Tungsten (VI) salts for use for increasing ongoing pregnancies, for increasing live birth rates and / or for increasing the biochemical pregnancy rate in infertile women

Abstract

In the present invention it has been found that a tungsten (VI) salt or a solvate thereof can be used in a method of increasing the live birth delivery rate in an infertile women, increasing the ongoing pregnancy rate in infertile women and / or increasing the biochemical pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day and / or following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng·h / ml to 25000ng·h / ml.

Description

[0001] TUNGSTEN (VI) SALTS FOR USE FOR INCREASING ONGOING PREGNANCIES, FOR INCREASING LIVE BIRTH RATES AND / OR FOR INCREASING THE BIOCHEMICAL PREGNANCY RATE IN INFERTILE WOMEN

[0002] The invention relates to the field of fertility. Particularly, it relates to the use of a tungsten (VI) salt or solvate thereof for increasing the ongoing pregnancy rate and / or the live birth rate and / or the biochemical pregnancy rate in infertile women.

[0003] STATE OF THE ART

[0004] Infertility can be defined as the failure to establish a clinical pregnancy after 12 months of regular unprotected sexual intercourse. The WHO assumes that approximately 17.5% of the adult population, roughly 1 in 6 worldwide, are affected. In vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI) followed by embryo transfer (ET) are commonly used procedures used to assist couples trying to become pregnant.

[0005] A number of factors may influence the chances of a successful pregnancy. These include age, eating habits and lifestyle. With respect to age, it is known that pregnancy rate in women 20 to 24 years of age is about 86%, while it diminishes to 50% in women 35 to 32 years of age (Management of the Infertile Woman by Helen A. Carcio; The Fertility Sourcebook by M. Sara Rosenthal, ASAS Summary of FAIR 2012). Other factors such as being overweight or underweight are also responsible for delays in achieving pregnancy naturally or even for the impossibility in achieving same (Fertil Steril 2013;100:631-7).

[0006] Different treatments for female infertility including, among others, the administration of medicinal products for treating hormonal problems involving ovulation disruption (such as, clomiphene citrate or gonadotropins, for example), are known. Likewise, some beneficial effects have been postulated with various treatments based on taking vitamin supplements, particularly vitamin B, vitamin C, vitamin E and folic acid, mineral supplements such as selenium, zinc or iron complexes or salts, essential fatty acids (omega-3), as well as extracts from plants such as chaste tree (Vitex agnus-castus), damiana, licorice, red clover flower, chasteberry, black cohosh, dong quai (Angelica sinensis), wild yam or sweet potato (Dioscorea villosa), false unicorn root, green tea, nettles (Urtica dioica), wild oats (Avena sativa), dandelion (Taraxacum officinale), etc., although the efficacy has not been clearly demonstrated in any of these treatments.

[0007] The percentage of pregnancies achieved by means of the aforementioned treatments has limitations. In this sense, for example, it has been observed that treatment of women with irregular or no ovulation by means of administering clomiphene citrate, a drug of the stilbene family, is able to substantially restore ovulation, but the pregnancy rate remains low, equal to or less than about 35%.

[0008] The present inventors previously reported that tungstate (VI) salts could be used for the treatment of female infertility in non-diabetic mammals (WO 2014 / 114644 A1 ). It was shown that administration of a tungsten (VI) salt was able to restore ovulation and increase zygote implantation in the uterine wall.

[0009] Furthermore, the present inventors also found that the administration of a tungsten (VI) salt or a solvate thereof is effective in treating infertility in a non-diabetic female mammal, for favouring normal reproduction and fertility in a non-diabetic female mammal, and for increasing the efficacy of assisted reproductive techniques applied to a mammal (WO 2016 / 012632 A1 ).

[0010] In both WO 2014 / 114644 A1 and WO 2016 / 012632 A1 IRS2’7- female mice were administered sodium tungstate in an amount of 180 mg / kg / day. IRS2’ / _female mice were chosen as the animal model as they show low follicular development and persistent anovulation, accompanied by the absence of the estrous cycle. The pregnancy rate in IRS2’ / ’female mice is 9% compared to a rate of 100% in IRSwt(IRS- 2+ / +wild type) female mice, as reported in both WO 2014 / 114644 A1 and WO 2016 / 012632 A1 . The in vivo studies on mice having impaired fertility reported in WO 2014 / 114644 A1 and WO 2016 / 012632 A1 show that a tungsten (VI) salt is effective treatment for recovering ovulation and / or increasing oocyte implantation.

[0011] With respect to the dose of sodium tungstate to be administered to recover ovulation and increase oocyte implantation, the FDA guidelines consider that doses used in mice need to be transformed by a factor of 12.3 due to differences in body surface area between humans and mice (Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), July 2005). Therefore, according to the in vivo data in infertile mice, the dose of 180mg / kg / day administered to mice corresponds to a dose of 14.6 mg / Kg / day for a human, which corresponds to a dose of 878.05 mg / day for a 60 kg woman.

[0012] In view of the unpredictability in the field of the treatment of infertility both with respect to finding a suitable dosage and regarding whether a proposed dosage would be successful without having tested it on infertile subjects, finding a dosage regimen for treating infertility is a complex matter.

[0013] SUMMARY OF THE INVENTION

[0014] The present inventors have surprisingly found that despite the results of the in vivo experiments in mice, it is not necessary to use a dose of 14.6 mg / Kg / day of a tungsten (VI) salt in women to treat infertility.

[0015] Furthermore, it has been found that a tungsten (VI) salt or a solvate thereof can be used in a method of increasing the live birth delivery rate in infertile women, increasing the ongoing pregnancy rate in infertile women and / or increasing the biochemical pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day. This corresponds to 1.6 to 6.6 mg / Kg / day in a 60 kg woman. This is substantially less than the dose of 14.6 mg / Kg / day of a tungsten (VI) salt predicted from the in vivo studies conducted in mice.

[0016] Although the present inventors previously demonstrated that a tungsten (VI) salt is able to treat infertility in non-diabetic female mammals, it was not known and it is surprising that administration of a tungsten (VI) salt or a solvate thereof in an amount of only 100 to 400 mg / day is able to increase the live birth delivery rate in infertile women, increase the ongoing pregnancy rate in infertile women and / or increase the biochemical pregnancy rate in infertile women.

