NZ733869B2 - Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies - Google Patents
Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies Download PDFInfo
- Publication number
- NZ733869B2 NZ733869B2 NZ733869A NZ73386915A NZ733869B2 NZ 733869 B2 NZ733869 B2 NZ 733869B2 NZ 733869 A NZ733869 A NZ 733869A NZ 73386915 A NZ73386915 A NZ 73386915A NZ 733869 B2 NZ733869 B2 NZ 733869B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- embryo
- antagonist
- day
- stage
- female
- Prior art date
Links
- 239000002464 receptor antagonist Substances 0.000 title claims abstract description 64
- 102000004279 Oxytocin receptors Human genes 0.000 title claims abstract description 60
- 108090000876 Oxytocin receptors Proteins 0.000 title claims abstract description 60
- 238000002513 implantation Methods 0.000 title claims abstract description 60
- 230000035935 pregnancy Effects 0.000 title claims abstract description 45
- 230000029849 luteinization Effects 0.000 title claims abstract description 42
- 230000001850 reproductive Effects 0.000 title claims abstract description 14
- 238000002560 therapeutic procedure Methods 0.000 title description 3
- 210000001161 Embryo, Mammalian Anatomy 0.000 claims abstract description 184
- 230000003042 antagnostic Effects 0.000 claims abstract description 97
- 239000005557 antagonist Substances 0.000 claims abstract description 97
- 210000004696 Endometrium Anatomy 0.000 claims abstract description 61
- 230000000694 effects Effects 0.000 claims abstract description 39
- 206010049550 Live birth Diseases 0.000 claims abstract description 22
- 238000005516 engineering process Methods 0.000 claims abstract description 10
- 229940084986 Human Chorionic Gonadotropin Drugs 0.000 claims description 47
- UGNGRKKDUVKQDF-IHOMMZCZSA-N Barusiban Chemical compound N1C(=O)CCSCC[C@@H](C(=O)N(C)[C@H](CO)CCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]([C@H](C)CC)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H]1CC1=CNC2=CC=CC=C12 UGNGRKKDUVKQDF-IHOMMZCZSA-N 0.000 claims description 34
- 229950009748 Barusiban Drugs 0.000 claims description 33
- 108010040145 barusiban Proteins 0.000 claims description 33
- 210000000287 oocyte Anatomy 0.000 claims description 24
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 claims description 20
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 20
- 239000000186 progesterone Substances 0.000 claims description 20
- 229960003387 progesterone Drugs 0.000 claims description 20
- 230000027758 ovulation cycle Effects 0.000 claims description 17
- 230000004720 fertilization Effects 0.000 claims description 8
- 230000012447 hatching Effects 0.000 claims description 8
- 230000001502 supplementation Effects 0.000 claims description 8
- 239000000556 agonist Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000006062 fragmentation reaction Methods 0.000 claims description 6
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 5
- 210000001109 Blastomeres Anatomy 0.000 claims description 5
- 229960005309 Estradiol Drugs 0.000 claims description 5
- 230000000270 postfertilization Effects 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 102000017937 Vasopressin/oxytocin receptor family Human genes 0.000 claims description 4
- 108060003373 Vasopressin/oxytocin receptor family Proteins 0.000 claims description 4
- 239000000583 progesterone congener Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003488 releasing hormone Substances 0.000 claims description 3
- 230000032692 embryo implantation Effects 0.000 abstract description 6
- 210000002459 Blastocyst Anatomy 0.000 description 50
- 210000002257 embryonic structures Anatomy 0.000 description 39
- 229940040129 Luteinizing Hormone Drugs 0.000 description 32
- 102000009151 Luteinizing Hormone Human genes 0.000 description 32
- 108010073521 Luteinizing Hormone Proteins 0.000 description 32
- 230000000638 stimulation Effects 0.000 description 16
- 230000002611 ovarian Effects 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 239000003336 oxytocin antagonist Substances 0.000 description 12
- 229940121361 oxytocin antagonists Drugs 0.000 description 12
- 206010049975 Uterine contractions during pregnancy Diseases 0.000 description 11
- 239000000902 placebo Substances 0.000 description 11
- 229940068196 placebo Drugs 0.000 description 11
- 230000000875 corresponding Effects 0.000 description 8
- 235000013601 eggs Nutrition 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 239000002609 media Substances 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 210000004291 Uterus Anatomy 0.000 description 7
- -1 aliphatic alpha-amino acid Chemical class 0.000 description 7
- 230000003111 delayed Effects 0.000 description 7
- 230000002459 sustained Effects 0.000 description 7
- VWXRQYYUEIYXCZ-OBIMUBPZSA-N Atosiban Chemical compound C1=CC(OCC)=CC=C1C[C@@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)CSSCCC(=O)N1 VWXRQYYUEIYXCZ-OBIMUBPZSA-N 0.000 description 6
- 229960002403 Atosiban Drugs 0.000 description 6
- 210000003101 Oviducts Anatomy 0.000 description 6
- 230000016087 ovulation Effects 0.000 description 6
- 210000004952 Blastocoel Anatomy 0.000 description 5
- 210000004027 cells Anatomy 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229940028334 Follicle Stimulating Hormone Drugs 0.000 description 4
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 4
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 238000007477 logistic regression Methods 0.000 description 4
- 230000000938 luteal Effects 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 230000000877 morphologic Effects 0.000 description 4
- 210000003754 Fetus Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000002357 endometrial Effects 0.000 description 3
- 230000002068 genetic Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- PLVGDGRBPMVYPB-FDUHJNRSSA-N (3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione Chemical compound O=C([C@H](N1[C@@H](C(N[C@@H](C1=O)C1CC2=CC=CC=C2C1)=O)[C@@H](C)CC)C=1N=C(C)OC=1)N1CCOCC1 PLVGDGRBPMVYPB-FDUHJNRSSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-Methyl-2,4-pentanediol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 210000004246 Corpus Luteum Anatomy 0.000 description 2
- 229950009963 EPELSIBAN Drugs 0.000 description 2
- UWHCWRQFNKUYCG-QUZACWSFSA-N Epelsiban Chemical compound O=C([C@H](N1[C@@H](C(N[C@@H](C1=O)C1CC2=CC=CC=C2C1)=O)[C@@H](C)CC)C=1C(=NC(C)=CC=1)C)N1CCOCC1 UWHCWRQFNKUYCG-QUZACWSFSA-N 0.000 description 2
- 210000002458 Fetal Heart Anatomy 0.000 description 2
- 210000001667 Gestational Sac Anatomy 0.000 description 2
- 230000036499 Half live Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 210000002394 Ovarian Follicle Anatomy 0.000 description 2
- 210000004681 Ovum Anatomy 0.000 description 2
- 229950010622 Retosiban Drugs 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- 210000001215 Vagina Anatomy 0.000 description 2
- 210000004340 Zona Pellucida Anatomy 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037028 contraction frequency Effects 0.000 description 2
- 230000001082 cryoprotectant Effects 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229940083433 diuretics Vasopressin antagonists Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000003325 follicular Effects 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229940121381 gonadotrophin releasing hormone (GnRH) antagonists Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000009027 insemination Effects 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001360 synchronised Effects 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 239000003038 vasopressin antagonist Substances 0.000 description 2
- GIUFQWFJHXXXEQ-PHSYAEQHSA-N (2S)-2-amino-N-[(3S)-7,7-dimethyl-4-[[4-(2-methylphenyl)piperazin-1-yl]sulfonylmethyl]-3-bicyclo[2.2.1]heptanyl]-4-methylsulfonylbutanamide;hydrochloride Chemical compound Cl.CC1=CC=CC=C1N1CCN(S(=O)(=O)CC23[C@H](CC(CC2)C3(C)C)NC(=O)[C@@H](N)CCS(C)(=O)=O)CC1 GIUFQWFJHXXXEQ-PHSYAEQHSA-N 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical group OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 210000003679 Cervix Uteri Anatomy 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N Clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 Clomifene Drugs 0.000 description 1
- 229940046989 Clomiphene Citrate Drugs 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 229960000905 Indomethacin Drugs 0.000 description 1
- 208000000509 Infertility Diseases 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- 206010049513 Luteal phase deficiency Diseases 0.000 description 1
- 210000003097 Mucus Anatomy 0.000 description 1
- 108010061543 Neutralizing Antibodies Proteins 0.000 description 1
- 101710008205 OXT Proteins 0.000 description 1
- 102100017240 OXT Human genes 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N Oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 Oxytocin Drugs 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 206010068042 Premature ovulation Diseases 0.000 description 1
- 230000025458 RNA interference Effects 0.000 description 1
- 210000003856 Spermatozoa Anatomy 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 102000004136 Vasopressin Receptors Human genes 0.000 description 1
- 108090000643 Vasopressin Receptors Proteins 0.000 description 1
- 230000003187 abdominal Effects 0.000 description 1
- 230000001594 aberrant Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000692 anti-sense Effects 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000029578 entry into host Effects 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000002871 fertility agent Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 201000002406 genetic disease Diseases 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000011599 ovarian follicle development Effects 0.000 description 1
- 101700057139 oxyT Proteins 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 230000002987 rna-interference Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 230000001349 uterorelaxant Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N α-Aminobutyric acid Chemical group CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/42—Gynaecological or obstetrical instruments or methods
- A61B17/425—Gynaecological or obstetrical instruments or methods for reproduction or fertilisation
- A61B17/435—Gynaecological or obstetrical instruments or methods for reproduction or fertilisation for embryo or ova transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention relates to the use of an oxytocin receptor antagonist in females undergoing embryo transfer as part of an assisted reproductive technology. In particular, methods are provided for increasing ongoing implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate in a female subject undergoing embryo transfer. Specifically, the antagonists are released such that they take effect in the luteal phase when the endometrium is receptive for embryo implantation and when the embryo has reached the blastocyst-stage. ancy rate, and/or increasing live birth rate in a female subject undergoing embryo transfer. Specifically, the antagonists are released such that they take effect in the luteal phase when the endometrium is receptive for embryo implantation and when the embryo has reached the blastocyst-stage.
