EP0739352A1 - Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivität - Google Patents
Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivitätInfo
- Publication number
- EP0739352A1 EP0739352A1 EP95907574A EP95907574A EP0739352A1 EP 0739352 A1 EP0739352 A1 EP 0739352A1 EP 95907574 A EP95907574 A EP 95907574A EP 95907574 A EP95907574 A EP 95907574A EP 0739352 A1 EP0739352 A1 EP 0739352A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- isoforms
- mean
- fsh
- org
- glycoprotein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 102000001708 Protein Isoforms Human genes 0.000 title claims abstract description 55
- 108010029485 Protein Isoforms Proteins 0.000 title claims abstract description 55
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 108090000288 Glycoproteins Proteins 0.000 title claims abstract description 32
- 102000003886 Glycoproteins Human genes 0.000 title claims abstract description 31
- 230000004936 stimulating effect Effects 0.000 title claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000035800 maturation Effects 0.000 claims abstract description 6
- 230000003325 follicular Effects 0.000 claims abstract description 5
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 claims description 64
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 claims description 64
- 229940028334 follicle stimulating hormone Drugs 0.000 claims description 64
- 229940088597 hormone Drugs 0.000 claims description 3
- 239000005556 hormone Substances 0.000 claims description 3
- 150000002482 oligosaccharides Polymers 0.000 claims description 3
- 230000002255 enzymatic effect Effects 0.000 claims description 2
- 230000000624 ovulatory effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 210000000287 oocyte Anatomy 0.000 abstract description 26
- 108010081934 follitropin beta Proteins 0.000 description 50
- ZDRRIRUAESZNIH-BZGUUIOASA-N (2s)-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2s)-butan-2-yl]-10-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-n-[(2s)-1-[(2-amino-2-oxoethyl)amino]- Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@H](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)[C@@H](C)O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZDRRIRUAESZNIH-BZGUUIOASA-N 0.000 description 43
- 108010047196 Urofollitropin Proteins 0.000 description 37
- 238000002360 preparation method Methods 0.000 description 19
- 238000011098 chromatofocusing Methods 0.000 description 14
- 230000002378 acidificating effect Effects 0.000 description 12
- 238000009826 distribution Methods 0.000 description 12
- 108010082302 Human Follicle Stimulating Hormone Proteins 0.000 description 11
- 102000003864 Human Follicle Stimulating Hormone Human genes 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000013256 coordination polymer Substances 0.000 description 10
- 238000011084 recovery Methods 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 108010037003 Buserelin Proteins 0.000 description 6
- 238000003744 In vitro fertilisation Methods 0.000 description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone 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 description 6
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 6
- 229960002719 buserelin Drugs 0.000 description 6
- 206010042573 Superovulation Diseases 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000002611 ovarian Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 150000001720 carbohydrates Chemical group 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000002257 embryonic structure Anatomy 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000001817 pituitary effect Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 239000012149 elution buffer Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000000509 infertility Diseases 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 231100000535 infertility Toxicity 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000029849 luteinization Effects 0.000 description 3
- 210000001161 mammalian embryo Anatomy 0.000 description 3
- 230000027758 ovulation cycle Effects 0.000 description 3
- 239000000186 progesterone Substances 0.000 description 3
- 229960003387 progesterone Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 208000007466 Male Infertility Diseases 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 230000004720 fertilization Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011599 ovarian follicle development Effects 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000009774 Follicular Cyst Diseases 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004198 anterior pituitary gland Anatomy 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000013590 bulk material Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019624 protein content Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/59—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g.hCG [human chorionic gonadotropin]; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- FSH is produced and secreted by the pituitary in different molecular forms (isohormones or isoforms), which vary in overall charge, receptor binding affinity, biological activity, and plasma residence time. This micro-heterogeneity is due to differences in the amount and/or composition of the carbohydrate residues, in particular sialic acid. Multiple forms of gonadotropins have been isolated and characterised from anterior pituitary glands, serum and urine of several non-mammalian and mammalian species, including man. Relatively acidic FSH isoforms, which are more heavily sialylated, exhibit lower receptor affinity and in vitro biological activities than more basic isoformes. However, due to their longer plasma residence time these more acidic forms have greater in vivo biological activities (UUoa- Aguirre et al., 1988, Hum.Reprod., 3, 491-501).
- FSH is used for ovulation induction and controlled ovarian stimulation in in vitro fertization (INF).
