
  • 4E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD 1 and Compound 207 at day 25 (last day at which all mice were still alive in every group).
  • Iso isotype control
  • 207 Compound 207
  • Average tumor volume (mm 2 ) and SD bars were also plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a one-way ANOVA.
  • FIG. 5A is a schematic diagram showing the design of the experiment performed to determine if the benefit of a combination between PAR2 inhibitors and immune-checkpoint inhibitors could also be observed at later stages of the tumor development.
  • MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice.
  • Anti-PD 1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage from day 5 post tumor inoculation to day 9.
  • FIG. 5B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : **** (C) Mean tumor growth. Fig.
  • 5C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD 1 and 1-117.
  • Iso isotype control
  • 5D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 15 (D15).
  • Fig. 5E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 15 (last day at which all mice were still alive in every group). For the combination groups start and end days of 1-117 treatment are indicated.
  • FIG. 6A is a schematic diagram showing the design of the experiment performed to determine the effect of the timing of priming doses of 1-117 on the anti-tumor efficacy of immune checkpoint inhibitors.
  • MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 or vehicle were given once a day by oral gavage at a 30mg/kg dose at different timings.
  • Fig. 6B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated.
  • Fig. 6C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1, or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. Average tumor volume (mm 2 ) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test .
  • FIG. 6D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated.
  • Iso isotype control
  • CR rate of complete response
  • the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides an immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a PAR2 inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAR2 inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a PAR2 inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor can be provided in the form of a pharmaceutical composition comprising the PAR2 inhibitor and optionally one or more pharmaceutically acceptable excipients.
  • the immune checkpoint inhibitor can be provided in the form of a pharmaceutical composition comprising the immune checkpoint inhibitor and optionally one or more pharmaceutically acceptable excipients.
  • the present invention also provides a pharmaceutical composition comprising a PAR2 inhibitor (and optionally one or more pharmaceutically acceptable excipients), for use in the treatment of cancer, wherein the pharmaceutical composition comprising the PAR2 inhibitor is administered in combination with a pharmaceutical composition comprising an immune checkpoint inhibitor (and optionally one or more pharmaceutically acceptable excipients), wherein the administration of the pharmaceutical composition comprising the PAR2 inhibitor is started at least 1 day earlier than the administration of the pharmaceutical composition comprising the immune checkpoint inhibitor.
  • Such different/separate pharmaceutical compositions i.e. the (first) pharmaceutical composition comprising the PAR2 inhibitor and the (second) pharmaceutical composition comprising the immune checkpoint inhibitor, can also be provided in the form a kit that comprises the corresponding pharmaceutical compositions.
  • the administration of the PAR2 inhibitor is started at least 1 day earlier than (or, in other words, prior to) the administration of the immune checkpoint inhibitor. Accordingly, the PAR2 inhibitor is administered at least 1 day before the first administration/dose of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor is started at least 2 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started from 2 to 30 days earlier than the administration of the immune checkpoint inhibitor, or from 2 to 21 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 14 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 7 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started, e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor is started at least 3 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started 3 to 14 days (e.g., 3, 5, 7, 10 or 14 days), particularly 3 to 7 days (e.g., 3 or 5 days), earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor is a small molecule (e.g., any one of the compounds described in WO 2022/117882 or WO 2023/233033), it is particularly preferred that it is administered once daily. If the PAR2 inhibitor is an antibody (or an antigen-binding fragment thereof or an antibody construct), it is preferably administered weekly or biweekly, particularly once every 1 or 2 weeks, more preferably once every 2 weeks.
  • the PAR2 inhibitor may be continued to be administered (preferably at a regular dosing interval, as described above) until the first administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor may be administered daily (preferably once daily) up until the day when the first dose of the immune checkpoint inhibitor is administered.
  • the administration of the PAR2 inhibitor may be discontinued (or, in other words, may be halted) or may be further continued.
  • the administration of the PAR2 inhibitor may also be discontinued/halted shortly (e.g., 1 day) before the first administration of the immune checkpoint inhibitor.
  • the present invention particularly relates to the sequential administration of the PAR2 inhibitor followed by the immune checkpoint inhibitor, whereby the administration of the PAR2 inhibitor is discontinued/halted when the administration of the immune checkpoint inhibitor is started.