Description
Title: Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women
undergoing assisted reproductive technologies
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of EP Application No. 14199709.8, filed
December 22, 2014, and U.S. Application No. 14/643307 filed 10 March 2015, the contents of which are
herein incorporated by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to the use of an oxytocin receptor antagonist in females
undergoing embryo transfer as part of an assisted reproductive technology. In particular, methods are
described for increasing ongoing implantation rate, increasing ongoing pregnancy rate, increasing clinical
pregnancy rate, and/or increasing live birth rate in a female subject undergoing embryo transfer.
Specifically, the antagonists are released in the luteal phase when the endometrium is receptive for
embryo implantation and/or when the embryo has reached the blastocyst-stage.
BACKGROUND OF THE INVENTION
In vitro fertilization (IVF) is a method for establishing pregnancy in a female subject. The
procedure typically involves ovarian stimulation with one or various hormones, mainly follicle-
stimulating hormone (FSH), and human chorionic gonadotropin (hCG) is usually administered to trigger
final follicular maturation. Oocyte retrieval takes place generally 2 days (around 36h) after hCG
administration. The ooctyes are then fertilized in vitro, cultured for several days, and are transferred into
the uterus. IVF also encompasses the transfer of embryos originating from the eggs of a first female (the
donor) into a second female (the gestational carrier). Embryos may be placed in frozen storage and
transferred (i.e., frozen embryo transfer) after several months or even years.
Improving the implantation rate of transferred embryos is one of the major challenges in
assisted reproductive technologies (ART) treatment. Approximately only one-third of the transferred
embryos implant in women undergoing controlled ovarian stimulation for IVF / intracytoplasmic sperm
injection (ICSI). Implantation and pregnancy rates are influenced by multiple factors related to the age
and other characteristics of the patient, the magnitude of the response to ovarian stimulation, the quality
of the embryos obtained, the endometrial receptivity as well as the actual transfer procedure.
[0005] Uterine contractility is considered a potentially important factor affecting implantation and
pregnancy rates in IVF/ICSI cycles (Fanchin et al. 1998; Schoolcraft et al. 2001; Bulleti and de Ziegler
2005). A high frequency of uterine contractions at the time of transfer appears to have a negative impact
on outcome, possibly by expelling the embryos in the uterine cavity or by displacing the embryos and
thereby reducing implantation and pregnancy rates.
Observational data indicated a decrease in clinical pregnancy rates with increasing
frequency of contractions at the time of cleavage-stage embryo transfer at hCG +4 days (i.e., four days
after hCG administration, corresponding to day 2 post-retrieval of oocytes) (Fanchin et al. 1998). A
prospective controlled study also observed that patients with a higher frequency of uterine contractions on
the day of cleavage-stage embryo transfer (day 3 post-retrieval) had lower pregnancy rates than patients
with lower frequency of uterine contractions at the time of transfer (Zhu et al. 2014).
Uterine contractility in controlled ovarian stimulation cycles has been compared to normal
menstrual cycles (Ayoubi et al. 2003). The frequency of uterine contractions was found to be similar
between the timepoint of hCG administration in a controlled ovarian stimulation cycle and at the time of
luteinizing hormone (LH) surge in a natural cycle. In the luteal phase, the frequency of uterine
contractions was higher at hCG +4 days (corresponding to day 2 post-retrieval) in a controlled ovarian
stimulation cycle compared to at LH +4 days (i.e., four days after LH surge) in a natural cycle (Ayoubi et
al. 2003). However, the frequency of uterine contractions at LH +6 days and hCG +6 days (corresponding
to day 4 post-retrieval) was not different and in both situations was low, indicating identical level of uterine
quiescence at that time point in controlled ovarian stimulation and natural cycles (Ayoubi et al. 2003). In
was assessed at the day of hCG administration, hCG +4 days
another study, uterine contractility
(corresponding to day 2 post- retrieval) and hCG +7 days (corresponding to day 5 post-retrieval) in women
undergoing a controlled ovarian stimulation cycle (Fanchin et al. 2001). The frequency of uterine
contractions was highest at the day of hCG administration, decreased slightly during the early luteal phase
as assessed at hCG +4 days, and reached nearly quiescent status at hCG+7 days (corresponding to day 5
post-retrieval). Another study reported a decrease in the number of junctional zone contractions in oocyte
donors in the early luteal phase from day 2 to day 3 and also to day 4 post-retrieval (Lesny et al. 1999).
Similarly, evaluation of uterine contractility in oocyte donors who had undergone controlled ovarian
stimulation and received exogenous progesterone luteal phase supplementation indicated that there was a
significant decrease in the frequency of uterine contractions from day 2 post-retrieval to day 5 post-
retrieval (Blockeel et al. 2009).
The highest level of uterine contractility is at the end of controlled ovarian stimulation
(day of hCG administration) and has been attributed to the high serum estradiol and low serum
progesterone concentrations at that time point. The decrease in uterine contractility during the luteal phase
is believed to be the result of the exposure to endogenous progesterone caused by the corpus luteum
function in response to the hCG administration as well as exogenous progesterone luteal supplementation
used in IVF/ICSI cycles. Although progesterone supplementation is used for luteal phase support in
IVF/ICSI patients and can reduce uterine contractility, there is elevated uterine activity during the early
luteal phase (day 2 or 3 post-retrieval) when transfer of cleavage-stage embryos is performed.
As uterine contractility is elevated during the early luteal phase (day 2 or 3 post-retrieval)
when transfer of cleavage-stage embryos is performed, investigations assessing the impact of different
interventions on uterine contractility for improving implantation have been conducted in the early luteal
phase (day 2 and 3 post-retrieval transfer; hCG +4 days). Randomized controlled trials (Moon et al. 2004;
Bernabeu et al 2006; Kim et al. 2008; Ng et al. 2014), quasi-randomized controlled trials (Moraloglu et al.
2010), retrospective studies in fresh and frozen embryo replacement cycles (Chou et al. 2011; Lan et al.
2012), or case studies in fresh and frozen embryo replacement cycles (Pierzynski et al. 2007; Liang et al
2009) reporting findings with compounds reducing uterine contractility, like atosiban (Kim et al 2008;
Moraloglu et al. 2010; Ng et al. 2014), indomethacin (Bernabeu et al. 2006) and piroxicam (Moon et al.
2004) have been all conducted on day 2 or 3 post- retrieval, i.e., at the time of cleavage-stage embryo
transfer.
[0010] A recent randomized controlled trial (Ng et al. 2014) compared the treatment outcome
after administration of atosiban or placebo in IVF/ICSI patients followed by cleavage-stage embryo
transfer on day 2 or day 3 post-retrieval. This large study was designed to determine whether the anecdotal
evidence found in the previous smaller studies could be confirmed. This adequately-designed, large
(N=800), double-blind, randomized, controlled trial found no significant increase in implantation or live
birth rates with atosiban compared to placebo, as illustrated by live birth rates of 39.8% versus 38.0%,
respectively (Ng et al. 2014). Atosiban administration on day 2 or day 3 post-retrieval therefore does not
significantly increase implantation or live birth rates.
Consequently, improving implantation of transferred embryos remains one of the major
challenges in assisted reproductive technologies (ART) treatment. It is an object of the present disclosure
to improve implantation rates, thereby increasing pregnancy rates and live birth rates, and/or to provide
the public with a useful choice.
SUMMARY OF THE INVENTION
[0011a] In a first aspect the present invention provides a use of an oxytocin receptor antagonist in
the manufacture of a medicament for use in increasing ongoing implantation rate, increasing ongoing
pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate, in a human female
subject undergoing embryo transfer as part of an assisted reproductive technology, wherein the antagonist
is to be provided to the female such that the effect of the antagonist overlaps with the receptive
endometrium stage in said female and the antagonist is to be provided to the female such that the effect of
the antagonist is present when the embryo has reached the blastocyst-stage.
[0011b] In a second aspect the present invention provides a method for increasing ongoing
implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or
increasing live birth rate, in a non-human female mammal undergoing embryo transfer as part of an
assisted reproductive technology, wherein the antagonist is to be provided to the female such that the
effect of the antagonist overlaps with the receptive endometrium stage in said female and the antagonist is
to be provided to the female such that the effect of the antagonist is present when the embryo has reached
the blastocyst-stage.
