Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.

STUDY QUESTION: Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF? SUMMARY ANSWER: In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%). WHAT IS KNOWN ALREADY: Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET. STUDY DESIGN, SIZE, DURATION: This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial. PARTICIPANT/MATERIAL, SETTING, METHODS: Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy. LIMITATIONS, REASON FOR CAUTION: The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date. WIDER IMPLICATIONS OF THE FINDINGS: The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF. STUDY FUNDING/COMPETING INTERESTS: The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885. TRIAL REGISTRATION DATES: December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). FIRST PATIENT'S ENROLMENT: January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).

Pharmacokinetic interactions of OBE001 and betamethasone in healthy female volunteers.

WHAT IS KNOWN AND OBJECTIVE: To treat preterm labour, antenatal corticosteroids and tocolytics are often co-administered. OBE001 is an orally active oxytocin receptor antagonist under development for preterm labour treatment. METHODS: Co-administration of OBE001 and betamethasone to determine pharmacokinetic interactions was studied during an open-label, randomized, three-period crossover study. Twelve healthy post-menopausal volunteers received either two consecutive OBE001 administrations of 600 mg/day, two intramuscular injections of 12 mg/day betamethasone or the two drugs administered in combination. The area under the plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) and the time to Cmax (tmax) for OBE001 and betamethasone were measured. RESULTS AND DISCUSSION: There was no effect on geometric mean Cmax after the second administration and AUCs of OBE001 [geometric mean ratio point estimate (90% CI): Cmax (Day2) 1·05 (0·98-1·12) and AUC(0-24 h )1·11 (0·99-1·23)/AUC(24 h-∞) 0·99 (0·93-1·06), respectively]; Cmax after the first administration together with betamethasone was increased by 12% [geometric mean ratio point estimates (90% CI): Cmax (Day1) 1·12 (0·96-1·32)]. Tmax after concomitant administration with betamethasone occurred with a median delay of 1 h. Geometric mean Cmax and AUCs of betamethasone were not affected by concomitant OBE001 administration [geometric mean ratio point estimate (90% CI): Cmax (Day1) 1·02 (0·98-1·07)/Cmax (Day2) 1·03 (0·98-1·08) and AUC(0-24 h) 1·07 (1·04-1·11)/AUC(24 h-∞ )1·04 (1·01-1·08), respectively], with no effect on median tmax . No subject was discontinued from the study due to adverse events. WHAT IS NEW AND CONCLUSION: AUC and Cmax of the betamethasone and OBE001 combination did not differ significantly between treatments. Co-administration of OBE001 and betamethasone was well tolerated and resulted in a tmax median delay of 1 h for OBE001 but not for betamethasone. Co-administration of OBE001 and betamethasone in clinics is feasible and does not require any specific precaution or administration adaptation.

Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for benign gynaecological conditions such as uterine myoma. The safety and pharmacokinetics of multiple-dose UPA and its N-mono-demethylated metabolite, PGL4002, were investigated in women. METHODS: The double-blind, placebo-controlled study randomized 32 healthy women of reproductive age to receive 10 consecutive daily doses of placebo, 10, 20 or 50 mg UPA. Safety assessments included vital signs, physical examination, ECG, clinical laboratory tests and reporting of adverse events. Blood samples for pharmacokinetic analysis were collected on Days 1 and 10 at intervals until 168 h after multiple dosing. RESULTS: UPA was well tolerated at all doses. Mild or moderate adverse events occurred with similar frequency in UPA and placebo groups. UPA median tmax was 0·75 and 0·89 h, and mean plasma half-life was between 38 and 49 h. Cmax values (Day 1) were 42·2, 130·9 and 354·8 ng/mL for the UPA 10, 20 and 50 mg treatment groups, respectively. Corresponding Cmax values for Day 10 were 63·7, 169·8 and 454·9 ng/mL. AUCSS values on Day 10 were 216·6, 602·8 and 1655·7 ng h/mL after 10, 20 and 50 mg UPA, respectively. For the principal metabolite PGL4002, tmax and plasma elimination half-life values were similar to those of UPA. PGL4002 AUCSS Day 10 values were 84·7, 203·6 and 452·1 ng h/mL for 10, 20 and 50 mg groups, respectively. WHAT IS NEW AND CONCLUSION: Daily administration of UPA at therapeutic and supratherapeutic doses was well tolerated by women of reproductive age. UPA exposure increases with dose. Exposure to PGL4002 is approximately one-third that of UPA.

Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate.

WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. In vitro, it is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and to a small extent by CYP1A2 and CYP2D6. Erythromycin, a macrolide antibiotic, has been shown to be a moderate CYP3A4 inhibitor. Thus, the aim of this study was to determine the effects of erythromycin at steady-state concentrations on the pharmacokinetics of UPA. Effects on the pharmacokinetics of the mono-demethylated metabolite of UPA (PGL4002) were also evaluated. METHODS: This was a non-randomized, single-sequence, two-period, open, single-dose study in 18 healthy female subjects. Subjects received oral UPA (20 mg) once daily on days 1 and 13 and twice-daily erythromycin propionate administrations (500 mg) from days 9 through 17. RESULTS: Geometric mean Cmax and AUCs of UPA were increased by 24% [geometric mean ratio point estimate (90% CI): 1·24 (1·01-1·52)] and +224% and +227% [geometric mean ratio point estimates (90% CI): AUC0-t 3·24 (2·75-3·83) and AUC0-∞ (3·27 (2·79-3·83)], respectively, with no effect on median tmax or t1/2. Geometric mean Cmax of PGL4002 was decreased by 47% [geometric mean ratio point estimate (90% CI): 0·523 (0·44-0·62)], but AUCs were increased by +62% and +66% [geometric mean ratio point estimates (90% CI): AUC0-t 1·62 (1·43-1·85) and AUC0-∞ by 1·66 (1·47-1·88)], respectively, with no effect on median tmax. However, geometric mean t1/2.doubled from 24 h to 48 h. No subject was discontinued from the study due to adverse events. WHAT IS NEW AND CONCLUSION: Concomitant use of ulipristal acetate with erythromycin at therapeutic concentrations led to a limited increase in Cmax and a 3-fold increase in AUCs for UPA and to a decrease in Cmax and an increase in AUCs and prolonged elimination for PGL4002. This indicates that inhibition of CYP3A4 impacted rate and extent of absorption of UPA and also its metabolism by slowing the elimination of its metabolite PGL4002.

Age-related memory decline and longevity under treatment with selegiline.

The MAO-B inhibitor selegiline is used in the treatment of Parkinson's disease. Further, beneficial effects in Alzheimer's disease have also been described as well as neuroprotective effects, increased longevity and an attenuation of age-related cognitive decline in experiments using rats. Our studies in mice and Syrian hamsters aim at the question whether the effects of selegiline reported in the rat can be generalized to other species. Aged female NMRI-mice (23 mo.) treated with selegiline (0.25 mg/kg, i.p., 3 times a week for 2-3 weeks) showed no treatment effect in the Morris water maze and in passive avoidance learning after 2 and 3 weeks of treatment. However, Syrian hamsters chronically treated with selegiline (0.05 mg/kg/day in the food, starting at 12 months old) showed a 3 month delay in the age-related decline of spontaneous alteration behavior, a measure of longer-term memory, compared to untreated controls. Since treated hamsters also show increased longevity (study still in progress) the data suggest a protective effect of a chronic treatment with selegiline against age-related cognitive and physical decline.

Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse.

Decreases in cell membrane fluidity may be a major mechanism of age-related functional decline. A prime cause for the decline of membrane fluidity may be the presence of free radicals. Gingko biloba extract EGb 761 protects neuronal cell membranes from free radical damage in vitro. Further, EGb 761 has repeatedly been shown to improve cognitive functions in man and in laboratory animals. To test if there is a link between these two actions we assessed the effects of EGb 761 on passive avoidance learning and on neuronal membrane fluidity in vivo in young (three-month-old), middle-aged (12-month-old) and aged (22 to 24-month-old) female NMRI mice. The animals were treated daily with 100 mg/kg EGb 761 for three weeks. There was a significant improvement in short-term memory, measured by the avoidance latency 60 seconds after the aversive stimulus (p < 0.0311), and of membrane fluidity (p < 0.01) in the aged animals, but no improvement in long-term memory as measured by the avoidance latency 24 hours after shock. However, no significant correlation between membrane fluidity and short-term memory performance was found. Taken together, these results indicate that EGb 761 independently improves changes in passive avoidance learning and brain membrane fluidity.

HBsAg-like structures in immunosuppressed mice inoculated with human hepatitis B virus.

Thymectomised and irradiated DBA/2 mice were injected intraperitoneally with human serum containing high titer of HBsAg, and were positive for HBsAg. Through the entire experiment neither degenerative and inflammatory lesions nor hepatitis B virus antigens could be detected in the liver of these animals by histomorphology and immunofluorescence, respectively. The sera of all these mice were negative for HBsAg by radioimmunoassay. By electron microscopy, however, increasing amounts of filaments and round particles measuring 20-22 nm in diameter could be observed in the endoplasmic reticulum of the mouse hepatocytes from the 8th day following injection. From the 90th day after inoculation the number of the filaments increased in an extreme degree. After fixation with KMnO4 and EDTA preferential staining, the filaments proved to be highly electrondense. According to the authors the filaments observed in mouse livers are lipoproteins produced by the hepatocytes in response to HBV inoculation. The appearance of the filaments is HBsAg-like, though their immunological characteristics become modified.