[0017] Thus, a first aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0018] A second aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0019] A third aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0020] A further aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0021] An additional aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0022] Another aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0023] BRIEF DESCRIPTION OF THE FIGURE

[0024] Figure 1 : Mean sodium tungstate plasma concentration / time over the course of one day for sodium tungstate doses of 100, 200, 300 and 500 mg / day, wherein the values are expressed as tungsten.

[0025] DESCRIPTION OF THE INVENTION

[0026] As indicated above, a first aspect of the present invention relates to a tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0027] The term “live birth delivery rate” (LBDR) following embryo transfer is defined as the number of deliveries that resulted in at least one live birth per 100 embryo transfer cycles.

[0028] The term “live birth delivery rate” (LBDR) following natural conception is defined as the number of deliveries that resulted in at least one live birth per 100 conceptions.

[0029] Conception occurs when a sperm fertilizes an oocyte.

[0030] The term “live birth” is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age, and after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached.

[0031] The term “infertile” describes a woman who fails to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse.

[0032] As indicated above, a second aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0033] The term “ongoing pregnancy rate” means the number of women with uterine pregnancy and a foetal heartbeat at 10 to 11 weeks following embryo transfer or at 12 weeks following conception per 100 embryo transfer cycles or per 100 conceptions, and wherein the uterine pregnancy and foetal heartbeat is confirmed by ultrasound.

[0034] The term “pregnancy” means a state of reproduction beginning with implantation of an embryo in a woman and ending with the complete expulsion and / or extraction of all products of implantation.

[0035] As indicated above, a third aspect of the present disclosure is a tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0036] The “biochemical pregnancy rate” means the number of women with a biochemical pregnancy per 100 embryo transfer cycles or per 100 conceptions, wherein the biochemical pregnancy is determined by detecting beta hCG (Human chorionic gonadotropin) in serum or urine measured from 10 to 15 days after embryo transfer or around 15 days after conception. For example where [3-hCG > 10 lll / L.

[0037] The term “clinical pregnancy rate” (CPR) means the number of women with a clinical pregnancy per 100 embryo transfer cycles or per 100 conceptions, wherein the clinical pregnancy is determined by ultrasonographic visualization of one or more gestational sacs.

[0038] In addition to intra-uterine pregnancy a clinical pregnancy includes a clinically documented ectopic pregnancy.

[0039] The term “clinical pregnancy rate with heart beat” (CPR with heart beat) means the number of women with clinical pregnancy with heart beat per 100 embryo transfer cycles or per 100 conceptions, wherein the clinical pregnancy with heart beat is determined by ultrasonographic or clinical documentation of at least one intrauterine gestational sac with a discernible heartbeat. This is generally measured at around week 8 following conception, which corresponds to around week 6 following embryo transfer. The term “gestational sac” means a fluid-filled structure associated with early pregnancy, which may be located inside or, in the case of an ectopic pregnancy, outside the uterus.

[0040] As indicated above, following administration of the tungsten (VI) salt or a solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0041] As commonly known in the field of pharmacokinetics, Cmax is the peak plasma concentration of a drug after administration.

[0042] The area under the curve (AUC) is the area under the plasma, serum, or blood concentration-time curve from time zero to time t (AUCo-t), where t is the last time point with a measurable concentration. It is reported in the present disclosure using the units ng h / ml (ng x h / ml).

[0043] All the features listed individually for different elements of the invention in the present disclosure can be combined with one another; all the possible combinations being included within the scope of the present invention.

[0044] Tungstate (VI) salt

[0045] In a particular embodiment of the present disclosure, the tungsten (VI) salt comprises a tungsten (VI) anion and a pharmaceutically, veterinary or dietetically acceptable cation.

[0046] “Pharmaceutically or veterinary acceptable cation” refers to any acceptable, non-toxic, organic or inorganic cation which is capable of forming a therapeutically effective tungsten (VI) salt and is suitable for use thereof in drug or veterinary therapy. The cation is preferably an alkaline or alkaline earth cation.

[0047] The cation is more preferably selected from the group consisting of sodium, potassium, magnesium, calcium and zinc. According to a particular embodiment, the cation is sodium. According to another particular embodiment, the cation is zinc. The tungsten (VI) anion in the tungsten (VI) salt is preferably selected from WO42, HWOT, W2O?2-and HW20?” ions. The anion is preferably WCU2-.

[0048] According to an additional particular embodiment, the solvate of the tungsten (VI) salt is a hydrate, such as a monohydrate or a dihydrate, more preferably a dihydrate.

[0049] In a particularly preferred embodiment of the present disclosure, the tungsten (VI) salt is sodium tungstate.

[0050] The tungsten (VI) salt may be formulated as a pharmaceutical, veterinary or food composition. Excipients or carriers may be used which are suitable for use in pharmaceutical, veterinary, or dietary technology for the preparation of the compositions for medical use. Such excipients include fillers, binders, lubricants, disintegrants and coatings. Examples of such excipients include microcrystalline cellulose, starch, sorbitol, mannitol, crospovidone, sodium croscarmellose, sucrose, lactose, silica, talc, stearic acid and magnesium stearate, among others.

[0051] Administration

[0052] The tungsten (VI) salt or solvate thereof for use for use in increasing the live birth delivery rate in infertile women, for use in increasing the ongoing pregnancy rate in infertile women and / or for increasing the biochemical pregnancy rate in infertile women may be administered at a dose of 100 mg / day to 400 mg / day, preferably the tungstate (VI) salt or solvate thereof is administered at a dose of 150 mg / day to 400 mg / day, more preferably at a dose of 200 mg / day to 400 mg / day, furthermore preferably at a dose of 200 mg / day to 300 mg / day.

[0053] The tungsten (VI) salt or solvate thereof is preferably administered at a dose of 200 mg / day or 300 mg / day.

[0054] In one aspect of the present disclosure sodium tungstate is administered at a dose of 100 mg / day to 400 mg / day, preferably sodium tungstate is administered at a dose of 150 mg / day to 400 mg / day, preferably at a dose of 200 mg / day to 400 mg / day, more preferably at a dose of 200 mg / day to 300 mg / day. In a preferred aspect of the present disclosure sodium tungstate is administered at a dose of 200 mg / day or 300 mg / day, preferably at a dose of 300 mg / day.

[0055] The tungstate (VI) salt or solvate thereof may be administered once, twice, three times, or more a day. Preferably the tungstate (VI) salt or solvate thereof is administered once or twice a day. More preferably, the tungstate (VI) salt or solvate thereof is administered once a day.