Also described is an oxytocin receptor antagonist for use in increasing ongoing
implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing
live birth rate, relative to control, in a female subject undergoing embryo transfer as part of an assisted
reproductive technology, wherein the antagonist is provided to the female such that the effect of the
antagonist is present when the female is in (or otherwise overlaps with) the receptive endometrium stage
and/or when the effect of the antagonist coincides with the embryo reaching the blastocyst-stage.
Preferably, the antagonist is provided such that it is released in the receptive endometrium stage and/or
when the embryo has reached the blastocyst-stage. Preferably, the antagonist is administered when the
female is in the receptive endometrium stage and/or when the embryo has reached the blastocyst-stage. In
certain embodiments, the antagonist is formulated for immediate release. In other embodiments, the
antagonist is formulated as a sustained or delayed release formulation, such as a depot, and is
administered prior to the receptive endometrium stage and/or when the embryo is still in cleavage stage
such that the antagonist is released or continues to be released once the receptive endometrium stage is
reached and/or the embryo has reached the blastocyst stage. Preferably, the antagonist is provided such
that a therapeutically effective amount of the antagonist is present when the female is in (or otherwise
overlaps with) the receptive endometrium stage and/or when the effect of the antagonist coincides with
the embryo reaching the blastocyst-stage.
In preferred embodiments, the receptive endometrium stage corresponds to:
a) between LH+6 days and LH+9 days, preferably between LH+6 days and LH+8 days, most
preferably on day LH+7 of a natural ovulation cycle;
b) between hCG+6 days and hCG+9 days, preferably between hCG+6 days and hCG+8 days;
most preferably on day hCG+7 of an induced ovulation cycle;
c) between day 4 and day 7, preferably between day 4 and day 6, more preferably on day 5 or 6,
most preferably on day 5, of luteal phase support, wherein luteal phase support begins the day following
oocyte retrieval in an IVF cycle, preferably wherein the female has undergone ovarian stimulation; or
d) between day 4 to day 9, preferably between day 5 to day 7, more preferably on day 5 or day 6
of luteal phase support, preferably in preparation for frozen embryo transfer or third party IVF, and
preferably wherein luteal support begins after the endometrium is primed for at least 6 days with
exogenous oestrogen.
Preferably, luteal phase support comprises supplementation with progesterone, human
chorionic gonadotropin, estradiol and progesterone, progestins and/or gonadatropin releasing hormone
(GnRH) agonists.
Accordingly, the disclosure describes oxytocin receptor antagonists which can be used to
prepare medicaments for increasing ongoing implantation rate, increasing ongoing pregnancy rate,
increasing clinical pregnancy rate, and/or increasing live birth rate, in a female subject undergoing
embryo transfer as part of an assisted reproductive technology. Also encompassed by the disclosure are
uses of oxytocin receptor antagonist for the preparation of a medicament for use in a female undergoing
transfer of a blastocyst-stage embryo. Preferably a medicament is administered such that its effect
overlaps with the receptive endometrium stage and/or when the embryo has reached the blastocyst-stage.
Preferably, an antagonist in a medicament is released in the female when the female is in the receptive
endometrium stage and/or when the embryo has reached the blastocyst-stage. Preferably, an antagonist is
described such that a therapeutically effective amount of the antagonist is present when the female is in
(or otherwise overlaps with) the receptive endometrium stage and/or when the effect of the antagonist
coincides with the embryo reaching the blastocyst-stage.
The disclosure further encompasses methods for increasing ongoing implantation rate,
increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate, in
a female subject undergoing embryo transfer as part of an assisted reproductive technology, comprising
administering to the female an oxytocin receptor antagonist such that the effect of the antagonist overlaps
with the receptive endometrium stage and/or when the embryo (e.g., transferred embryo) has reached the
blastocyst-stage. Preferably, methods are described for increasing ongoing implantation rate, increasing
ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate in a female ,
said method comprising administering to the female prior to and/or following embryo transfer an oxytocin
receptor antagonist such that a therapeutically effective amount of the antagonist is present during at least
a portion of the receptive endometrium stage of the female and/or during at least a portion of the
blastocyst-stage of a transferred embryo in the female, thereby increasing ongoing implantation rate,
increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate
relative to a control. In preferred embodiments, the methods further comprise transferring an embryo into
the uterus, the uterine cavity or the fallopian tubes of a female, preferably wherein a blastocyst-stage
embryo is transferred.
[0017] The disclosure further describes methods of implanting an embryo in a female subject,
comprising transferring an embryo into the uterus, the uterine cavity or the fallopian tubes of a female and
administering to the female an oxytocin receptor antagonist such that the effect of the antagonist overlaps
with the blastocyst-stage of the embryo and/or the female is in the receptive endometrium stage.
Preferably, an antagonist is described such that a therapeutically effective amount of the antagonist is
present when the female is in (or otherwise overlaps with) the receptive endometrium stage and/or when
the effect of the antagonist coincides with the embryo reaching the blastocyst-stage.
Methods are also described for implanting an embryo in a female subject, said method
comprising transferring an embryo into the uterus, the uterine cavity or the fallopian tubes of a female and
administering to the female an oxytocin receptor antagonist such that a therapeutically effective amount
of the antagonist is present in the female during at least a portion of the receptive endometrium stage of
the female and/or during at least a portion of the blastocyst-stage of the transferred embryo in the female
In preferred embodiments, the female is undergoing transfer of a blastocyst-stage embryo
and the antagonist is administered to the female such that the antagonist is released to the female on the
same day that the embryo is transferred. Preferably, the antagonist is administered between 2 hours prior
to and 2 hours post embryo transfer (for example, in an immediate release formulation), preferably
wherein the antagonist is administered twice, preferably wherein the first administration occurs around 45
minutes prior to embryo transfer and the second administration occurs around 60 minutes after the first
administration. Preferably, a blastocyst-stage embryo has an expansion and hatching status of 3, 4, 5, or 6,
more preferably wherein the blastocyst-stage embryo is a day 5 post-insemination embryo.
[0020] In preferred embodiments, the female is undergoing transfer of a cleavage-stage embryo
and the antagonist is administered to the female such that the antagonist is released two or three days after
the embryo is transferred. Preferably, a cleavage-stage embryo has at least 6 blastomeres and
fragmentation of 20% or less, preferably wherein the cleavage-stage embryo is a day 2 or day 3 post-
fertilization embryo.
[0021] In preferred embodiments, the antagonist is a selective oxytocin receptor antagonist or an
vasopressin/oxytocin receptor antagonist. More preferably, the antagonist is a selective oxytocin receptor
antagonist.
Preferably, the antagonist is barusiban. Preferably, barusiban is provided subcutaneously.
Preferably, between 30-80 mg, more preferably 50 mg of barusiban is administered. In some
embodiments, the female is undergoing transfer of a blastocyst-stage embryo and barusiban is
administered to the female as a depot prior to the day of embryo transfer. Preferably, the female is
undergoing transfer of a blastocyst-stage embryo and barusiban is administered to the female on the same
day as embryo transfer. Preferably, 40 mg barusiban is administered subcutaneously about 15, 30, 45, 60,
or 75 minutes (e.g., 45 minutes) prior to blastocyst stage embryo transfer and 10 mg barusiban is
administered subcutaneously about 15, 30, 45, 60, or 75 minutes (e.g., 60 minutes) after the first
administration.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1A and 1B depict examples of oxytocin receptor antagonists.
Figure 2 depicts odds ratio for ongoing implantation rate by day of transfer for (BASIC)
clinical trial.
Figure 3 is a graph of ongoing implantation rate by day of transfer for (BASIC) clinical
trial.
DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS
As used herein, "to comprise" and its conjugations is used in its non-limiting sense to
mean that items following the word are included, but items not specifically mentioned are not excluded.
In addition the verb “to consist” may be replaced by “to consist essentially of” meaning that a compound
or adjunct compound as defined herein may comprise additional component(s) than the ones specifically
identified, said additional component(s) not altering the unique characteristic of the invention.
The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at
least one) of the grammatical object of the article. By way of example, “an element” means one element
or more than one element.
[0028] The word “approximately” or “about” when used in association with a numerical value
(approximately 10, about 10) preferably means that the value may be the given value of 10 more or less
1% of the value.
When referring herein to a range, such as, e.g., a range of days, the range includes both end
points. For example, day LH+6 to day LH+9 encompasses day LH+6, day LH+7, day LH+8, and day
LH+9.
As used herein, the term "embryo” refers to a zygote up to eight weeks after fertilization.
"Embryo transfer" is the procedure in which one or more embryos are placed into the uterus, uterine
cavity, or fallopian tubes of a female.
As used herein, a female subject is a mammal which includes humans; companion
animals, e.g., dogs and cats; domestic livestock animals, such as pigs, horses, donkeys, goats, sheep,
llamas; as well as rare and threatened species. Preferably, the subject is human.
Assisted reproductive technology (ART) refers to methods for achieving pregnancy using
artificial means. Preferably, ART refers to methods in which an in vitro fertilized embryo is transferred
into a female subject, for example using IVF/ICSI.
“Fresh embryo transfer” refers to the transfer of an embryo without first freezing the
embryo.
Generally, the natural ovulation cycle ranges from 21 to 35 days, with the average length
being 28 days. The first part of the cycle is referred to as the follicular phase in which the ovarian follicles
mature. Ovulation follows by which a mature egg is released into the oviduct. The luteal phase refers to a
phase of the ovulation cycle beginning with the formation of the corpus luteum at LH+1 and finishing the
day before the first day of menstruation.