  • the administration of the PAR2 inhibitor may be started, e.g., 3 to 5 days earlier than the administration of the immune checkpoint inhibitor, whereby the PAR2 inhibitor may be administered daily (preferably once daily) over a period of at least 3 days before the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor to be used in accordance with the present invention may be, in principle, any compound/substance that decreases, reduces, prevents, blocks, antagonizes or inhibits the activity, function or gene expression of protease-activated receptor-2 (PAR2).
  • the PAR2 inhibitor may be a small molecule, a peptide, or an antibody (or an antigen-binding fragment thereof, or an antibody construct; e.g., a monoclonal antibody).
  • the PAR2 inhibitor may be a PAR2 inhibitor that is known in the art, including, e.g., any one of the compounds disclosed in: Yau et al., Expert Opin Ther Pat, 2016, 26(4):471-83; Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-57;
  • the PAR2 inhibitor may be, e.g., a compound disclosed in any one of the aforementioned documents (e.g., in the examples section of any one of the aforementioned patent documents), wherein said compound may be used in non-salt form or in the form of a pharmaceutically acceptable salt or solvate.
  • the PAR2 inhibitor may also be an anti-PAR2 antibody, e.g., any one of the antibodies (or antigen-binding fragments thereof) that are disclosed in WO 2018/167322 or WO 2022/040345, each of which is incorporated herein by reference in its entirety.
  • Preferred examples of the PAR2 inhibitor to be used in accordance with the present invention include any one of the compounds described in WO 2022/117882 or WO 2023/233033, particularly any one of the PAR2 inhibitors described in the examples section of WO 2022/117882 or in the examples section of WO 2023/233033, either in non-salt form and/or non-solvated form or as a pharmaceutically acceptable salt or solvate of the respective compound.
  • the PAR2 inhibitor may also be an antibody.
  • Corresponding preferred examples include, in particular, MEDI-0618 or PaB670129 (as described, e.g., in WO 2018/167322 which is incorporated herein by reference), or P24E1102 (as described, e.g., in WO 2022/040345 which is incorporated herein by reference).
  • the PAR2 inhibitor may also be a peptide, particularly a pepducin, e.g., any one of the PAR2 pepducins disclosed in WO 2012/139137 (which is incorporated herein by reference).
  • a pepducin e.g., any one of the PAR2 pepducins disclosed in WO 2012/139137 (which is incorporated herein by reference).
  • Corresponding preferred examples include any of PZ-235, OA-235i, OA-235c, or P2pal-18S (as described, e.g., in WO 2012/139137).
  • the PAR2 inhibitor to be used in accordance with the present invention is any one of the following compounds:
  • This compound has been described in Example 207 of WO 2023/233033 and is also referred to herein as "Compound 207”.
  • This compound has been described in Example 1.19 of WO 2018/057588 and is also referred to as compound "1-117”.
  • This compound has been described in Example 10 of EP 3 508 487 A1.
  • the PAR2 inhibitor may also be a stereoisomer of the aforementioned compound, e.g., (1 R)-[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol or a pharmaceutically acceptable salt or solvate thereof, or (1 S)- [7-fl uoro-3- ( 1 -methy I cy cl opropy I) benzofu ran-4-y I] -( 1 H-i mi d azol-2- yl)methanol or a pharmaceutically acceptable salt or solvate thereof.
  • This compound has been described in Example 10 of WO 2019/124567.
  • This compound has been described in WO 2019/199800 (see, e.g., the synthesis disclosed on pages 35 to 37) and is also referred to as compound "0781”.
  • the PAR2 inhibitor is any one of the following compounds:
  • the PAR2 inhibitor to be used in accordance with the present invention is 6-(4-(5'-(4-chloro-3- fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof, or 6-[4-[7-tert-butyl-5-(4-chloro-3- fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
  • the immune checkpoint inhibitor to be used in accordance with the present invention may be, in principle, any immune checkpoint inhibitor known in the art.
  • the immune checkpoint inhibitor may be an antibody (or an antigenbinding fragment thereof, or an antibody construct), typically a monoclonal antibody.
  • the immune checkpoint inhibitor is a monoclonal antibody (or an antigen-binding fragment thereof, or an antibody construct) directed against PD-1 , PD-L1 , CTLA-4, TIGIT, TIM3, VISTA, BTLA, CD47, LAG3, 0X40, or IGOS.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti- CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-ICOS antibody.