[0056] In one aspect of the present disclosure, the tungstate (VI) salt or solvate thereof is administered orally, vaginally, or intravenously, such as intramuscularly or subcutaneously. In a preferred aspect of the present disclosure, sodium tungstate is administered orally or vaginally, preferably orally.

[0057] The tungstate (VI) salt or solvate thereof, which is preferably sodium tungstate, may be administered in the form of a tablet, pastille, capsule, suppository, gel, pessary, powder, wafer, effervescent powder, solution, suspension, syrup or granules.

[0058] Preferably, the tungstate (VI) salt or solvate thereof, which is preferably sodium tungstate, is administered in the form of a tablet or a capsule, most preferably in the form of a tablet. The tablets may be film-coated.

[0059] Each tablet may contain 25 to 400 mg of the tungstate (VI) salt or solvate thereof. Preferably, each tablet contains 100 to 200 mg of the tungstate (VI) salt or solvate thereof. More preferably, each tablet contains 100 to 150 mg of the tungstate (VI) salt or solvate thereof, such as 100 mg or 150 mg of the tungstate (VI) salt or solvate thereof.

[0060] In one embodiment of the present disclosure, the infertile women undergo embryo transfer, and the embryo is a donor oocyte or an autologous oocyte, preferably a donor oocyte.

[0061] The tungstate (VI) salt or solvate thereof, may be administered 15 to 75 days before embryo transfer, preferably 20 to 65 days before embryo transfer. The tungsten (VI) salt or solvate thereof may be administered for up to 80 days after embryo transfer, preferably up to 70 days after embryo transfer, more preferably after 35 days after embryo transfer.

[0062] The tungsten (VI) salt or solvate thereof may be administered 15 to 75 days before embryo transfer, preferably 20 to 65 days before embryo transfer, and up to 45 days after embryo transfer, preferably up to 35 days after embryo transfer.

[0063] The tungstate (VI) salt or solvate thereof is preferably administered at least 2 hours after food intake.

[0064] Following administration of the tungstate (VI) salt or solvate thereof, there is preferably no food intake for at least 1 hour.

[0065] Thus, in a preferred embodiment, the tungstate (VI) salt or solvate thereof is preferably administered at least 2 hours after food intake and following administration, there is preferably no food intake for at least 1 hour. The tungstate (VI) salt or solvate thereof is preferably sodium tungstate.

[0066] Pharmacokinetic characteristics

[0067] Following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma may be 1200 ng / ml to 3200 ng / ml.

[0068] In one embodiment, following administration of the tungstate (VI) salt or solvate thereof the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma may be 1200 ng / ml to 3200 ng / ml, preferably 1700 ng / ml to 3200 ng / ml, more preferably 1700 ng / ml to 3000 ng / ml, further preferably 2200 ng / ml to 2900 ng / ml.

[0069] Furthermore, following administration of the tungstate (VI) salt or solvate thereof, the area under the curve (AUC) from 0 to 24 hours may be 8000ng h / ml to 25000ng h / ml.

[0070] In one embodiment, following administration of the tungstate (VI) salt or solvate thereof the area under the curve (AUC) from 0 to 24 hours may be 8000ng h / ml to 25000ng h / ml, preferably 10000ng h / ml to 25000ng h / ml, more preferably 10000ng h / ml to 22000ng h / ml, further preferably 17000ng h / ml to 21000ng h / ml.

[0071] In a further embodiment, following administration of the tungstate (VI) salt or solvate thereof the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma may be 1700 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours may be 10000ng h / ml to 25000ng h / ml.

[0072] In a further embodiment, following administration of the tungstate (VI) salt or solvate thereof the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma may be 1700 ng / ml to 3000 ng / ml and the area under the curve (AUC) from 0 to 24 hours may be 10000ng h / ml to 22000ng h / ml.

[0073] In a further embodiment, following administration of the tungstate (VI) salt or solvate thereof the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma may be 2200 ng / ml to 2900 ng / ml and the area under the curve (AUC) from 0 to 24 hours may be 17000ng h / ml to 21000ng h / ml.

[0074] Subject to be treated

[0075] The women treated with a tungsten (VI) salt or solvate thereof in accordance with the present disclosure, may be 18 to 45 years of age, preferably 18 to 40 years of age. In one embodiment of the present disclosure, women are 33 to 40 years of age. In a further embodiment the women are 35 to 40 years of age.

[0076] In one embodiment of the present disclosure, the women are 33 to 40 years of age and the tungstate (VI) salt or solvate thereof is administered at a dose of 300 mg / day.

[0077] It was surprisingly found that administering 300 mg / day of a tungstate (VI) salt to women 33 to 40 years of age resulted in an increased live birth rate compared to administering 300 mg / day to women of 18 to 32 years of age.

[0078] According to another embodiment, the women are 35 to 40 years of age and the tungstate (VI) salt or solvate thereof is administered at a dose of 300 mg / day. The women may have a body mass index of greater than or equal to 18 kg / m2and less than 30 kg / m2.

[0079] Additional aspects of the present disclosure

[0080] The present disclosure can also be described with reference to the following aspects:

[0081] Aspects of the present disclosure-.

[0082] <1 >. A tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0083] <2>. A tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0084] <3>. A tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the biochemical pregnancy rate is determined by detecting beta hCG in serum or urine 10 to 15 days after embryo transfer or about 15 days after conception, and wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0085] <4>. A tungsten (VI) salt or a solvate thereof, for use in increasing the clinical pregnancy rate with heartbeat, wherein the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day.

[0086] <5>. A tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0087] <6>. A tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0088] <7>. A tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the biochemical pregnancy rate is determined by detecting beta hCG in serum or urine 10 to 15 days after embryo transfer or about 15 days after conception, and wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0089] <8>. A tungsten (VI) salt or a solvate thereof, for use in increasing the clinical pregnancy rate with heartbeat, wherein following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0090] <9>. A tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein

[0091] (i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or

[0092] (ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0093] <10>. A tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein

[0094] (i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or

[0095] (ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0096] <11 >. A tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the biochemical pregnancy rate is determined by detecting beta hCG in serum or urine from 10 to 15 days after embryo transfer or at about 15 days after conception, and wherein

[0097] (i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or

[0098] (ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0099] <12>. A tungsten (VI) salt or a solvate thereof, for use in increasing the clinical pregnancy rate with heartbeat, wherein

[0100] (i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or

[0101] (ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0102] <13>. The tungsten (VI) salt for use according to aspect <1 >, <5> or <9>, wherein live birth rate following embryo transfer is the number of deliveries that resulted in at least one live birth per 100 embryo transfer cycles.