“Ongoing implantation rate” as used herein refers to the number of intrauterine viable
fetuses 10-11 weeks after transfer divided by number of embryos/blastocysts transferred. Preferably, the
administration of an oxytocin receptor antagonist as disclosed herein increases the ongoing implantation
rate by at least 5%, more preferably by at least 10% and most preferred by at least 20%.
“Ongoing pregnancy rate” as used herein refers to a pregnancy with at least one
intrauterine viable fetus 10-11 weeks after transfer divided by number of embryos/blastocysts transferred.
Preferably, the administration of an oxytocin receptor antagonist as disclosed herein increases the ongoing
pregnancy rate by at least 5%, more preferably by at least 10% and most preferred by at least 20%.
“Implantation rate” as used herein refers to the number of intrauterine gestational sacs
with fetal heart beat 5-6 weeks after transfer divided by number of embryos/blastocysts transferred.
Preferably, the administration of an oxytocin receptor antagonist as disclosed herein increases the ongoing
implantation rate by at least 5%, more preferably by at least 10% and most preferred by at least 20%.
“Clinical pregnancy rate” as used herein refers to a pregnancy with at least one
intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer divided by number of
embryos/blastocysts transferred. Preferably, the administration of an oxytocin receptor antagonist as
disclosed herein increases the clinical pregnancy rate by at least 5%, more preferably by at least 10% and
most preferred by at least 20%.
“Live birth rate” refers to the number of live births per women treated. Preferably, the
administration of an oxytocin receptor antagonist as disclosed herein increases the live birth rate by at least
%, more preferably by at least 10% and most preferred by at least 20%.
“Therapeutically effective amount”, as used herein, refers to an amount that produces the
desired effect for which it is administered. In some embodiments, the term refers to an amount that is
sufficient, when administered to a female subject undergoing embryo transfer in accordance with a
therapeutic dosing regimen, to increase ongoing implantation rate, to increase ongoing pregnancy rate, to
increase clinical pregnancy rate, and/or to increase live birth rate. Those of ordinary skill in the art will
appreciate that the term "therapeutically effective amount" does not in fact require successful treatment be
achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that
provides a particular desired pharmacological response in a significant number of subjects when
administered to female subjects in need of such treatment. Those of ordinary skill in the art will
appreciate that, in some embodiments, a therapeutically effective amount of a particular agent or therapy
may be formulated and/or administered in a single dose. In some embodiments, a therapeutically
effective agent may be formulated and/or administered in a plurality of doses, for example, as part of a
dosing regimen.
One aspect of the disclosure describes oxytocin receptor antagonists for use in increasing
ongoing implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or
increasing live birth rate, relative to a control, in a female subject undergoing embryo transfer. Preferably,
the ongoing implantation rate is increased relative to a control.
Previous large studies in the art report administration of oxytocin receptor antagonists in
the early luteal phase (corresponding to day 2 or 3 post-retrieval) when uterine contraction frequency is
high. The expectation was that these compounds, which reduce uterine contractility, would improve
embryo implantation. However, the oxytocin receptor antagonists demonstrated no improved effects on
implantation when provided in the early luteal phase (Ng et al. 2014). Thus, in certain embodiments, the
present disclosure excludes immediate release or substantially immediate release formulations of oxytocin
receptor antagonists administered in the early luteal phase (i.e., preceding the receptive endometrium
stage).
The present disclosure demonstrates the effectiveness of oxytocin receptor antagonists on
embryo implantation when provided after the early luteal phase, or rather, at the receptive endometrium
stage and/or the when the embryo has reached the blastocyst-stage (see Example 1). Since the frequency
of uterine contractions has returned or nearly returned to baseline at this stage, it was surprising and
unexpected that a oxytocin receptor antagonist had an effect on the implantation rate.
Implantation is a critical process in which an embryo apposes, attaches and invades the
endometrium. The uterus will accept the implanting embryo only during a limited period of time described
as the “window of implantation” or “receptive window” (Makrigiannakis and Minas 2006; Strowitzki et al.
2006). The window of implantation is a period of a few days in which the endometrium acquires the
receptive stage allowing embryo adhesion and invasion (Koot and Macklon 2013). This stage is referred to
herein as the “receptive endometrium stage”.
Successful implantation depends not only a receptive endometrium, but also on a
functional embryo and the synchronized communication between the embryo and maternal tissues.
Therefore, during the receptive window of implantation, the embryo also needs to be at the appropriate
stage. Implantation occurs after a blastocyst hatches from the zona pellucida. Therefore, as is well known
if the field of ART, if a blastocyst stage embryo is transferred, the woman should ideally be in the
receptive endometrium stage, so that both the endometrium and the embryo are synchronized for implantation. If
a cleavage stage embryo is transferred, then the woman should be in the pre-receptive stage. The endometrium
and embryo will both further develop such that when the embryo reaches the blastocyst stage, the endometrium
will have reached the receptive stage.
Accordingly, the antagonists disclosed herein are administered such that the effect of the
antagonist overlaps with the receptive endometrium stage and/or the embryo reaching the blastocyst-stage.
Preferably, the antagonists are provided such that the antagonist is released or continues to be released in the
receptive endometrium stage and/or the embryo reaching the blastocyst-stage. As discussed further herein, the
antagonists are usually formulated as immediate release compositions such that they are administered during the
receptive endometrium stage. However, the disclosure also encompasses antagonists formulated as control or
delayed release formulations, for example as a depot, such that they are administered during the pre-receptive
stage, but are released during the receptive stage. Preferably, a therapeutically effective amount of the antagonist
is present during at least a portion of the receptive endometrium stage of the female.
A number of cellular and morphological changes are associated with the transformation of a
pre-receptive endometrium to a receptive endometrium. Biomarkers have also been identified which can be used
to evaluate whether the endometrium is in a receptive stage. For example, the Endometrial Receptivity Array
from Ignomix analyzes the expression of 238 genes in order to determine whether the endometrium is in the
receptive stage (see, WO2010010201 and WO2010010213). Preferably, the receptive endometrium stage is
defined as having a normal receptive profile based on the expression profile of one or more (e.g., all) of the 238
genes of the Endometrial Receptivity Array (ERA).
The receptive endometrium stage can also be characterized based on the stage of a normal
ovulation cycle. Ovulation occurs after the luteinizing hormone (LH) surge, which normally takes place
around day 14 of a normal ovulation cycle. The precise stage of the ovulation cycle can be characterized
based on the timing of the LH surge. The LH surge can be measured by taking blood samples at various days
of a woman’s cycle. The day of the LH surge is considered as day LH 0. LH+1 then usually corresponds to
day 15 of the cycle and LH+7 usually to day 21. The endometrium becomes receptive to implantation at
around day LH +7 in natural cycles and remains receptive for usually about 4 days (Bergh and Navot
1992), although this timing varies for each woman. In preferred embodiments, the receptive endometrium
stage corresponds to between day LH+6 and day LH+9 of a natural ovulation cycle, more preferably
between LH+6 and LH+8. The receptive window lasts normally only 2-3 days per ovulation cycle. However, as
is well-known in the art, there exists variability between women in both the length of the window and when it
occurs.
In women undergoing oocyte retrieval for fresh embryo transfer, the receptive window can
be characterized based on the day post-oocyte retrieval, the number of days in luteal phase support following
oocyte retrieval, and/or the number of days following hCG administration.
In a typical IVF procedure, ovarian stimulation is used in order to stimulate the ovaries to
produce multiple eggs. Gonadatropin releasing hormone (GnRH) agonists and GnRH antagonists can be
given to prevent premature ovulation while human menopausal gonadotropin (hMG), follicle stimulating
hormone (FSH), luteinizing hormone (LH), and clomiphene citrate can be given to stimulate the
production of multiple eggs. Typically, eight to fourteen days of stimulation are required before the
ovarian follicles are sufficiently developed. Human chorionic gonadotropin (hCG) is usually then
administered to ensure the final stage of maturation and the eggs are retrieved prior to ovulation, usually
around 36 hours after hCG administration. The day of hCG administration is defined as hCG+0 and
oocyte retrieval is performed on hCG+2.
[0051] In preferred embodiments, the receptive endometrium stage corresponds to between day
hCG+6 and day hCG+9 (or rather, 4 to 7 days post-oocyte retrieval), preferably between day hCG+6 and
day hCG+8.
Egg retrieval is a minor surgical procedure that can be performed, for example, using
transvaginal ultrasound aspiration. The eggs may be inspected microscopically and diagnosed to observe
their morphological features. Insemination is then performed in vitro, for example by incubating oocytes
together with sperm or by intracytoplasmic sperm injection (ICSI) in which sperm is injected with a
microscopic needle into the egg. “Fertilization" refers to the penetration of the ovum by the spermatozoa
and combination of their genetic material resulting in the formation of a zygote.
