A Potent Kisspeptin Agonist: Exploration of the Low Dose Response Range and Non-Desensitizing Regimens for Physiological Stimulation of the Male and Female Gonadal Axis

Presentation Number: SUN 481
Date of Presentation: April 2nd, 2017

Akira Tanaka*, Kazutaka Ushio, Atsuko Suzuki, Satoshi Okanishi and Hisanori Matsui
Takeda Pharmaceutical Company, Limited, Fujisawa, Japan


Introduction: TAK-448, an agonist analog of kisspeptin, primarily stimulates gonadotropins (LH and FSH) and gonadal hormones secretion via activation of GnRH secretion, while continuous administration of TAK-448 leads to down-regulation of reproductive hormone secretion. Based on the latter suppressive effect, TAK-448 was previously developed as an anti-prostate cancer agent. In contrast, based on the former stimulatory effect, we investigated the repurposing opportunity for non-oncology therapeutic areas, especially for clinical reproductive disorders such as male hypogonadotrpic hypogonadism (HH). We hypothesized that appropriate dosing regimen consisted of the optimized dose and dosing frequency could continuously stimulate gonadal hormone secretion without desensitization. Method: Therefore, we investigated the effect of single and repeated subcutaneous (SC) dosing of TAK-448 on reproductive hormone secretion in male rats and cynomolgus monkeys. In addition, in order to investigate the therapeutic potential for various sex hormone related diseases in females (e.g., infertility, polycystic ovarian syndrome, endometriosis, uterine fibroids, etc.), we examined the single SC dosing effect of TAK-448 in female rats and cynomolgus monkeys. The change of plasma LH, FSH and testosterone levels were determined as PD markers. Results: Single dosing studies in male animals demonstrated that TAK-448 showed clear PD response and the minimum effective dose (MED) was 1.2 and 1.0 ng/kg in male rats and monkeys, respectively. Repeated doses of TAK-448 in male monkeys showed attenuation of PD response at 1 and 10 ng/kg daily and 100 ng/kg biweekly dosing groups. In contrast, 10 and 100 ng/kg once-weekly and 10 ng/kg biweekly groups showed slight attenuation of LH responses on day 7, while the equivalent LH elevations were maintained thereafter with functional activity. On the other hand, female animals exhibited different PD responses to SC bolus TAK-448 dosing compared to male animals. The amplitude and duration of plasma LH and FSH response in early follicular phase in rats and monkeys were smaller and shorter than that in male animals, and the MED was more than 10-fold higher compared to that in male animals. Conclusion: Data from these studies demonstrated that with the appropriate combination of dose and dosing frequency, continuous stimulation of male reproductive hormone secretion without desensitization can be achieved, suggesting that TAK-448 could be a novel therapeutic option for a variety of sex hormone related diseases in both males and females. TAK-448 is currently being developed as RVT-602 by Myovant.


Disclosure: AT: Employee, Takeda. KU: Employee, Takeda. AS: Employee, Takeda. SO: Employee, Takeda. HM: Employee, Takeda.