OR33-4 A Single Subcutaneous Injection Of The Kisspeptin Analogue, MVT-602, Induces A More Prolonged LH Surge Compared With Kisspeptin-54 In Healthy Women

Abstract

Background Kisspeptin is a hypothalamic neuropeptide that is requisite for normal reproductive health. A subcutaneous bolus of the native form of kisspeptin (kisspeptin-54; KP54) induces an LH-surge lasting 12-14hrs, to safely mature oocytes during in vitro fertilisation (IVF) treatment. The kisspeptin analogue, MVT-602, has a longer half-life (t1/2 1.5-2.2h) than native KP54 (t1/2 0.5h), which could therefore confer significant advantages as an oocyte maturation trigger in the treatment of infertility. Whilst MVT-602 has been shown to stimulate LH release in men, its effects in women have not previously been investigated. To address this, we studied the effect of MVT-602 on gonadotrophin release in healthy women for the first time. Methods A two-phase dose-finding study was undertaken during the early follicular phase (Day 1-4) of 12 healthy women aged 18-35yrs with regular menstrual cycles. During phase 1, a broad dose-range for MVT-602 was determined: three women received a single subcutaneous bolus of one of five doses of MVT-602 (0.003, 0.03, 0.1, 0.3, or 1.0nmol/kg) in successive menstrual cycles. Reproductive hormones were measured every 30min for 14hrs post-MVT-602, and again at 24hrs and 48hrs post-injection. During phase 2, an additional 9 women received either KP54 (9.6nmol/kg), or MVT-602 at doses of 0.01 or 0.03nmol/kg during the follicular phase of successive menstrual cycles, following which reproductive hormone levels were monitored every 30mins for 24hrs post-injection. Intervention groups were compared by one-way ANOVA with post hoc Tukey’s test. ResultsPhase 1: Peak serum LH levels occurred between 14-24hrs and no further increases occurred with MVT-602 at doses greater than 0.03 nmol/kg. Phase 2: Peak amplitude of serum LH was found to be similar following KP54 and MVT-602 (mean±SD of peak LH KP54 12.3 ±5.3iU/L; MVT-602 0.01nmol/kg 11.4 ±4.2iU/L; MVT-602 0.03nmol/kg 11.1 ±3.0iU/L, p>0.05). However, time to peak LH was later following MVT-602 (22hrs) when compared with KP54 (4.9hrs; P<0.0001). Thus, the area under the curve (AUC) for LH exposure was significantly increased following MVT-602 when compared with KP54 (mean±SD of AUC LH KP54 9,095 ±5,632iU.min/L; MVT-602 0.01nmol/kg 18,129 ±6,471iU.min/L, P=0.02 vs KP54; MVT-602 0.03nmol/kg 20,086 ±6,227iU.min/L, P=0.004 vs KP54). Conclusion A single subcutaneous bolus of MVT-602 in healthy women resulted in an LH surge of similar amplitude, but of longer duration than by KP54. During studies evaluating the utility of KP54 as a trigger of oocyte maturation in IVF treatment, extending the duration of LH surge with a second bolus of KP54 safely optimised oocyte maturation. Thus, the prolonged gonadotrophin surge induced by MVT-602 could be of significant utility not only to safely optimise oocyte maturation in IVF treatment, but also to treat other reproductive disorders affecting women’s health.