After fertilization, embryos are cultured in vitro. Methods for culturing and staging
embryos are well-known in the art and are described in, e.g., US 20140134632, US 20140017717, US
20120252119, and US 20120252119, which are herein incorporated by reference in their entirety. Culture
media known in the art that are suitable for use for the in vitro support of cell development and growth
include human tubal fluid (HTF) (Irvine Scientific), Nhydroxyethylpiperazine-N'ethane (HEPES)
media (Irvine Scientific), IVF-50 (Scandanavian IVF Science), S2 (Scandanavian IVF Science), Gl and
G2 (Scandanavian IVF Science), UnilVF, ISM-1, BlastAssist, UTM media (sold as MEDICULT® media
by Origio A/S), Modified Whittens medium, Wittinghams T6 media, Ham's F-10 media, and Earle's
solution. Gl and G2 media were specifically formulated to meet the physiological needs of the cleavage
stage embryo and the embryo in the eight-cell through blastocyst stage of development. U.S. Pat. No.
6,605,468 discloses a medium for the propagation of early stage embryos to blastocyst stage.
Embryos may also be subjected to morphological, kinetic and/or genetic testing.
Preferably, visual observation of the embryo by microscopy is used to determine if aberrant physical or
morphological features are present (see, e.g., WO2013078312). Preimplantation genetic diagnosis is
commonly performed to screen for inherited diseases. For this method, one or two cells are removed from
an embryo to test for genetic diseases.
Methods of embryo transfer are well known in the art. One or more embryos may be
aspirated into a catheter and inserted into the uterus, the uterine cavity or the fallopian tubes.
In some embodiments a cleavage-stage embryo is transferred. “Cleavage-stage” embryos
range from 2-cells to 16 cells and can be characterized based on, e.g., fragmentation, symmetry of
division, and absence of multinucleation (see Prados et al. Human Reproduction 2012 27:50-71 for
review). Fragmentation is generally characterized by the percent of embryo volume that is replaced by
fragments. Preferably, a cleavage-stage embryo is characterized as having 4 blastomeres on day 2 post-
insemination and 6-8 blastomers on day 3 post-insemination. Preferably, the cleavage-stage embryo has at
least 6 blastomeres and fragmentation of 20% or less.
Preferably, a day 2 or day 3 cleavage stage embryo is transferred. In fresh embryo
transfers where the female has undergone oocyte retrieval, the day 2 or day 3 cleavage stage embryo is
then usually transferred 2 or 3 days post-oocyte retrieval, respectively. The blastocyst stage of the embryo
and the receptive endometrium stage are reached, ideally simultaneously, several days after transfer.
[0058] Preferably, a blastocyst-stage embryo is transferred. A "blastocyst-stage" embryo has an
inner cell mass, an outer cell layer called the trophectoderm, and a fluid-filled blastocele cavity containing
the inner cell mass from which the whole of the embryo is derived. An embryo normally reaches this
stage at day 5 or 6 post-retrieval. A blastocyst-stage embryo can be characterized based on its expansion
and hatching status. Expansion relates to the increasing volume of the cavity (i.e. blastocoel), while
hatching refers to the herniation or escape of the blastocyst from its membrane (i.e. zona pellucida). The
expansion and hatching status is characterized as follows:
1. An early blastocyst, blastocoel being less than half volume of that of the embryo
2. A blastocyst with a blastocoel whose volume is half of, or greater than half of, that of the
embryo
3. A blastocyst with a blastocoel completely filling the embryo
4. An expanded blastocyst with a blastocoel volume larger than that of the early embryo, with a
thinning zona
. A hatching blastocyst with the trophectoderm starting to herniate through the zona
6. A hatched blastocyst, in which the blastocyst has completely escaped from the zona.
In preferred embodiments, the blastocyst-stage embryo for transfer has an expansion and
hatching status of 3, 4, 5, or 6.
[0060] In fresh embryo transfers where the female has undergone oocyte retrieval, the blastocyst
stage embryo is usually transferred to the female 5 or 6 days post-oocyte retrieval, preferably 5 days post-
retrieval.
For women undergoing fresh embryo transfer following oocyte retrieval, the
endometrium on day 2 and day 3 post-oocyte retrieval is typically in a pre-receptive stage and is not
conducive to implantation. In preferred embodiments, the receptive endometrium stage corresponds to
between day 4 and day 7 post-oocyte retrieval, preferably between day 5 and day 6. If hCG is used to
induce ovulation or trigger final maturation, days 4 to 7 post-oocyte retrieval will normally correspond to
hCG+6 to hCG+9.
Ovarian stimulation with fertility drugs usually leads to luteal phase deficiency.
Therefore, it is generally standard practice for luteal phase support to be used in women following oocyte
retrieval. Luteal phase support refers to therapeutic interventions during the luteal phase aiming at
supplementing corpus luteal function for improving the embryo implantation and the early pregnancy
development. Luteal phase support is known in the art and usually comprises supplementation with
progesterone, estradiol and progesterone, progestins, hCG, and/or a GnRH agonist, or rather the
administration of exogenous progesterone, estradiol and progesterone, progestins, hCG, and/or a GnRH
agonist. Progesterone is normally administered intramuscularly or vaginally, while hCG is administered
intra-muscularly or subcutaneously. Preferably, luteal phase support begins the first day after oocyte
retrieval, i.e., day 1 post-oocyte retrieval.
Preferably, the receptive endometrium stage corresponds to between day 4 and day 7,
preferably between day 4 and day 6, of luteal phase support in women who have undergone oocyte
retrieval. In preferred embodiments, the female has undergone ovarian stimulation in preparation for
oocyte retrieval.
The present disclosure encompasses the transfer of embryos into a female within a few
days post fertilization (i.e., fresh embryo transfer), as well as the use of frozen embryos. Frozen embryo
transfer (FET) is a known procedure that utilizes cryopreserved embryos from a previous cycle of in vitro
fertilization or ICSI. The cryopreserved embryos are thawed and transferred into the uterine cavity
through a catheter. The disclosure also encompasses the use of cryopreserved oocytes for fertilization. In
these embodiments, oocytes can be later thawed, fertilized, and cultured and transferred as described
herein.
Rapid freezing can be used for these purposes, for example together with a
cryoprotectant. Conventional cryoprotectants include glycols such as ethylene glycol, propylene glycol,
and glycerol; 2-methyl-2,4-pentanediol (MPD); dimethyl sulfoxide (DMSO) and sucrose. Alternatively,
vitrification can also be used to freeze oocytes or embryos.
FET, as well as “third-party IVF” (gestational surrogacy, ovum donation, embryo
donation), may be performed during a natural ovulation cycle. The receptive window for these women
can be determined based on a natural ovulation cycle as described herein. In some embodiments,
ovulation is induced with the administration of, e.g., hCG. Preferably, in these women the receptive
window corresponds to between hCG+6 and hCG+9, preferably between hCG+6 and hCG+8.
In some embodiments, women undergoing FET or third party IVF also receive luteal
support as described above. Preferably in these women the receptive window corresponds to between day
4 and day 9, preferably between day 5 and day 7, of luteal phase support. Luteal phase support is often
used when FET or third party IVF is performed during an “artificial cycle”. In these cases, the
endometrium is prepared by administering estrogen and/or progesterone using methods known in the art.
Preferably, luteal phase support begins after the endometrium is primed for at least 6 days with exogenous
estrogen in order to induce an artificial cycle.
In an exemplary embodiment of FET or third party IVF, estrogen is provided orally or
vaginally in doses of 4-8 mg daily for about 10 days, at which time luteal phase support is initiated with
the administration of vaginal progesterone and blastocyst transfer occurs 6 days after starting
progesterone.
In one embodiment of the disclosure, the effect of the oxytocin receptor antagonist
overlaps with the blastocyst-stage of the embryo. Preferably, the antagonist is released when the embryo
has reached the blastocyst-stage. Preferably, a blastocyst-stage embryo is transferred to said female and
the antagonist is administered on the same day that the embryo is transferred. Preferably, a therapeutically
effective amount of the antagonist is present during at least a portion of the blastocyst-stage of the
transferred embryo.
The disclosure also contemplates the transfer of a cleavage-stage embryo. In these
embodiments, the antagonist may be provided as a sustained or controlled release formulation for release
several days after transfer. Alternatively, the antagonist may be administered as an immediate release
formulation several days after transfer. As shown in the examples, administration of barusiban (an
oxytocin receptor antagonist) when an embryo is in the blastocyst-stage results in an increase in ongoing
implantation rate from 27% to 45%, a significant increase.
Oxytocin receptor antagonists are known in the art, and any oxytocin receptor antagonist
can be used in the methods of the disclosure. Preferably, the oxytocin receptor antagonists are selected
from selective oxytocin antagonists and mixed vasopressin/oxytocin receptor antagonists. A selective
oxytocin antagonist has a Ki for the oxytocin receptor which is at least one order of magnitude higher
than the Ki for the vasopressin receptor.
Receptor antagonists include compounds which reduce the expression and/or activity of
an oxytocin receptor. A preferred vasopressin/oxytocin receptor antagonist is atosiban (1-(3-
mercaptopropanoic acid)- 2-(O-ethyl-D-tyrosine)L-threonineL-ornithine-oxytocin).
[0073] Oxytocin receptor antagonists also include RNA interference or RNA antisense
molecules directed against said receptor.
Preferably, the antagonist binds to the receptor and prevents receptor activity. Such
antagonists include, e.g., antibodies directed against the receptor (e.g., “neutralizing antibodies”) as well
as small molecules. Preferably, the antagonist acts as a competitive antagonist and competes with
oxytocin for binding to the oxytocin receptor. Preferably, the antagonists are small molecules that bind to
the receptor and antagonize receptor activity. A preferred selective oxytocin antagonist is barusiban.