  • Corresponding preferred examples include, but are not limited to, any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX- 4014, or APE02058, any one of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736,
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, particularly an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
  • the PAR2 inhibitor for use according to item 1 the immune checkpoint inhibitor for use according to item 2, the combination for use according to item 3, the method according to item 4, or the use according to any one of items 5 to 7, wherein the administration of the PAR2 inhibitor is started 2 to 14 days earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor is 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'- pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti-CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
  • an anti-PD-1 antibody or an anti-PD-L1 antibody which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplima
  • Example 1 Effect of PAR2 knock out on the anti-tumor efficacy of immune checkpoint inhibitors
  • the same MC38 model was used (see Example 1 above).
  • the compound 1-117 described in patent application WO 2018/057588, was used as it is a potent and selective PAR2 inhibitor with proven in vivo activity.
  • 0.5x10 6 MC38 cells were subcutaneously injected into groups of 15 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 100 g of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 in 10% Ethanol- 100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water was given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose. For the monotherapy, treatment with 1-117 started at day 6 post tumor inoculation and lasted for 21 days.
  • MC38 model was used.
  • 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory).
  • 200pig of anti-PD 1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose.
  • both 5 days and 21 days administration of PAR2 inhibitor improved the anti-tumor efficacy of anti-PD-1 treatment in a similar way. Indeed, increased progression-free survival rate and a decreased tumor growth were observed in both combination groups compared to monotherapies. When compared head-to- head, the differences in progression-free survival and tumor growth observed between anti-PD1 alone and the combination of anti-PD1 and a 5 day treatment with 1-117 are statistically significant. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased to 90% and 80% when 1-117 was administered for 5 days and 21 days respectively.
  • Compound 207 This small molecule is structurally different from 1-117 but with similar pharmacokinetic properties and potency on PAR2 inhibition.
  • MC38 cells 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 12 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days.
  • the PAR2 inhibitor Compound 207 or vehicle (1 ,2% methylcellulose, 0, 1 % tween80) were given once a day by oral gavage. This treatment started at day 2 post tumor inoculation and lasted for 5 days (days 2 to 6 post tumor inoculation). For the monotherapy, Compound 207 was given at a 30mg/kg dose.
  • Compound 207 was given at a 30mg/kg or 100mg/kg dose. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm 2 . A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
  • priming doses of Compound 207 increased the anti-tumor efficacy of anti-PD1 in a similar way as 1-117. Indeed, as seen in the previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group with the highest dose of Compound 207 (1 OOmg/kg) compared to monotherapies. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased in a dose dependent manner to 58% and 70% when Compound 207 was administered at 30mg/kg and 100mg/kg respectively.
  • Example 4 Effect of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors at later stages of tumor development
  • 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose from day 5 to day 9 post tumor inoculation. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm 2 .
  • a complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
  • priming doses of 1-117 increased the anti-tumor efficacy of anti-PD 1 at later stages of tumor development. Indeed, similarly to previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when both treatments were delayed. Furthermore, tumors were rejected in 40% of animals when treated with anti-PD 1 alone. In the combination groups, the rate of complete response increased to 70%.
  • Example 5 Influence of the timing of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors
  • MC38 cells 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage at a 30mg/kg dose.
  • priming doses of 1-117 increased the anti-tumor efficacy of anti-PD1 treatment even when a 2-day washout period was allowed between the 2 treatments.
  • an increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when 1-117 was administered from day 5 to day 9 or from day 3 to day 7 post tumor inoculation.
  • tumors were rejected in 50% of animals when treated with anti-PD 1 alone.
  • the rate of complete response increased to 70-80% with both regimens.
  • a similar rate of complete response (70%) was also observed when 1-117 was administered for 3 days (from day 5 to day 7 post tumor inoculation) instead of 5 days.

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Abstract

La présente invention concerne un inhibiteur du récepteur 2 activé par protéase (PAR2) en combinaison avec un inhibiteur de point de contrôle immunitaire destiné à être utilisé dans le traitement du cancer par l'intermédiaire d'un régime d'administration/dosage spécifique, l'administration de l'inhibiteur de PAR2 étant démarrée au moins 1 jour plus tôt (par exemple, 3 à 7 jours plus tôt) que l'administration de l'inhibiteur de point de contrôle immunitaire.
PCT/EP2025/054098 2024-02-16 2025-02-14 Combinaisons d'inhibiteurs de par2 et d'inhibiteurs de points de contrôle immunitaires pour le traitement du cancer Pending WO2025172573A1 (fr)

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