Patent application EP19168253A (EP), filed 2019-04-09
Publication number: EP3722319A1
Title: PHARMACEUTICAL COMBINATION OF AN EP4 ANTAGONIST AND IMMUNE CHECKPOINT INHIBITORS FOR THE TREATMENT OF TUMOURS
Abstract: The present invention provides a pharmaceutical combination comprising the EP4 antagonist of Formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)-benzoic acid or a pharmaceutically acceptable salt thereof and at least one immune checkpoint inhibitor, preferably the sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid. A polymorphic form A of sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate characterized by a powder XRD spectrum with peaks at values of the angle 2θ ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9 is also described. The combination and the polymorphic form A are described for use in the treatment of tumours.
IPC codes: A61K  31/    00            A I
C07K  16/    30            A I
Claims: number: 1
text: A pharmaceutical combination comprising the EP4 antagonist of Formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)-benzoic acid or a pharmaceutically acceptable salt thereof and at least one immune checkpoint inhibitor.
number: 2
text: The pharmaceutical combination according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sodium salt, potassium salt, and lithium salt.
number: 3
text: The pharmaceutical combination according to claim 1 or claim 2 wherein the EP4 antagonist is sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid.
number: 4
text: A polymorphic form A of sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid characterized by a powder XRD spectrum with peaks at values of the angle 2θ ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9.
number: 5
text: The polymorphic form A according to claim 4 for use as a medicament.
number: 6
text: The polymorphic form A according to claim 4 for use in the treatment of tumours.
number: 7
text: A pharmaceutical combination comprising the polymorphic form A of the sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido) cyclopropyl)benzoic acid according to claim 4 and at least one immune checkpoint inhibitor.
number: 8
text: The pharmaceutical combination according to anyone of claims 1-4, wherein the at least one immune checkpoint inhibitor is selected from the group consisting of PD-1 (Programmed Death-1), PD-L1 (Programmed Death-Ligand 1), CTLA-4 (Cytotoxic T lymphocyte Antigen - 4), TIM3 (T cell immunoglobulin and mucin-3), OX-40 and its ligand OX40L, LAG-3 (lymphocyte activation gene-3), KIR (Killer-cell Immunoglobulin-like Receptor), VISTA (V-domain lg-containing suppressor of T cell activation), IDO1 (Indoleamine 2,3-dioxygenase), TIGIT (T cell immunoglobulin and ITIM domain), BTLA (B and T lymphocyte attenuator), A2AR (Adenosine receptor A2), SIGLEC7 (Sialic acid-binding immunoglobulin-type lectin 7), GITR (Glucocorticoid-Induced TNFR family Related gene), ICOS (Inducible T-cell costimulator), NOX-2 (nicotinamide adenine dinucleotide phosphate NADPH oxidase isoform 2), Arginase I, CD276 (Cluster of Differentiation 276,also referred to as B7H4), CD27 (Cluster of Differentiation 27) and its ligand CD27 (Cluster of Differentiation 27), CD160 (Cluster of Differentiation 160) and CD39 (Cluster of Differentiation 39).
number: 9
text: The pharmaceutical combination according to claim 8, wherein the at least one immune checkpoint inhibitor is selected from the group consisting of neutralizing antibodies anti PD-1 (e.g. Nivolumab (Opdivo), Pembrolizumab (Keytruda)), anti CTLA-4 (e.g., ipilimumab, Tremelimumab), anti TIM-3 antibodies (e.g. MBG453) or anti LAG-3 antibody.
number: 10
text: A pharmaceutical combination comprising an EP4 antagonist selected from (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid or a pharmaceutically acceptable salt and at least one immune checkpoint inhibitor for the use in the treatment of tumours.
number: 11
text: A pharmaceutical combination comprising the EP4 antagonist consisting of the polymorphic Form A of sodium (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro [2.5]octane-5-carboxamido)cyclopropyl)benzoate according to claim 4 and at least one immune checkpoint inhibitor for the use in the treatment of tumours.
Office action: search_report, dated 2020-10-14
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Final disposition: pending (2020-10-14)