Suitable oxytocin receptor antagonists are well-known to the skilled person and can be
easily identified based on known screening methods which use, e.g., receptor activation and/or receptor
binding as a read-out. Suitable antagonists include those disclosed in US6143722, which is hereby
incorporated by reference in its entirety. US6143722 discloses heptapeptide analogues, or a
pharmaceutically acceptable salts thereof, having oxytocin antagonist activity and consisting of a
hexapeptide moiety S and a C-terminal beta-aminoalcohol residue Z bound to the moiety S by an amide
bond, wherein the beta-aminoalcohol Z is:
wherein Q is (CH2)n-NH-A, n is 1-6 and A is H or -C(=NH) NH2 ,
and wherein R is CH3 or C2H5;
and the moiety S is:
wherein Mpa, Ile, Asn and Abu have the following meaning:
Mpa 3 mercaptopropionic acid residue
Ile isoleucine residue
Asn asparagine residue
Abu alpha-aminobutyric acid residue;
and wherein X is a D-aromatic alpha-amino acid; and Y is an aliphatic alpha-amino acid. Preferred
oxytocin antagonists are listed in Figure 1.
Further antagonists include OBE001/ AS-602305 (in particular oral formulations
thereof), TT-235 (Northwestern University), the selective oxytocin receptor antagonist Epelsiban
((3R,6R)(2,3-dihydro-1H-indenyl)[(1R)(2,6-dimethylpyridinyl)(morpholinyl)
oxoethyl][(1S)methylpropyl]piperazine-2,5-dione); Retosiban ((3R,6R)[(2S)-butanyl](2,3-
dihydro-1H-indenyl)[(1R)(2-methyl-1,3-oxazolyl)(morpholinyl)oxoethyl]piperazine-
2,5-dione); PF-3274167 (5-(3-(3-(2-chlorofluorophenoxy)azetidinyl)(methoxymethyl)-4H-1,2,4-
triazolyl)methoxypyridine); and L-368,899 hydrochloride (CAS 1489270); L-371,257 (1-[1-[4-
(1-acetylpiperidinyl)oxymethoxybenzoyl]piperidinyl]-4H-3,1-benzoxazinone). Additional
oxytocin antagonists are also described, e.g., in WO2004020414 and WO2005/028452, which are hereby
incorporated by reference in their entirety. Preferably, the antagonist is selected from barusiban, atosiban,
OBE001/ AS-602305, PF-3274167 Epelsiban, and retosiban.
Preferably, the oxytoxin receptor antagonist is formulated in a pharmaceutical
composition. The composition may also include pharmaceutically acceptable additives such as
preservatives, diluents, dispersing agents, agents to promote mucosal absorption (examples of which are
disclosed by Merkus, F. W. H. M. et al., J. Controlled Release 24, 201-208, 1993, and which include
surfactants, bile acids, fusidates, phospholipids and cyclodextrins), buffering agents and flavourings. Such
compositions may be formulated as solids (for example as tablets, capsules or powders) or liquids (for
example as solutions or suspensions), which is here taken to include creams and ointments, for oral or
parenteral administration. Oral (including sublingual and buccal), intranasal, pulmonary, transdermal,
rectal, vaginal, subcutaneous, intramuscular and intravenous administration may all be suitable routes for
dosing.
In some embodiments, the pharmaceutical composition can be delivered in a sustained or
delayed release system. For example, the antagonist may be administered using a transdermal patch or
formulated in lipophilic depots (e.g. fatty acids, waxes, oils). As used herein, a sustained or delayed
release system ensures that the antagonist is also present in the subject at a time point after administration,
e.g., several hours or even several days after administration. Such sustained or delayed release systems
allow the administration of the receptor antagonists before the female is in a receptive endometrium stage.
The sustained or delayed release, however, ensures that a sufficient amount (or rather a therapeutically
effective amount) of the antagonist is still present when the female enters the receptive endometrium
stage and/or when the embryo has reached the blastocyst-stage.
In embodiments where the female is undergoing transfer of a cleavage-stage embryo, the
antagonist should be released when the cleavage-stage embryo has developed into a blastocyst-stage
embryo and/or when the female has reached the receptive endometrium stage. If an immediate release
formulation is used, then the antagonist should be administered several days after embryo transfer,
preferably two or three days after embryo transfer as this will correspond to the time when the cleavage-
stage embryo has developed into a blastocyst-stage embryo and/or when the female has reached the
receptive endometrium stage. If sustained or delayed release formulations are used, these may be
administered earlier, for example on the day of embryo transfer, provided that the antagonist is released
when the cleavage-stage embryo has developed into a blastocyst-stage embryo and/or when the female
has reached the receptive endometrium stage.
In embodiments where the female is undergoing transfer of a blastocyst-stage embryo,
the antagonist should be released on the same day as embryo transfer (e.g., within the same 24 hour
period), as this will correspond to the time when the embryo has reached the blastocyst-stage and the
female has reached the receptive endometrium stage. Preferably, the antagonist is administered between 2
hours prior to and 2 hours post embryo transfer. More preferably, the antagonist is administered twice. In
an exemplary embodiment using barusiban, the first administration may take place around 45 minutes
prior to embryo transfer and the second administration around 60 minutes after the first administration.
[0081] As is well-known to a skilled person, the timing of administration is dependent of the
particular antagonist used, in particular on the half-life of the antagonist. Antagonists with relatively short
half-lives may need to be administered multiple times in order to ensure that their effects overlap the
blastocyst-stage and/or the receptive endometrium stage.
References
Ayoubi J-M, Epiney M, Brioschi PA, Fanchin R, Chardonnens D, de Ziegler D. Comparison of
changes in uterine contraction frequency after ovulation in the menstrual cycle and in in vitro fertilization
cycles. Fertil Steril 2003; 79: 1101-1105.
Bergh PA, Navot D. The impact of embryonic development and endometrial maturity on the
timing of implantation. Fertil Steril 1992; 58: 537-542.
Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte
recipients. Hum Reprod 2006; 21: 364-369.
Blockeel C, Pierson R, Popovic-Todorovic B, Visnova H, García-Velasco JA, Mrázek M, Chou
P-Y, Wu M-H, Pan H-A, Hung K-H, Chang F-M. Use of an oxytocin antagonist in in vitro fertilization-
embryo transfer for women with repeated implantation failure: a retrospective study. Taiwan J Obstet
Gynecol 2011; 40: 136-140.
Fanchin R, Righini C, Olivennes F, Taylor S, de Ziegler D, Frydman R. Uterine contractions at
the time of embryo transfer alter pregnancy rates after in-vitro fertilization. Hum Reprod 1998; 13: 1968-
1974.
Fanchin R, Righini C, de Ziegler D, Olivennes F, Ledée N, Frydman R. Effects of vaginal
progesterone administration on uterine contractility at the time of embryo transfer. Fertil Steril 2001; 75:
1136-1140.
Fuchs A-R, Behrens O, Maschek H, Kupsch E, Einspanier A. Oxytocin and vasopressin receptors
in human and uterine myomas during menstrual cycle and early pregnancy. Hum Reprod Update 1998; 4:
594-604.
Killick SR. Ultrasound and the receptivity of the myometrium. RBM Online 2007; 15: 63-67.
Kim CH, Lee JW, Jeon IK, Park E, Lee YJ, Kim SH, Chae H, Kang BM, Lee HA. Administration
of oxytocin antagonist improves the implantation rates in patients with repeated failure of IVF/ICSI
treatment. Hum Reprod 2008; 23 (Suppl. 1): i124.
Koot YEM, Macklon NS. Embryo implantation: biology, evaluation, and enhancement. Curr
Opin Obstet Gynecol 2013; 25: 274-279.
Lan VT, Khang VN, Nhu GH, Thuong HM. Atosiban improves implantation and pregnancy rates
in patients with repeated implantation failure. RBM Online 2012; 25: 254-260.
Lesny P, Killick SR, Tetlow RL, Robinson J, Maguiness SD. Embryo transfer – can we learn
anything new from the observation of junctional zone contractions? Hum Reprod 1998; 13: 1540-1546.
Liang YL, Kuo TC, Hung KH, Chen TH, Wu MH. Oxytocin antagonist for repeated implantation
failure and delay of delivery. Taiwan J Obstet Gynecol 2009; 48: 314-316.
Makrigiannakis A, Minas V. Mechanisms of implantation. RBM Online 2006; 14: 102-109.
Moon HS, Park SH, Lee JO, Kim KS, Joo BS. Treatment with piroxicam before embryo transfer
increases the pregnancy rate after in vitro fertilization and embryo transfer. Fertil Steril 2004; 82: 816-
820.
Moraloglu O, Tonguc E, Turgut V, Zeyrek T, Batıoglu S. Treatment with oxytocin antagonists
before embryo transfer may increase implantation rates after IVF. RBM Online 2010; 21: 338-343.
Ng EH, Li RH, Chen L, Lan VT, Tuong HM, Quan S. A randomized double blind comparison of
atosiban in patients undergoing IVF treatment. Hum Reprod 2014; 29: 2687-2694.