[0103] <14>. The tungsten (VI) salt for use according to aspect <1 >, <5> or <9>, wherein live birth rate following natural conception is the number of deliveries that resulted in at least one live birth per 100 conceptions.

[0104] <15>. The tungsten (VI) salt for use according to aspect <13> or <14>, wherein live birth is the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age, and after such separation, breathes or shows any other evidence of life. <16>. The tungsten (VI) salt for use according to aspect <2>, <6> or <10>, wherein ongoing pregnancy rate is the number of women with uterine pregnancy and a foetal heartbeat at 10 to 11 weeks following embryo transfer or at 12 weeks following conception per 100 embryo transfer cycles or per 100 conceptions, and wherein the uterine pregnancy and foetal heartbeat is confirmed by ultrasound.

[0105] <17>. The tungsten (VI) salt for use according to aspect <3>, <7> or <11 > wherein biochemical pregnancy rate is the number of women with a biochemical pregnancy per 100 embryo transfer cycles or per 100 conceptions determined by detecting beta hCG in serum or urine measured from 10 to 15 days after embryo transfer or about 15 days after conception.

[0106] <18>. The tungsten (VI) salt for use according to aspect <4>, <8> or <12>, wherein clinical pregnancy rate with heartbeat is the number of women with clinical pregnancy with heart beat per 100 embryo transfer cycles or per 100 conceptions, wherein the clinical pregnancy with heart beat is determined by ultrasonographic or clinical documentation of at least one intrauterine gestational sac with a discernible heartbeat.

[0107] <19>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the increase is with respect to infertile women who are not administered the tungsten (VI) salt or a solvate.

[0108] Tungsten (VI) salt:

[0109] <20>. The tungsten (VI) salt for use according to any one of the previous aspects, where said salt comprises a tungsten (VI) anion and a pharmaceutically, veterinary or dietetically acceptable cation.

[0110] <21 >. The tungsten (VI) salt for use according to aspect <20>, characterized in that the cation is selected from the group consisting of sodium, potassium, magnesium, calcium and zinc.

[0111] <22>. The tungsten (VI) salt for use according to aspect <20> or <21 >, characterized in that the cation is sodium. <23>. The tungsten (VI) salt for use according to aspect <20> or 21 >, characterized in that the cation is zinc.

[0112] <24>. The tungsten (VI) salt for use according to any one of aspects <20> to <23>, characterized in that the tungsten (VI) anion is selected from WCU2-, HWCU’, W2O?2-and HW20?” ions.

[0113] <25>. The tungsten (VI) salt for use according to any one of aspects <20> to <24>, characterized in that the anion is WCU2-.

[0114] <26>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungsten (VI) salt is sodium tungstate.

[0115] <27>. The tungsten (VI) salt for use according to any one of the previous aspects, where the solvate is a monohydrate.

[0116] <28>. The tungsten (VI) salt for use according to any one of the previous aspects, where the solvate is a dihydrate.

[0117] Administration:

[0118] <29>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered daily at a dose of 150 mg / day to 400 mg / day, such as at a dose of 150, 200, 250, 300, 350 or 400 mg / day.

[0119] <30>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered at a dose of 200 mg / day to 400 mg / day.

[0120] <31 >. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered at a dose of 200 mg / day to 300 mg / day. <32>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered at a dose of 200 mg / day or 300 mg / day.

[0121] <33>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered once, twice or three times a day.

[0122] <34>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered twice a day.

[0123] <35>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered once a day.

[0124] <36>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered orally.

[0125] <37>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered in the form of a tablet, pastille, capsule, powder, wafer, effervescent powder, solution, suspension, syrup or granules.

[0126] <38>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered in the form of a tablet.

[0127] <39>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered in the form of a film- coated tablet.

[0128] <40>. The tungsten (VI) salt for use according to any one of aspects <37> to <39>, wherein the tablet contains 25 to 400 mg of the tungstate (VI) salt or solvate thereof.

[0129] <41 >. The tungsten (VI) salt for use according to aspect <40>, wherein the tablet contains 100 to 200 mg of the tungstate (VI) salt or solvate thereof. <42>. The tungsten (VI) salt for use according to any one of aspects <40> or 41 >, wherein the tablet contains 100 to 150 mg of the tungstate (VI) salt or solvate thereof, such as 100 mg or 150 mg.

[0130] <43>. The tungsten (VI) salt for use according to any one of aspects <1 > or 35>, wherein the tungstate (VI) salt or solvate thereof is administered vaginally.

[0131] <44>. The tungsten (VI) salt for use according to aspect <43>, wherein the tungstate (VI) salt or solvate thereof is administered in the form of a tablet, pastille, capsule, suppository, gel, pessary, powder, wafer, solution, suspension, syrup or granules.

[0132] <45>. The tungsten (VI) salt for use according to any one of aspects <1 > or 35>, wherein the tungstate (VI) salt or solvate thereof is administered intravenously.

[0133] <46>. The tungsten (VI) salt for use according to any one of aspects <1 > or 35>, wherein the tungstate (VI) salt or solvate thereof is administered intramuscularly or subcutaneously.

[0134] <47>. The tungsten (VI) salt for use according to aspect <45> or <46>, wherein the tungstate (VI) salt or solvate thereof is administered in the form of a solution or a suspension.

[0135] <48>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the infertile women undergo embryo transfer.

[0136] <49>. The tungsten (VI) salt for use according to aspect <48>, wherein the embryo is a donor oocyte or an autologous oocyte.

[0137] <50>. The tungsten (VI) salt for use according to aspect <48> or <49>, wherein the embryo is a donor oocyte.

[0138] <51 >. The tungsten (VI) salt for use according to any one of aspects <48> to <50>, wherein the tungstate (VI) salt or solvate thereof is administered 15 to 75 days before embryo transfer, preferably 20 to 65 days before embryo transfer.

[0139] <52>. The tungsten (VI) salt for use according to any one of aspects <48> to <51 >, wherein the tungstate (VI) salt or solvate thereof is administered for up to 80 days after embryo transfer, preferably up to 70 days after embryo transfer, more preferably after 35 days after embryo transfer.