- the aim of controlled superovulation is to increase the number of retrievable mature oocytes for INF and subsequent embryo transfer (ET). Generally, up to three embryos are replaced per transfer. As usually more than one treatment is necessary, in most infertility clinics spare embryos or fertilized oocytes are frozen and transferred in subsequent cycles. Assuming normal fertilization, the more oocytes retrieved the higher the number of possible transfers and thus the higher the chance of a woman to become pregnant after one treatment cycle. In case of male infertility, the chances of establishing fertilization, and thus pregnancy, also increases with the number of oocytes recovered.
- FSH preparations have been used which have been isolated from natural sources. Isohormone distribution profiles of commercially available preparations have been reported (e.g. Harlin et al, 1986, Fert. Ster., 46, 1055-1061). It appears that these FSH compositions consist of relatively acidic isohormone fractions.
- glycoprotein isoforms with isoelectric points in between and extending from the range 4.8 to 4.2 , having follicle stimulating activity which consists for more than 15% of isoforms with isoelectric points above 4.8 and for less than 30% of isoforms with isoelectric points below 4.2 , when used in the same clinical settings, exert a better effect than the known glycoprotein compositions.
- glycoprotein isohormone mixture according to the invention contains a relatively high proportion of relatively basic isoforms.
- This can be established by having glycoprotein isoform compositions having more than 15% of the isoforms with isoelectric points above 4.8 and less than 30% below 4.2 , also preferably, isoforms mixtures can be used wherein more than 15% of the isoforms have isoelectric points above 4.8 and less than 25% below 4.2 , also preferably more than 25% of the isoforms have isoelectric points above 4.8 and less than 25% below 4.2 , also preferably more than 25% of the isoforms have isoelectric points above 4.8 and less than 20% below 4.2
- the percentage of the isoforms as used herein is defined as the relative amount of immunoreactive isoforms recovered after chromatofocussing.
- protein contents can be determined by colorimetric assays.
- glycoproteins according to this invention may be derived from urinary origin.
- the number and relative amount of each isoform species depends on the source
- the glycoprotein might also be a recombinant glycoprotein.
- recombinant FSH FSH
- the charge heterogeneity is determined by the host cell-line chosen for its production as well as cell culture conditions.
- glycoproteins such as FSH
- CHO Chinese Hamster Ovary
- a recombinant FSH preparation according to this invention can be produced by a CHO cell line stably transfected with a plasmid containing the two subunit genes encoding human FSH (hFSH).
- FSH preparations according to the invention can be selected based upon their chromatofocusing profile.
- the profile can be influenced by a particular host cell line choice or by adaptation of culture conditions.
- basic isohormones can be obtained by expression of recombinant FSH in cell lines which are impaired in glycosylation.
- a cell line might be e.g. a cell line deficient in the enzyme N-acetylglucosamine transferase or in sialic acid transport into the Golgi (Galway et al., 1990, Endocrinology, 127, 93-100).
- inventions are basic glycoprotein isoforms mixtures obtained by enzymatic or chemical modification. With such a treatment parts of the carbohydrate chains can be removed without affecting the amino acid sequence. Glycoprotein batches can e.g. be treated with HF (Chen et al, 1982, J.Biol.Chem., 257, 14446- 14452). Partial desialylation can be performed by enzymatic hydrolysis with neuraminidase (Vaitukaitis and Ross, 1971, J.Clin.Endocrinol.- Metab., 55, 308-311).
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising these glycoprotein isoforms admixed with pharmaceutically acceptible auxiliairies.
- Methods for making preparations and admixtures are disclosed in Remingtons 's Pharmaceutical Sciences, pp. 1463-1497 (16th ed. 1980, Mack Publ. Co of Easton, Pa, USA).
- ampoules containing the pharmaceutical composition according to the invention may contain 1 to 1000 ⁇ g of the glycoprotein mixture (e.g. 75 IU is considered a therapeutic amount).
- Such mixtures can also be prepared by isolation of only basic isoforms e.g. by preparative chromatofocussing. Preferably such isoforms have an isoelectric point above 4.2 . It will be clear that fractionation of isoform mixtures can be performed on glycoprotein batches obtained from different origins such as preparations isolated from urine or recombinant DNA cell lines which may or may not be chemically or enzymatically modified.
- compositions according to this invention can be used in clinical treatments in combination with e.g. GnRH antagonists or agonists and/or LH activity e.g. HCG or LH to induce superovulation.