Papanikolaou EG, Kolibianakis EM, Tournaye H, Venetis CA, Fatemi H, Tarlatzis B and
Devroey P. Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in
IVF. A systematic review and meta-analysis. Hum Reprod 2008; 23: 91-99.
Pierzynski P, Reinheimer TM, Kuczynski W. Oxytocin antagonists may improve infertility
treatment. Fertil Steril 2007; 88: e19-e22.
Richter ON, Bartz C, Dowaji J, Kupka M, Reinsberg J, Ulrich U, Rath W. Contractile reactivity
of human myometrium in isolated non-pregnant uteri. Hum Reprod 2006; 21: 36-45.
Schoolcraft WB, Surrey ES, Gardner DK. Embryo transfer: techniques and variables affecting
success. Fertil Steril 2001; 76: 863-870.
Simón C, Martin JC, Pellicer A. Paracrine regulators of implantation. Clin Obstet Gynaecol 2000;
14: 815-826.
Shukovski L, Healy DL, Findlay JK. Circulating immunoreactive oxytocin during the human
menstrual cycle comes from the pituitary and is estradiol dependent. J Clin Endocrinol Metab 1989; 68:
455-460.
Strowitzki T, Germeyer A, Popovici R, Wolff M. The human endometrium as a fertility-
determining factor. Hum Reprod Update 2006; 12: 617-630.
Zhu L, Che HS, Xiao L, Li YP. Uterine peristalsis before embryo transfer affects the chance of
clinical pregnancy in fresh and frozen-thawed embryo transfer cycles. Hum Reprod 2014; 29: 1238-1243.
All patent and literature references cited in the present specification are hereby
incorporated by reference in their entirety.
The invention is further explained in the following examples. These examples do not
limit the scope of the invention, but merely serve to clarify the invention.
EXAMPLES
Example 1: A randomized, placebo-controlled, double-blind, parallel groups, multinational, multicenter
trial assessing the effect of barusiban administered subcutaneously on the day of transfer on implantation
and pregnancy rates in IVF/ICSI patients
Methodology
BASIC was a randomized, double-blind, placebo-controlled, parallel groups,
multinational, multicenter trial. It was designed to evaluate the effects of barusiban, administered either
on the day of cleavage-stage embryo transfer or on the day of blastocyst transfer, on ongoing implantation
rate in IVF/ICSI patients. The patients underwent controlled ovarian stimulation in the long GnRH
agonist or GnRH antagonist protocol, received hCG for triggering of final follicular maturation, had
undergone oocyte retrieval, and had daily luteal phase support by supplementation with vaginal
progesterone starting on day 1 post-retrieval, and transfer on day 3 or 5 post-retrieval. Patients were
randomized in a 1:1 ratio to either the barusiban group or the placebo group, with stratification according
to the day of transfer (day 3 post-retrieval or day 5 post-retrieval) and the number of embryos/blastocysts
to be transferred (1 or 2). In total, 255 IVF/ICSI patients were randomized in the trial and contributing
with 440 embryos/blastocysts.
Investigational medicinal product, i.e., barusiban or placebo according to randomization,
was administered as subcutaneous injections at two time points: 1st administration of 40 mg barusiban or
placebo was 45 min prior to transfer and the 2nd administration of 10 mg barusiban or placebo was 60
min after the 1st administration.
Transfer was performed on day 3 (cleavage-stage embryos) or day 5 (blastocysts) after
oocyte retrieval. On day 3, only embryos of good quality defined as ≥ 6 blastomeres and ≤ 20%
fragmentation were transferred. On day 5, blastocysts with expansion and hatching status 3, 4, 5 or 6 were
transferred. The actual number of transferred embryos/blastocysts for each individual patient depended on
the availability of embryos/blastocysts of the required morphological quality, local regulations and
clinical practice for the patient’s age, but the maximum number was 2.
Key aspects related to the transfer procedure had been standardized. A speculum was
inserted into the vagina and cleaning of the vagina and cervix was done according to local practices but
with minimal manipulation and disturbance. Soft or ultrasoft catheters were used. The outer sheath of the
catheter was inserted just protruding to the internal os (i.e. keeping the outer sheath in the cervical canal).
The embryo(s)/blastocyst(s) were loaded into the inner sheath which was then inserted through the outer
sheath. Using abdominal ultrasound guidance, the embryo(s)/blastocyst(s) were placed 1.5-2.0 cm from
the fundus. The time from loading the inner catheter to placing the embryo(s)/blastocyst(s) should not
have exceeded 1 min. After placement, the inner and outer catheters were withdrawn and checked for
retained embryo(s)/blastocyst(s), mucus and blood. After confirmation that there were no
embryo(s)/blastocyst(s) left in the catheters, the speculum was subsequently removed; this occurred
approximately within 2 min after placement of the embryo(s)/blastocyst(s). Any difficulties/eventualities
occurring during the transfer procedure were recorded.
Patients received vaginal progesterone tablets 100 mg twice daily from the day after
oocyte retrieval and until the day of the clinical pregnancy visit. On the day of transfer, patients should
insert the progesterone tablets at least 3 hours before transfer and at least 3 hours after transfer. Ongoing
implantation rate (primary endpoint) was defined as the number of intrauterine viable fetuses 10-11 weeks
after transfer divided by number of embryos/blastocysts transferred.
With respect to statistical methodology, the primary hypothesis was tested using a
logistic regression model with ongoing implantation (yes/no) as the outcome and treatment and
randomization strata as factors. The treatment effect is presented on the odds ratio scale, as this represents
the outcome of the logistic regression analysis; an analysis that allows for inclusion of factors and co-
variates. It must be stressed that the odds ratio based on the logistic regression model provides the most
appropriate way of representing the data and the basis for evaluation of treatment effect.
Several factors impact the probability of a successful outcome of an embryo transfer,
including the day of transfer, the number of embryos/blastocyst transferred, and the quality of the
embryo/blastocyst transferred. The randomization was stratified for the first two of these factors ensuring
comparable groups. However, as the embryos develop continuously it was not feasible to stratify for the
quality of the transferred embryo/blastocyst. Instead, adjustment for the quality of the embryo/blastocyst
was included in the primary analysis.
Results
The impact of treatment on the different receptivity stages and implantation potential of
cleavage-stage embryos and blastocysts was apparent, as illustrated by overall ongoing implantation rates
of 19% for day 3 post-retrieval transfers and 38% for day 5 post-retrieval transfers. The same pattern was
observed in both the barusiban and placebo groups.
The observed overall (day 3 + day 5) ongoing implantation rate in the trial was 27.1% for
barusiban and 28.2% , corresponding to an odds ratio of 1.1 (95% confidence interval 0.7- 1.8;
p=0.6960), i.e., in favor of barusiban but not significant. Therefore, the primary endpoint for the overall
trial population was not met, but as described below this was because the day of transfer had an
interaction. Transfer of cleavage-stage embryos on day 3 post-retrieval yielded an odds ratio of 0.3 (0.3-
1.2; p=0.1509) (Figure 2). Analysis of the day 5 post-retrieval strata resulted in an odds ratio of 2.3 (1.1-
4.7; p=0.0270) and thereby demonstrated a significant treatment effect of barusiban on ongoing
implantation rate for blastocyst transfers (Figure 2). An odds ratio of 2.3 corresponds to adjusted means of
ongoing implantation rates for blastocyst transfers of 45% for barusiban vs 27% for placebo (relative ∆ of
67%) (Figure 3).
The results from the BASIC trial indicated that interpretation of the effects of an oxytocin
antagonist on implantation rate was affected by day of transfer; cleavage-stage embryo transfer (day 3
post-retrieval) or blastocyst transfer (day 5 post-retrieval). No effect on ongoing implantation rate was
established for barusiban when cleavage-stage embryo transfer was done on day 3 (pre-receptive stage).
However, a significant (p=0.0270) effect of barusiban on improving ongoing implantation rate was
observed when blastocyst transfer was done on day 5 (receptive stage).
The BASIC trial identified the time window for a clinically relevant impact of barusiban,
or generally for oxytocin antagonists and mixed oxytocin/vasopressin antagonists, on implantation, which
was not predicted in advance of the trial. An effect on implantation rate is seen when the oxytocin
antagonist is administered at the time of implantation, on day 5 post-retrieval (or later), but not in the
early luteal phase on day 2-3 post-retrieval.
The lack of a consistent effect between day 3 post-retrieval cleavage-stage embryo
transfers and day 5 post-retrieval blastocyst transfers is of importance for the hypotheses on the
mechanisms related to uterine contractility and consequences for cycle outcome. For both days, the dose
and method of administration of pharmacological intervention as well as the transfer procedure were the
same. Therefore, the mechanisms proposed such as expulsion or dispersion of embryos/blastocysts due to
uterine contractility in the early luteal phase or due to the embryo/blastocyst transfer procedure should no
Data presented in this document are for the per-protocol (PP) population. Similar results were observed for the
intention-to-treat (ITT) population. For example, the ongoing implantation rate for the ITT population was 26.2%
for barusiban and 27.9% for placebo.
