Endometriosis - asoprisnil
Endometriosis is a condition in which the lining of the uterus develops outside the womb, resulting in pain and, often, infertility. It is treated with agents that act on gonadotropin-releasing hormone and block the secretion of oestrogen from the ovaries or progestins that inhibit the stimulation of the ectopic endometrium by oestrogen.
Endometriosis is a condition in which the lining of the uterus develops outside the womb, resulting in pain and, often, infertility. It is treated with agents that act on gonadotropin-releasing hormone and block the secretion of oestrogen from the ovaries or progestins that inhibit the stimulation of the ectopic endometrium by oestrogen.
But these drugs can lead to serious side-effects, such as breakthrough bleeding, mood changes, acne and hirsutism.
Schering has been investigating the potential of a drug that has only the positive effects: asoprisnil has a high affinity for the progesterone receptors, and a low affinity for the glucocorticoid receptors, with a mixed progesterone agonist/antagonist activity.1 It is the first of these selective progesterone receptor modulator to reach clinical trials.
It was given to 60 healthy women in a placebo-controlled Phase I trial.2 Subjects were given 5, 10 or 25 mg of the drug once a day; 2, 25 or 50mg twice a day or placebo for 28 days, with the first dose administered at the beginning of the menstrual cycle. Seven of the eight women given the highest dose experienced sufficient progesterone suppression to stop lutenisation, but the effect was inconsistent in those given lower doses. No breakthrough bleeding was seen, basal oestrogen concentrations were unaltered and there were no antiglucocorticoid effects. Biopsies of the endometrium indicated that its effect was indeed largely on the endometrium.
In a randomised dose-finding Phase II study, 130 patients with endometriosis and moderate to severe pain were given 5, 10 or 25mg asoprisnil or placebo for 12 weeks.3 All doses of the active significantly reduced their pain scores: by the third month, the mean reduction was around 0.1, compared with less than 0.1 in those given placebo. Although the pain reduction was not dose-dependent, amenorrhoea was induced in none of those given placebo, and 50, 71 and 93% respectively of those given the three doses. The drug was well tolerated, and those adverse events that were observed were largely mild and self-limiting.
A second Phase II study was carried out using lower asoprisnil doses of 0.5, 1.5 and 5mg. The highest dose was the only one that gave effective pain relief. Trials continue, and the drug is also being investigated as a treatment for uterine fibroids: in a Phase II study it reduced the size of the fibroids, controlled excessive bleeding and reduced symptoms.4