- GnRH antagonists or agonists and/or LH activity e.g. HCG or LH to induce superovulation.
- LH activity e.g. HCG or LH to induce superovulation.
- hFSH isoelectric point
- Chromatofocusing was performed in the range of pH 6-3 on a fast protein liquid chromatography (FPLC) column HR 5/20 (Pharmacia, Woerden, The Netherlands) packed with polybuffer exchanger 94
- FSH immunoreactivity was measured in a two-site sandwich enzyme immunoassay, using a ⁇ -directed capturing antibody (monoclonal antibody 4B) and an ⁇ -directed HRP-labeled detection antibody (monoclonal antibody 116B) as described previously (Mannaerts et al., 1991, Endocrinology, 129, 2623-2630). This assay recognises only intact dimers and was found to detect all FSH isoforms equally well.
- the assay sensitivity in terms of IS 70/45 was 0.4 IU/1 and the intra- and interassay coefficients of variations were 7% and 8%, respectively.
- the cross-reactivity with hLH and hCG was ⁇ 0.01 % and ⁇ 0.01 % , respectively
- the study was designed as a multicentre, randomized, assessor- blind, group-comparative study, in which safety and efficacy of Org 32489 and Metrodin R were compared in infertile pituitary-suppressed subjects undergoing in vitro fertilisation (IVF) and embryo transfer (ET). Approximately one thousand subjects were included in this study with a ratio between subjects treated with Org 32489 and with Metrodin R of 3:2. The study period covered no more than 3 treatment cycles. Analysis of efficacy included first treatment cycles only.
- Inclusion criteria At least 18 and at most 39 years of age at the time of screening;
- Infertility caused by endocrine abnormalities such as hyperprolactinaemia, polycystic ovary syndrome, and absence of ovarian function;
- Male infertility defined according to the following criteria: ⁇ 10x10 ⁇ sperms per mL and/or ⁇ 40% normal morphology and/or 40% normal motility;
- the total number of oocytes recovered in the first treatment cycle was a primary efficacy variable.
- Other analysed variables in the first treatment cycle were the number of FSH ampoules administered for ovarian stimulation and the duration of FSH treatment.
- the outcome of these parameters were analysed by means of Cochran's method of combining individual centre results.
- the Wilcoxon rank sum test and an analysis of variance (ANOVA) were applied to consolidate the outcome of Cochran's method.
- the number of oocytes recovered in each treatment group per centre is presented in Table 3.
- the overall mean number of oocytes was 10.84 oocytes in the Org 32489 group and 8.95 oocytes in the Metrodin group, resulting in a treatment difference of 1.89 oocytes in favour of Org 32489.
- the difference of 1.89 oocytes is more than 5 times its standard error and highly significant (P ⁇ 0.0001).
- the resulting 95% confidence interval indicated that on the average subjects treated with Org 32489 end up with at least 1.2 and at most 2.6 oocytes more than those treated with Metrodin R . Exclusion of immature oocytes from the total number of recovered oocytes did not influence the treatment effect (see Table 4).
- Percentage basic isoforms defined as FSH immunoreactivity at pi > 4.8
- percentage acidic isoforms defined as FSH immunoreactivity at pi ⁇ 4.2 of the Org 32489 and Metrodin R CP's used to compare the clinical efficacy (see Example 2).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Reproductive Health (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95907574A EP0739352A1 (de) | 1994-01-20 | 1995-01-20 | Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivität |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94200140 | 1994-01-20 | ||
EP94200140 | 1994-01-20 | ||
PCT/EP1995/000212 WO1995019991A1 (en) | 1994-01-20 | 1995-01-20 | New composition of glycoprotein isoforms having follicle stimulating activity |
EP95907574A EP0739352A1 (de) | 1994-01-20 | 1995-01-20 | Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivität |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0739352A1 true EP0739352A1 (de) | 1996-10-30 |
Family
ID=8216602
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95907574A Withdrawn EP0739352A1 (de) | 1994-01-20 | 1995-01-20 | Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivität |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0739352A1 (de) |