[0140] <53>. The tungsten (VI) salt for use according to any one of aspects <48> to <50>, wherein the tungstate (VI) salt or solvate thereof is administered 15 to 75 days before embryo transfer, preferably 20 to 65 days before embryo transfer, and up to 45 days after embryo transfer, preferably up to 35 days after embryo transfer.

[0141] <54>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the tungstate (VI) salt or solvate thereof is administered at least 2 hours after food intake.

[0142] <55>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following tungstate (VI) salt or solvate thereof administration, there is no food intake for at least 1 hour.

[0143] Pharmacokinetic characteristics:

[0144] <56>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml.

[0145] <57>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3200 ng / ml.

[0146] <58>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3000 ng / ml.

[0147] <59>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 2200 ng / ml to 2900 ng / ml.

[0148] <60>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

[0149] <61 >. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to 25000ng h / ml.

[0150] <62>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to 22000ng h / ml.

[0151] <63>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein following administration of the tungstate (VI) salt or solvate thereof, the area under the curve (AUC) from 0 to 24 hours is 17000ng h / ml to 21000ng h / ml.

[0152] <64>. The tungsten (VI) salt for use according to any one of aspects <1 > to <55>, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to 25000ng h / ml.

[0153] <65>. The tungsten (VI) salt for use according to any one of aspects <1 > to <55>, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3000 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to 22000ng h / ml.

[0154] <66>. The tungsten (VI) salt for use according to any one of aspects <1 > to <55>, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 2200 ng / ml to 2900 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 17000ng h / ml to 21000ng h / ml.

[0155] Characteristics of women'.

[0156] <67>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 18 to 45 years of age.

[0157] <68>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 18 to 40 years of age.

[0158] <69>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 33 to 40 years of age.

[0159] <70>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 35 to 40 years of age.

[0160] <71 >. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 33 to 40 years of age and the tungstate (VI) salt or solvate thereof is administered at a dose of 300 mg / day.

[0161] <72>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are 35 to 40 years of age and the tungstate (VI) salt or solvate thereof is administered at a dose of 300 mg / day.

[0162] <73>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women have a body mass index of greater than or equal to 18 kg / m2and less than 30 kg / m2. <74>. The tungsten (VI) salt for use according to any one of the previous aspects, wherein the women are non-diabetic.

[0163] EXAMPLES

[0164] Example 1. Pharmacokinetic studies

[0165] Two randomized, double-blind phase I clinical trials were conducted, administering ST or a placebo orally in healthy women with regular cycles.

[0166] The first study constituted of multiple administrations for one menstrual cycle in normo / overweight and obese subjects. The second study included both single (SAD) and multiple (MAD) administrations and BMI was restricted to < 30 kg / m2Safety and tolerability were evaluated by the incidence of adverse effects (AEs), physical and gynaecological evaluation with TVIIS (transvaginal ultrasound), vital signs and clinical laboratory tests, in a cycle before the treatment cycle, during treatment and in the cycle after treatment. Blood samples were obtained during the absorption and elimination phases at specified timepoints. Pharmacokinetic analyses were performed using a non-compartmental approach.

[0167] Baseline characteristics: Within the clinical normality. No differences were observed between the placebo and treated groups at the beginning of the studies.

[0168] Table 1. Baseline characteristics from both studies

[0169] Safety: Few related adverse events (AEs) occurred with similar frequency in the placebo and the treated groups were observed, with no relationship to doses. The most frequent AEs observed with ST were headaches, nausea, somnolence and nasopharyngitis (>20%). No relevant changes were observed for physical examination, vital signs, and laboratory tests.

[0170] Pharmacokinetics: All doses examined had a similar PK profile with a fast peak absorption and elimination phase (see Figure 1 ). There were no relevant differences between normo / overweight and obese subjects. No accumulation was observed in any of the dose studies. The dose of 500 mg / day achieved highest sodium tungstate concentration in blood.

[0171] This study was conducted in healthy women with regular cycles. While it was useful to establish pharmacokinetic profiles for different doses, it was not intended to provide information on the efficacy of the treatment in infertile women.

[0172] It is known, for example, that gene expression in the endometrium of healthy women and infertile women is different (Diaz-Gimeno et al. Fertility and Sterility®, Vol. 95, No. 1 , January 2011 , pages 50-60; Jimenez Guerrero et al. The European Journal of Contraception & Reproductive Health Care, 2021 , pages 199-207). Therefore, it is not possible to expect that medicinal products which have been shown to enhance expression of certain genes in the endometrium of healthy women will be able to treat infertility in infertile women, for example.

[0173] To determine the efficiency of treatment of infertile women with a tungstate (VI) salt, a phase II clinical trial was conducted, as described in Example 2 below.

[0174] Example 2. Phase Clinical Trial Study

[0175] Methods:

[0176] The Phase II Clinical Trial Study was a randomised, double-blind, placebo-controlled multicentre trial in parallel groups. The main part of the trial consisted of a screening period of up to 5 weeks, a treatment period with 4 to 9 weeks treatment prior to embryo transfer (ET) and 5 weeks treatment after ET, and a post-treatment period of additional 5 weeks, until 10 weeks after ET. Subjects with confirmed ongoing clinical pregnancy had to be further followed-up to assess the outcome of pregnancy and the infant’s health status approximately 28 days after pregnancy outcome as well as 6 months after birth.

[0177] Number of subjects (planned and analysed): planned: 351 randomised subjects enrolled: 408 screening failures: 29 randomised: 379 withdrawn: 74 completed: 305 analysed (safety): 368 analysed (efficacy): 335 follow-up (Fll): pregnancy Fll: 141 infant FU: 148

[0178] Diagnosis and main criteria for inclusion and exclusion:

[0179] Infertile, otherwise healthy women eligible to undergo an egg donor programme in the context of assisted reproductive technology (ART) between 18 and 45 years of age, inclusive, with a body mass index (BMI) > 18.0 and < 30.0 kg / m2and normal results of a transvaginal ultrasound (TVIIS), i.e. , no presence of any gynaecological abnormality suspected to affect the ART procedure with a planned donor embryo transfer.

