Introduction

Estetrol (E4) is a natural human estrogen, which is solely produced in large quantities during human pregnancy by the male and female fetal liver. It was discovered by Egon Diczfalusy in 1965 and rejected as a potential diagnostic marker for fetal well-being. Based on low receptor binding E4 was thought to be a weak estrogen. Since the early eighties the molecule was more or less forgotten. E4 has never been investigated for its potential pharmaceutical use. Oral bioactivity in animals or the human has never been studied before.

The role of E4 in embryonic physiology and/or human pregnancy is not known. E4 reaches the maternal blood circulation via transport through the placenta. During human pregnancy E4 is detectable from 9 weeks pregnancy onwards. Maternal and fetal E4 concentrations increase exponentially during pregnancy and peak at high levels at term with fetal levels about 10-20 times higher than maternal levels. This experiment of nature during the most vulnerable physiological situation strongly suggests superior safety of this molecule.

Clinical study results

Recently, Pantarhei Bioscience demonstrated several unique features of E4 in terms of its pharmaceutical properties and profile. In a clinical study, E4 showed a high, dose-proportional, oral bioavailability with a surprisingly long elimination half-life (28 hrs.), making it a suitable oral estrogen for human use. After single administration of up to 10 times the anticipated daily human dose to post-menopausal volunteers, no relevant side effects appeared.  The highest dose group of a phase IB multiple dose study during 28 days in post-menopausal women is ongoing, and until now E4 appears to be safe and well tolerated. In addition a phase IB multiple dose study in men and a neoadjuvant breast cancer study in women are currently being performed.

Preclinical study results

After demonstrating for the first time that E4 is orally bioavailable in the rat, the pharmacological profile of E4 has been characterized in detail by Pantarhei Bioscience in a series of preclinical studies. E4 showed several important potential advantages over presently used estrogens such as conjugated equine estrogens (CEE), estrone (E1), estradiol (E2), estriol (E3), and ethinyl estradiol (EE). When administered orally, E4 acts as an estrogen on vagina, uterus and bone and shows a "liver-friendly" profile. E4 suppresses hot flushes and inhibits ovulation. Most surprisingly, E4 acts as an estrogen antagonist on the breast because in a validated rat model it showed to prevent development of breast tumours and to remove pre-existing breast tumours.

Possible indications

The intrinsic properties of E4 offer a wide range of opportunities for positioning the compound in key drug markets. Currently, Pantarhei Bioscience is pursuing the development of E4 as a new drug candidate for several therapeutic indications, including breast cancer, prostate cancer, contraception, osteoporosis, a new cardiovascular application and auto-immune diseases. All indications are covered by several patent applications. Additionally, Pantarhei Bioscience has developed a new route of synthesis to produce E4 on an industrial scale, covered by a separate patent application.

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