JP (1) | JPH09508114A (de) |
CN (1) | CN1138864A (de) |
AU (1) | AU1575195A (de) |
BR (1) | BR9506557A (de) |
CA (1) | CA2181711A1 (de) |
FI (1) | FI962923A0 (de) |
HU (1) | HUT76660A (de) |
WO (1) | WO1995019991A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
AU770933B2 (en) | 1998-12-01 | 2004-03-11 | N.V. Organon | Improvement of folliculogenesis |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1057895B (it) * | 1975-02-17 | 1982-03-30 | Serono Lab | Gonadotropina corionica umana parzialmente desalinizzata per indurre l'ouvulazione |
US5260421A (en) * | 1987-12-21 | 1993-11-09 | Applied Research Systems Ars Holding N.V. | Site-directed mutagenesis modified glycoprotein hormones |
US5087615A (en) * | 1989-03-17 | 1992-02-11 | Applied Research Systems Ars Holding N.V. | Novel method of ovulation induction in humans |
-
1995
- 1995-01-20 HU HU9601975A patent/HUT76660A/hu unknown
- 1995-01-20 BR BR9506557A patent/BR9506557A/pt not_active Application Discontinuation
- 1995-01-20 WO PCT/EP1995/000212 patent/WO1995019991A1/en not_active Application Discontinuation
- 1995-01-20 CN CN 95191276 patent/CN1138864A/zh active Pending
- 1995-01-20 EP EP95907574A patent/EP0739352A1/de not_active Withdrawn
- 1995-01-20 CA CA 2181711 patent/CA2181711A1/en not_active Abandoned
- 1995-01-20 JP JP7519345A patent/JPH09508114A/ja active Pending
- 1995-01-20 AU AU15751/95A patent/AU1575195A/en not_active Abandoned
-
1996
- 1996-07-19 FI FI962923A patent/FI962923A0/fi not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9519991A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1995019991A1 (en) | 1995-07-27 |
HUT76660A (en) | 1997-10-28 |
CA2181711A1 (en) | 1995-07-27 |
FI962923A (fi) | 1996-07-19 |
FI962923A0 (fi) | 1996-07-19 |
CN1138864A (zh) | 1996-12-25 |
BR9506557A (pt) | 1997-10-28 |
AU1575195A (en) | 1995-08-08 |
JPH09508114A (ja) | 1997-08-19 |
HU9601975D0 (en) | 1996-09-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Mclachlan et al. | Plasma inhibin levels during gonadotropin-induced ovarian hyperstimulation for IVF: a new index of follicular function? | |
Al-Hader et al. | Neurons from fetal rat brains contain functional luteinizing hormone/chorionic gonadotropin receptors | |
Ludwig et al. | Ovarian stimulation: from basic science to clinical application | |
US20230357345A1 (en) | Glycoprotein Hormone Long-Acting Superagonists | |
KR20240073153A (ko) | 불임 치료용 조성물 | |
Schwartz et al. | Biological activity of adrenocorticotropic hormone precursors on ovine adrenal cells | |
Roberts | A role for interferons in early pregnancy | |
AU7078391A (en) | Method for inhibiting follicular maturation | |
AU2014346859B2 (en) | Glycoprotein hormone long-acting superagonists | |
Vernon et al. | Role of growth hormone in the regulation of adipocyte growth and function | |
DE3853383T2 (de) | Isolierung von einkettigen proteinen mit fsh unter- drückender aktivität aus follikularflüssigkeit. | |
MacLennan | Relaxin–a review | |
JP5249044B2 (ja) | Fsh突然変異体 | |
JP2009523445A (ja) | 新規fshグリコシル化変異体d3n | |
EP0739352A1 (de) | Neue zusammensetzung von glykoprotein-isoformen mit follikelstimulierenden aktivität | |
Burger | Inhibin, a member of a new peptide family | |
Fauser | Endocrinology and Paracrinology: Interference with follicle stimulating hormone regulation of human ovarian function | |
MXPA96002845A (en) | New composition of glucoprotein isoforms that have a stimulating activity of folicu | |
Geurts et al. | PUREGON"(ORG 32489)-RECOMBINANT HUMAN | |
Chakravorty et al. | Control of peptides regulating mitosis of granulosa cells in immature rat ovary by oestrogen and gonadotrophin | |
JPH10502623A (ja) | O−グリコシル化真正igf−iおよびその切断変種、その製造方法、並びに医薬組成物 | |
Ludwig et al. | Ovarian stimulation: from basic science to clinical application | |
Chappel | Biochemical and biological characterization of LH and FSH expressed by recombinant DNA technology | |
de Kretser | Inhibin, activin, and follistatin: placental production and physiology | |
Shoham | Recombinant human follicle-stimulating hormone: a controversial issue–without controversy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19960820 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI NL PT SE |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 19961227 |