[0180] Measures of protection of subjects taken:

[0181] Routine procedures for IVF / ICSI and ET of oocyte donor cells were applied for each subject, following the local standards of each site. As far as possible, endometrial preparation prior to ET transfer was standardised among all participating sites, providing a range of 5 to 22 days for oestrogen treatment followed by a fixed duration of 5 days for progesterone treatment prior to ET. In addition, 3 different options for ovarian suppression with either gonadotropin releasing hormone (GnRH) antagonists, GnRH agonists or hormonal combined oral contraceptives were allowed, if deemed necessary prior to start of oestrogen treatment, to provide the most promising procedure for each individual subject.

[0182] Taking into account the positive safety profile of sodium tungstate observed in previous trials, neither treatment with placebo nor treatment with sodium tungstate prior to ET and for 5 weeks thereafter were expected to cause major risk to the subjects. Nevertheless, all subjects were closely monitored during the trial and any change of the subject’s medical condition was recorded as an adverse event (AE) and followed- up, including a follow-up of the exposed foetus until pregnancy outcome and the born child until 6 months after expected birth date.

[0183] Test products, dose and mode of administration:

[0184] Sodium tungstate film-coated tablets, containing 100 mg or 150 mg of sodium tungstate were used for oral administration.

[0185] Two tablets of the respective dose strength were taken once daily for a total daily dose of 200 mg (0X0-001 200mg) or 300 mg (0X0-001 300mg), respectively, swallowed whole with approximately 240 mL of tap water under fasting conditions for at least 2 hours before and 1 hour after intake in the early morning.

[0186] Duration of treatment:

[0187] Treatment with sodium tungstate started 26 to 62 days prior to ET and was continued for 5 weeks after ET, i.e. , complete treatment duration lasted for 61 to 97 days (9 to 14 weeks).

[0188] Reference therapy, dose and mode of administration:

[0189] OXO-placebo, film-coated tablets for oral administration, matching the test product.

[0190] Two placebo tablets were taken once daily, swallowed whole with approximately 240 mL of tap water under fasting conditions for at least 2 hours before and 1 hour after intake in the early morning.

[0191] Statistical methods:

[0192] The analysis of the primary endpoint was performed using a logistic regression model with treatment group, age group (< 35, 35-37, 38-40, 41 -42, > 43), pooled site (Site 1 subgroup) and blastocyst quality (3, 4, 5-6) as factors, with a two-sided type I error of 0.05. The treatment effect was characterised by (adjusted) odds ratio of each dose group relative to placebo with associated two-sided 95% confidence intervals (Cis). Supportive additional analyses were applied as well. The secondary efficacy endpoints, including pregnancy and infant follow-up, were analysed in an exploratory manner using the same logistic regression model and supportive analyses as for the primary endpoint.

[0193] Safety and pharmacodynamic endpoints were analysed by providing descriptive statistics.

[0194] SUMMARY OF RESULTS

[0195] Subject Disposition:

[0196] A total of 379 subjects were randomised for treatment and out of these, 368 (97.1 %) subjects received at least one dose of sodium tungstate and were included to the safety set. 335 subjects (88%) were included in the FAS for evaluation of the primary endpoint, with 107 and 112 subjects in the sodium tungstate 200mg and 300mg groups respectively and 116 subjects in placebo, Embryo transfer criteria were achieved by 309 (81.5%) randomised subjects and ET was performed in 308 (81.3%) subjects, ranging from 98 (77.8%) subjects in the sodium tungstate 200 mg group up to 106 (84.1 %) subjects in the sodium tungstate 300 mg group. One subject in the sodium tungstate 200 mg group underwent ET although ET eligibility criteria were not fulfilled and thus was excluded from the full analysis set (FAS). Finally, 307 subjects (81 %) underwent the study-related ET and were included in the mFAS.

[0197] A total of 305 (80.5%) subjects completed the trial as intended, 74(19.5%) subjects were reported to have terminated the trial prematurely, including 11 subjects who terminated prior to the first sodium tungstate intake.

[0198] A total of 146 subjects with ongoing pregnancy (start of pregnancy during IP intake or within 14 days after last IP intake) were followed-up until Visit 10 (6 months after expected birth). Efficacy Results:

[0199] Treatment compliance was high with more than 95% compliant subjects at each relevant timepoint and in each treatment group. The mean (SD) treatment duration in mFAS was 47.9 (6.38) days prior to ET and 25.9 (10.50) days after ET with comparable duration among treatment groups.

[0200] The vast majority of the 307 performed ETs was judged to have been easy, sperm quality was good in at least 95% of the total population and the vast majority of fertilisations were performed via ICSI. In all treatment groups, the proportion of subjects receiving fresh oocytes was slightly higher than the proportion of subjects receiving frozen oocytes.

[0201] The primary endpoint of this trial was the ongoing pregnancy rate (OPR), defined as confirmed intrauterine pregnancy with confirmed foetal heartbeat at Visit 8 (10 to 11 weeks post ET). Sodium tungstate at the dose of 300 mg showed a clinically meaningful increase in embryo implantation with higher biochemical, clinical and ongoing pregnancy rates as compared to placebo. In the FAS, presenting best the “real-life population”, the sodium tungstate 300 mg group achieved a biochemical pregnancy rate of 69.64%, a clinical pregnancy rate of 49.11 % and an ongoing pregnancy rate of 45.54%, while lower pregnancy rates were achieved under treatment with placebo (56.90%, 42.24% and 42.24%, respectively). The pregnancy follow-up analysis revealed live birth delivery rates in the total population equal or close to the ongoing pregnancy rates and higher in sodium tungstate 300mg (42.86%) than in placebo group (41.38%) (Table 2).

[0202] Table 2. Results of efficacy analyses in the FAS dataset overall

[0203] N: Number of subjects in the specified analysis set overall and in corresponding subgroup % based on N. “0X0-001 denotes tablets containing 300 mg of sodium tungstate” FAS (Full analysis set): Randomized subjects who received at least one dose of IP, excluding subjects who dropped out not related to IP as withdrawal of Informed Consent (no safety reasons), no quality blastocyst available or no blastocyst available.

[0204] Applied subgroup analyses demonstrated minor differences between several subgroup categories as compared to the total population. Most remarkable effects were observed for subgroups up to 40 years of age and the subgroup with endometrial thickness below or equal to 7-7.5 mm, indicating a remarkably higher ongoing pregnancy rate as compared to placebo in at least one group under treatment with sodium tungstate. An additional exploratory subset analysis was done including the summarised subset of subjects up to 40 years.