The odds ratios are based on the logistic regression model, for which the analyses are adjusted for site, primary
reason for infertility and embryo/blastocyst quality.
longer be considered potential explanations for improvement of implantation rates with utero-relaxant
agents, including oxytocin antagonists or mixed oxytocin/vasopressin antagonists. In case these
mechanisms were the most relevant, the findings should have been the same for day 3 and day 5 post-
retrieval observations.
Claims (31)
1. Use of an oxytocin receptor antagonist in the manufacture of a medicament for use in increasing ongoing implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or 5 increasing live birth rate, in a human female subject undergoing embryo transfer as part of an assisted reproductive technology, wherein the antagonist is to be provided to the female such that the effect of the antagonist overlaps with the receptive endometrium stage in said female and the antagonist is to be provided to the female such that the effect of the antagonist is present when the embryo has reached the blastocyst-stage.
2. The use of an oxytocin receptor antagonist according to claim 1, wherein the receptive endometrium stage corresponds to: a) between LH+6 to LH+9 of a natural ovulation cycle; b) between hCG+6 to hCG+9 of an induced ovulation cycle; 15 c) between day 4 to day 7 of luteal phase support following oocyte retrieval; d) between day 4 to day 9 of luteal phase support.
3. The use of an oxytocin receptor antagonist according to claim 2, wherein the receptive endometrium stage corresponds to: 20 a) between LH+6 to LH+8, of a natural ovulation cycle; b) between hCG+6 to hCG+8 of an induced ovulation cycle; c) between day 4 to day 6 of luteal phase support following oocyte retrieval; d) between day 5 to day 7 of luteal phase support. 25
4. The use of an oxytocin receptor antagonist according to claim 2 or 3, wherein the luteal phase support comprises supplementation with progesterone, estradiol and progesterone, human chorionic gonadotropin, progestins and/or gonadatropin releasing hormone (GnRH) agonists.
5. The use of an oxytocin receptor antagonist according to any one of the preceding claims, wherein 30 the female is undergoing transfer of a blastocyst-stage embryo and the antagonist is to be provided to the female such that the antagonist is released on the day of embryo transfer.
6. The use of an oxytocin receptor antagonist according to claim 5, wherein the antagonist is to be administered to the female on the day of embryo transfer.
7. The use of an oxytocin receptor antagonist according to claim 4 or 5, wherein the antagonist is to 5 be administered between 2 hours prior to and 2 hours post embryo transfer.
8. The use of an oxytocin receptor antagonist according to claim 7, wherein the antagonist is to be administered twice. 10
9. The use of an oxytocin receptor antagonist according to claim 8, wherein the first administration occurs around 45 minutes prior to embryo transfer and the second administration occurs around 60 minutes after the first administration.
10. The use of an oxytocin receptor antagonist according to any one of claims 5-9, wherein the 15 blastocyst-stage embryo has an expansion and hatching status of 3, 4, 5, or 6.
11. The use of an oxytocin receptor antagonist according to claim 10 wherein the blastocyst-stage embryo is a day 5 post-fertilization embryo. 20
12. The use of an oxytocin receptor antagonist according to any one of claims 1-4, wherein the female is undergoing transfer of a cleavage-stage embryo and the antagonist is to be provided to the female such that the antagonist is released two or three days after embryo transfer.
13. The use of an oxytocin receptor antagonist according to claim 12, wherein the antagonist is to be 25 administered to the female two or three days after embryo transfer.
14. The use of an oxytocin receptor antagonist according to claim 12 or 13, wherein the cleavage- stage embryo has at least 6 blastomeres and fragmentation of 20% or less. 30
15. The use of an oxytocin receptor antagonist according to claim 14, wherein the cleavage-stage embryo is a day 2 or day 3 post-fertilization embryo.
16. The use of an oxytocin receptor antagonist according to any one of the preceding claims, wherein the antagonist is a selective oxytocin receptor antagonist or a vasopressin/oxytocin receptor antagonist.
17. The use of an oxytocin receptor antagonist according to claim 16, wherein the antagonist is 5 barusiban.
18. The use of an oxytocin receptor antagonist according to claim 17, wherein barusiban is to be provided subcutaneously. 10
19. The use of an oxytocin receptor antagonist according to claim 17 or 18, wherein between 30-80 mg of barusiban is to be administered.
20. The use of an oxytocin receptor antagonist according to claim 19, wherein 50mg of barusiban is to be administered.
21. The use of an oxytocin receptor antagonist for use according to any one of claims 17-20 wherein the female is undergoing transfer of a blastocyst-stage embryo and barusiban is to be administered to the female on the same day as embryo transfer. 20
22. The use of an oxytocin receptor antagonist according to claim 21, wherein 40 mg barusiban is to be administered subcutaneously 45 minutes prior to embryo transfer and 10 mg barusiban is to be administered subcutaneously 60 minutes after the first administration.
23. A use as claimed in any one of claims 1-22 substantially as herein described and exemplified.
24. A method for increasing ongoing implantation rate, increasing ongoing pregnancy rate, increasing clinical pregnancy rate, and/or increasing live birth rate, in a non-human female mammal undergoing embryo transfer as part of an assisted reproductive technology, wherein the antagonist is to be provided to the female such that the effect of the antagonist overlaps with the receptive endometrium 30 stage in said female and the antagonist is to be provided to the female such that the effect of the antagonist is present when the embryo has reached the blastocyst-stage.
25. The method of claim 24, wherein the female mammal is undergoing transfer of a blastocyst-stage embryo and the antagonist is to be administered to the female on the day of embryo transfer.
26. The method according to claim 25, wherein the blastocyst-stage embryo is a day 5 post- 5 fertilization embryo.
27. The method of claim 24, wherein the female is undergoing transfer of a cleavage-stage embryo and the antagonist is to be provided to the female such that the antagonist is released two or three days after embryo transfer.
28. The method according to claim 27, wherein the antagonist is to be administered to the female two or three days after embryo transfer.
29. The method according to claim 27 or 28, wherein the cleavage-stage embryo is a day 2 or day 3 15 post-fertilization embryo.
30. The method according to any one of claims 24-29, wherein the antagonist is barusiban.
31. A method as claimed in any one of claims 24-30 substantially as herein described and 20 exemplified.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14199709.8A EP3037101B1 (en) | 2014-12-22 | 2014-12-22 | Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies |
EP14199709.8 | 2014-12-22 | ||
US14/643,307 US9579305B2 (en) | 2014-12-22 | 2015-03-10 | Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies |
US14/643,307 | 2015-03-10 | ||
PCT/NL2015/050893 WO2016105190A1 (en) | 2014-12-22 | 2015-12-21 | Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ733869A NZ733869A (en) | 2020-10-30 |
NZ733869B2 true NZ733869B2 (en) | 2021-02-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11752157B2 (en) | Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies | |
Neglia et al. | Reproductive management in buffalo by artificial insemination | |
Erb et al. | Gonadotropin-releasing hormone agonist or human chorionic gonadotropin for final oocyte maturation in an oocyte donor program | |
Brasil et al. | Superovulatory and embryo yielding in sheep using increased exposure time to progesterone associated with a GnRH agonist | |
AU2020104306B4 (en) | Method for enhancing assisted breeding techniques | |
NZ733869B2 (en) | Oxytocin receptor antagonist therapy in the luteal phase for implantation and pregnancy in women undergoing assisted reproductive technologies | |
JP2023527221A (en) | Compositions containing HP-HMG for use in treating infertility | |
Ayres et al. | Superovulation in goats during the second follicular wave, with or without exogenous progesterone | |
EA042397B1 (en) | USE OF THE OXYTOCIN RECEPTOR ANTAGONIST AS PART OF ASSISTED REPRODUCTIVE TECHNOLOGIES | |
Brasil et al. | Synchronization of follicular wave emergence does not improve embryonic yield in superovulated ewes | |
Kahraman et al. | The effect of endometrial polyps on pregnancy rates in intracytoplasmic sperm injection cycles | |
Akın et al. | Comparison of GnRH antagonist and agonist mini-dose long protocols in infertile cases undergoing controlled ovarian hyperstimulation | |
WO2020061612A1 (en) | Method for enhancing assisted breeding techniques | |
Rajamahendran et al. | Synchronization of estrus and ovulation in cattle | |
Patrizio et al. | The Role of Assisted Reproduction in the Cancer Patient | |
Ganla et al. | A Prospective Comparative Interventional Study of Dydrogesterone (Progestin Primed Ovarian Stimulation) Versus Ganirelix Acetate (GnRh Anatgonist) for Freeze-all IVF/ICSI Cycles | |
Bessow et al. | Desogestrel for preventing a premature luteinizing hormone (LH) surge in a cycle for oocyte cryopreservation | |
Takenaka et al. | Case of ovarian hyperstimulation and oocyte pick‐up during very early period of unnoticed pregnancy followed by ongoing normal pregnancy | |
LeBlanc | An approach to the diagnosis of infertility in the mare. | |
Zuluaga Velez | Pre-and post-synchronization methodologies to enhance the efficiency of fixed timed artificial insemination in pharmacologically-controlled breeding systems with Bos indicus-influenced cattle | |
Shamma et al. | P-33: Comparison of daily cetrorelix acetate administration to a long leuprolide acetate protocol for controlled ovarian hypersimulation in oocyte donors: The results of a prospective randomized controlled trial | |
Chen et al. | Leuplin increases pregnancy rates of IVF in patients with severe endometriosis |