• Diabetes & Endocrinology Clinical Trials
• Hormone Therapy

• Diabetes & Endocrinology Clinical Trials
• Hormone Therapy
• Endocrinology
• Diabetes & Metabolic Syndrome

TAK-488 is an oligopeptide analog of kisspeptin, which is a hypothalmic protein that activates the G-protein-coupled receptor GPR54 [Navarro VM, Tena-Sempere M. Nat Rev Endocrinol 2011]. A randomized, placebo-controlled Phase 1 study that used various, continuously administered doses of TAK-488 has demonstrated its safety, tolerability, and effectiveness in suppressing pituitary secretion of luteinizing hormone (LH) and follicular-stimulating hormone (FSH), which are key in the regulation of testosterone synthesis. Accordingly, serum testosterone declined to below castrate levels in most of the healthy male volunteers. The results of the study were presented by David MacLean, MD, Takeda Pharmaceuticals, Cambridge, Massachusetts, USA.

Following screening, 30 healthy male volunteers, most of whom were white, aged 51 to 78 years with a body mass index≤18.5 but <32 kg/m² and normal levels of all relevant hormones were enrolled. They had not received hormonal therapy other than inhaled and topical steroids within the previous 4 weeks. The 30 participants were randomized to subcutaneously receive a 0.1 mg/kg bolus dose of TAK-448 on Day 1, and a continuous subcutaneous infusion of TAK-448/placebo (0.01 mg/kg, n=6/2; 0.1 mg/kg, n=6/2; 0.3 mg/kg, n=6/2; or 1.0 mg/kg, n=5/1) each day from Days 2 to 14. Evaluations were done at predetermined times up to Day 44. The primary endpoints were safety and tolerability. The secondary endpoints were endocrine-release profile and TAK-448 pharmacokinetics. Serum LH and FSH were quantified by radioimmunoassay. Serum testosterone, 5α-dihydrotestosterone (5α-DHT) and androstenedione were measured using liquid chromatography-tandem mass spectrometry.

The initial bolus dose of TAK-448 produced an increase in serum levels of LH and FSH, which subsequently declined to below the baseline levels of those receiving placebo during the 13-day continuous infusion period. By Day 17 (LH) or 21 (FSH), the hormone levels had recovered to baseline and were maintained through Day 44.

Serum testosterone levels displayed a similar pattern, declining in most participants to nearly undetectable levels (<0.7 nmol/L) during and for several days after the 13-day period of subcutaneous infusion of TAK-448 before rebounding to exceed baseline levels by Day 29. The pattern for 5α-DHT was similar.

Serum levels of androstenedione were suppressed in all subjects during an evaluation from Days 1 to 21, indicating an effect of the initial bolus administration of TAK-448. Steady-state concentrations of TAK-448 were evident within 6 hours of the continuous infusion and remained constant as a function of dose during the 13-day infusion period. All adverse events were mild or moderate in severity and most commonly included hot flushes, dizziness when standing, headache, diarrhea, and reaction at the site of subcutaneous injection. No adverse event resulted in discontinuation.

More research is necessary to extend the findings to different races and to clarify whether the novel GPR54-mediated mechanism for medical castration might be advantageous in hindering tumor invasion or metastasis in prostate cancer. The possible therapeutic value of TAK-448 in hormone-directed diseases including endometriosis and breast cancer also needs to be evaluated.

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