[0205] Table 3. Summary and Analysis of Pregnancy Rates - Population < 40 Years of Age

[0206] (FAS:Full Analysis Set)

[0207] 0X0-001 0X0-001

[0208] Placebo Variables Statistic 200 mg / day 300 mg / day

[0209] (N = 49) (N = 54)<N"42>

[0210] Biochemical Pregnancy % 62.96% 74.55%* 51.11 %

[0211] Pregnancy ratea(95% Cl) (48.74; 75.71) (61 .00; 85.33) (35.77; 66.30)

[0212] Clinical Pregnancy % 44.44% 49.09% 35.56%

[0213] Pregnancy ratea(95% Cl) (30.92; 58.60) (35.35; 62.93) (21 .87; 51 .22)

[0214] Ongoing Pregnancy % 42.59% 45.45% 35.56%

[0215] Pregnancy ratea(95% Cl) (29.23; 56.79) (31 .97; 59.45) (21 .87; 51 .22)

[0216] Live Birth Delivery % 42.59% 41.82% 35.56%

[0217] Ratea(95% Cl) (29.23; 56.79) (28.65; 55.89) (21 .87; 51 .22)

[0218] Cl: Confidence interval; N: number of subjects in the specified analysis set;; %: based on N a Clopper-Pearson Cl is provided for the pregnancy rate p<0.05 (results are based on a logistic regression model with age, blastocyst quality, pooled site 1 b and treatment as factors).

[0219] “0X0-001 denotes tablets containing 200 mg or 300 mg of sodium tungstate”

[0220] For the subgroup of subjects up to 40 years of age, remarkably higher biochemical pregnancy rates (above 67%), clinical pregnancy rates (above 46%) and ongoing pregnancy rates (above 44%) could be observed for both 0X0-001 treatment groups as compared to placebo (52.38%, 35.71% and 35.71 %, respectively). Logistic regression analyses revealed a clinically meaningful and statistically significant difference of the biochemical pregnancy rate in favour of treatment with 0X0-001 300 mg (odds ratio: 2.537, p-value = 0.0458) as compared to placebo. Furthermore, a clinically meaningful difference for clinical pregnancy rate (odds ratio: 1.482) and ongoing pregnancy rate (odds ratio: 1.275) in favour of 0X0-001 300 mg could be detected. Live birth delivery rate was remarkably higher in subjects up to 40 years in both doses (42.59% in 200mg, 41.82% in 300mg and 35.56% in placebo). The live birth delivery rate wax promising in both 0X0-001 doses (odds ratio 1.390 and 1.075 respectively). When analysing the biochemical, clinical and ongoing pregnancy rates using a logistic regression model with treatment, blastocyst quality, age group, pooled sites 1 and age groups as factors, p-values did not indicate a potential impact of the factors. Moreover, additional analyses by blastocyst quality, BMI, sites, P4, E2 levels, treatment duration prior ET, endometrial thickness on day of ET, type of donor or ovarian suppression as covariates and other factors indicated no significant influence on the primary outcome.

[0221] Late pregnancy loss more than 10 weeks after ET was low (4 subjects overall) and was most frequently reported in the sodium tungstate 300 mg group (3 out of 77 pregnant subjects, 3.90%). No late pregnancy loss was reported in the 0X0-001 200 mg group. Late spontaneous abortion was not observed in 0X0-001 groups, while in placebo one late spontaneous abortion was found (1 out of 64 pregnant subjects, 1.56%)

[0222] Age subgroup analysis:

[0223] Administration of 0X0-001 300 mg to women from 33 to 40 years of age compared to women of 32 years of age or younger was surprisingly found to lead to higher biochemical pregnancy rates than in the placebo group:

[0224] Table 4. Biochemical pregnancy rate (BPR) of women 32 years of age or younger Table 5. Biochemical pregnancy rate (BPR) of women 33 to 40 years of age

[0225] Administration of 0X0-001 300 mg to women from 35 to 40 years of age compared to women of 34 years of age or younger was found to follow the same trend:

[0226] Table 6. Biochemical pregnancy rate and ongoing pregnancy rate of women 34 years of age or younger

[0227] Table 7. Biochemical pregnancy rate and ongoing pregnancy rate of women 35 to 40 years of age

[0228] These results are surprising as it is known that pregnancy rate in women 20 to 24 years of age is about 86%, while it diminishes to 50% in women 32 to 35 years of age [Management of the Infertile Women by Helen A. Carcio; The Fertility Sourcebook by M. Sara Rosenthal, ASAS Summary of FAIR 2012], Therefore, higher biochemical pregnancy rates and ongoing pregnancy rates would have been expected for the younger groups of women than for the older groups of women.

[0229] Case Study: Two of the women enrolled in the Phase II clinical trial study became pregnant during the treatment phase before embryo transfer. They were being administered 0X0-001 200 mg. Subject 201002 gave birth, and subject 209005 had a spontaneous miscarriage. The details of each of the subjects is shown below:

[0230] Subject 201002: - Age: 37 years

[0231] Race: white

[0232] Country: Czech Republic

[0233] Body Mass Index: 26 kg / m2

[0234] Smoking status: Non-smoker Medical history: history of two spontaneous abortion from natural conception in 2019.

[0235] Days of treatment: 38 days

[0236] Biochemical Pregnancy: YES

[0237] Clinical Pregnancy: YES

[0238] Ongoing Pregnancy: YES

[0239] Live birth delivery: YES

[0240] Subject 209005

[0241] Age: 44 years

[0242] Race: white

[0243] Country: Czech Republic

[0244] Body Mass Index: 22,9 kg / m2

[0245] Smoking status: Non-smoker

[0246] Medical history: history of one delivery, two spontaneous abortions and one induced abortion all from natural conception.

[0247] Days of treatment: 19 days

[0248] Biochemical Pregnancy: YES

[0249] Clinical Pregnancy: NO

[0250] Ongoing Pregnancy: NO

[0251] Live birth delivery: NO.

[0252] Safety Results:

[0253] Overall, 368 subjects received sodium tungstate: 121 received 0X0-001 200 mg, 125 received 0X0-001 300 mg and 122 received placebo.

