NBI-56418, is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.
An orally administered non-peptide small molecule GnRH antagonist would have advantages over peptide agonists regarding the degree of down-regulation of GnRH receptors that can be readily adjusted by dose. This level of flexibility will allow greater control over sex hormone regulation. This would allow for a small amount of circulating oestrogen, e.g. in endometriosis, to mitigate long-term bone demineralisation.
Neurocrine researchers believe this orally active, non-peptide GnRH antagonists should provide the potential to eliminate hormone add-back therapy, a rapid onset of action, an increased dosing flexibility, and a greater patient acceptability over currently available treatments.
The trial was designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of two dose levels of NBI-56418 given once daily for 6 weeks in 60 healthy pre- menopausal women. NBI-56418 demonstrated a dose-dependent suppression of estradiol that was observed throughout the duration of dosing.
Estradiol is the most potent estrogen of a group of endogenous estrogen steroids. At menopause, estrogen concentrations in the body fall to low levels. This decrease is often accompanied by vascular instability (hot flashes and night sweats), a rise in incidence of heart disease, and an increasing rate of bone loss (osteoporosis). Estrogen replacement for alleviation of menopausal symptoms or to prophylax against heart disease and osteoporosis has become very common.
60 healthy pre-menopausal women took part in a double-blind, placebo-controlled trial involving randomised equally to one of three treatment groups: placebo, 50mg of NBI-56418, or 150mg of NBI-56418 each administered for 42 days. Dosing started on Day 2 to Day 7 following the onset of the menstrual cycle.
On day 42 of the study there were reductions of 40 per cent and 79 per cent in mean estradiol concentration in the 50mg and 150mg dose groups respectively compared with that in the placebo group. At times prior to day 42 of the study, the data showed early achievement of estradiol suppression.
While estradiol suppression was not complete, the data suggested that it was possible to achieve efficacy and avoid the adverse impact of other hormonal treatments for the condition.
"As in our previous Phase I studies, we have once again shown that our GnRH antagonist can modulate estradiol levels. Since the effects of reduction in estradiol have been well correlated with a reduction of pain and other symptoms of endometriosis, we believe our GnRH antagonist will have significant therapeutic application in endometriosis," said Dr Wendell Wierenga, executive vice president of research and development for Neurocrine Biosciences.
"Based on these data, doses have been selected for a 3-month Phase II study evaluating NBI-56418 in patients with endometriosis, which is expected to be initiated in the 2nd Quarter of 2005," added Wierenga.
Despite a multitude of potential applications, consequences of GnRH agonist therapy, especially permanent bone loss in women's health diseases, have limited the useful duration of treatment. GnRH is a neuroendocrine peptide which stimulates the secretion of the pituitary LH, which in turn stimulates the production of oestrogen by the ovary or testosterone by the testes.
However, GnRH peptide agonists have proven clinically useful in the treatment hormone dependent diseases such as endometriosis, uterine fibroids, prostate cancer and breast cancer, as well as being used for assisted-reproductive therapy.
The most widely prescribed drugs which modulate the GnRH receptor are peptide agonists, such as, Lupron and Zoladex, with estimated combined sales in excess of $2.5 billion (€1.9 billion) worldwide in 2003. These compounds act by inhibiting the secretion of pituitary LH and consequently, oestrogen or testosterone production.