[0254] The mean (SD) overall treatment duration was 67.9 (18.65) days, the median duration was 70.0 days (range: 3 to 104 days). The mean and median treatment duration was similar between the treatment groups during each period. In total, 513 TEAEs (treatment-emergent adverse events) were reported by 223 (60.6%) subjects, with 199 (54.1 %) subjects experiencing a total of 428 events during the treatment phase and 58 (15.8%) subjects experiencing a total of 85 events during the post-treatment phase.

[0255] The overall frequency of TEAEs was comparable between subjects taking 0X0-001 200 mg (overall: 75 subjects, 62.0%; treatment: 69 subjects, 57.0%; post-treatment: 19 subjects, 15.7%) and 300 mg (overall: 81 subjects, 64.8%; treatment: 72 subjects, 57.6%; post-treatment: 22 subjects, 17.6%) doses, whereas the lowest frequency of TEAEs was observed in the placebo group (overall: 67 subjects, 54.9%; treatment: 58 subjects, 47.5%; post-treatment: 17 subjects, 13.9%).

[0256] Overall, the most frequent individual TEAEs were headache (48 subjects, 13.0%), abortion spontaneous (37 subjects, 10.1 %) and vaginal haemorrhage (36 subjects, 9.8%), followed by COVID-19 positive (COVID-19 / SARS-CoV-2 test positive) TEAEs (35 subjects) and nausea (31 subjects, 8.4%). Headache was the most frequent in the 0X0-001 300 mg and 200 mg treatment groups: 15.2% and 14.0% of subjects compared to 9.8% of placebo subjects and abortion spontaneous was more frequent in the placebo group (11 .5% of subjects) and the 0X0-001 300 mg group (11 .2% of subjects) than observed in the 0X0-001 200 mg group (7.4% of subjects). No major differences between the treatment groups was observed with regard to vaginal haemorrhage and nausea. Most TEAEs were mild or moderate in severity.

[0257] The mean infant’s gestational age at outcome was close to 39 weeks and thus comparable in all 3 treatment groups. Neonate assessments in terms of height, weight and head circumference as well as concerning the proportion of neonates per Apgar score categories at all 3 timepoints were comparable. Caesarean section was the most frequently reported mode of delivery for all treatment groups, with the highest proportion observed in the placebo group (63.3%) and the lowest proportion observed in the 0X0-001 300 mg group (47.2%). Accordingly, the proportion of subjects with vaginal delivery, the second frequently mode, was highest in the 0X0-001 300 mg group (45.3%) as compared to the other pregnancy groups.

[0258] Results of the ASQ-3 assessments demonstrated that the vast majority of neonates followed-up were of good developmental status. In each domain, at least 90% of infants overall reached or exceeded the cut-off score value, with similar proportions between all treatment groups except for the domain “problem solving” with lower proportions in placebo (91.5%) compared to 0X0-001 200mg and 300mg (>95.9%).

[0259] Treatment with 200 mg and 300 mg 0X0-001 was safe and well-tolerated in women undergoing ET following IVF or ICSI in this trial and did not affect the neonate’s development during the first 6 months after adjusted birth date.

Claims

CLAIMS1 . A tungsten (VI) salt or a solvate thereof, for use in increasing the live birth delivery rate in infertile women, wherein(i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or(ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

2. A tungsten (VI) salt or a solvate thereof, for use in increasing the ongoing pregnancy rate in infertile women, wherein(i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or(ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

3. A tungsten (VI) salt or a solvate thereof, for use in increasing the biochemical pregnancy rate in infertile women, wherein the biochemical pregnancy rate is determined by detecting beta hCG in serum or urine from 10 to 15 days after embryo transfer or at about 15 days after conception, and wherein(i) the tungsten (VI) salt or a solvate thereof is administered in an amount of 100 to 400 mg / day; and / or(ii) following administration, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1200 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 8000ng h / ml to 25000ng h / ml.

4. The tungsten (VI) salt for use according to claim 1 , wherein live birth rate following embryo transfer is the number of deliveries that resulted in at least one live birth per 100 embryo transfer cycles and wherein the live birth rate following naturalconception is the number of deliveries that resulted in at least one live birth per 100 conceptions.

5. The tungsten (VI) salt for use according to claim 2, wherein ongoing pregnancy rate is the number of women with uterine pregnancy and a foetal heartbeat at 10 to 11 weeks following embryo transfer or at 12 weeks following conception per 100 embryo transfer cycles or per 100 conceptions, and wherein the uterine pregnancy and foetal heartbeat is confirmed by ultrasound.

6. The tungsten (VI) salt for use according to any one of claims 1 to 5, wherein the tungsten (VI) salt is sodium tungstate.

7. The tungsten (VI) salt for use according to any one of claims 1 to 6, where the solvate is a dihydrate.

8. The tungsten (VI) salt for use according to any one of claims 1 to 7, wherein the tungstate (VI) salt or solvate thereof is administered daily at a dose of 150 mg / day to 350 mg / day.

9. The tungsten (VI) salt for use according to any one of claims 1 to 8, wherein the tungstate (VI) salt or solvate thereof is administered at a dose of 200 mg / day to 300 mg / day, preferably at a dose of 200 mg / day or 300 mg / day.

10. The tungsten (VI) salt for use according to any one of claims 1 to 9, wherein the tungstate (VI) salt or solvate thereof is administered orally, vaginally or intravenously.11 . The tungsten (VI) salt for use according to any one of claims 1 to 10, wherein the infertile women undergo embryo transfer.

12. The tungsten (VI) salt for use according to claim 11 , wherein the tungstate (VI) salt or solvate thereof is administered 15 to 75 days before embryo transfer, preferably 20 to 65 days before embryo transfer.

13. The tungsten (VI) salt for use according to any one of claims 1 to 12, whereinthe women are 18 to 40 years of age.

14. The tungsten (VI) salt for use according to any one of claims 1 to 13, wherein the women are 33 to 40 years of age and the tungstate (VI) salt or solvate thereof is administered at a dose of 300 mg / day.

15. The tungsten (VI) salt for use according to any one of claims 1 to 14, wherein following administration of the tungstate (VI) salt or solvate thereof, the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3200 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to25000ng h / ml, preferably the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 1700 ng / ml to 3000 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 10000ng h / ml to 22000ng h / ml, more preferably the maximum concentration (Cmax) of the tungsten (VI) salt in the blood plasma is 2200 ng / ml to 2900 ng / ml and the area under the curve (AUC) from 0 to 24 hours is 17000ng h / ml to 21000ng h / ml.

Images