Two months after acquiring the rights to Estetrol in the field of oral contraceptives and the recent capital inflow from M. Coucke, Mithra Pharmaceuticals is once again consolidating its innovation portfolio, this time by acquiring full rights to Estetrol from Pantarhei Bioscience. This agent offers therapeutic prospects perfectly in keeping with the four main spheres of gynaecology covered by Mithra Pharmaceuticals.
“Mithra is a pharmaceutical company focused on women’s health. Through our products and Research & Development projects, we cover the four major spheres of gynaecology, namely fertility and contraception, the menopause and osteoporosis, gynaecological infections, and also cancer. The acquisition of Donesta gives us the opportunity to operate several patents in three of our four therapeutic areas. This is major progress in our company’s position,” explains François Fornieri, CEO of Mithra Pharmaceuticals.
Pantarhei Bioscience will receive an initial payment, together with milestones based on the successful development of projects relating to the menopause.
Mithra Pharmaceuticals will grant Pantarhei Bioscience a licence for the development of human applications in oncology and veterinary applications. The Dutch firm will study therapies for reproductive organ cancers, such as ovarian cancer and breast cancer. Mithra will have the right to first refusal should Pantarhei Bioscience undertake partnership negotiations.
Professor Herjan Coelingh Bennink, CEO of Pantarhei Bioscience, will be on the board of Mithra Pharmaceuticals and will become Co-Chairman of the scientific committee.
“We are delighted about this acquisition which has given Mithra Pharmaceuticals additional essential assets. Mithra intends to focus initially on the applications relating to contraception and the menopause, two essential and extremely dynamic markets,” declares François Fornieri, CEO of Mithra Pharmaceuticals.
Estetrol (E4) is a natural oestrogen produced in large quantities by the human foetal liver. The role of E4 in embryonic physiology and/or human pregnancy has not yet been determined. E4 passes into the maternal blood circulation via the placenta. E4 can be detected from the ninth week of pregnancy. Maternal and foetal E4 concentrations increase exponentially throughout pregnancy, reaching their maximum at term, when the foetal concentrations recorded are approximately 10 to 20 times higher than maternal levels. This natural evidence during the most vulnerable physiological situation that exist tends to suggest the superior safety of this substance.
Result of preclinical studies
The pharmacological profile of E4 was characterised in detail by Pantarhei Bioscience in the context of a series of preclinical studies. E4 has revealed several major potential advantages relative to the oestrogens currently used, such as conjugated equine oestrogens (CEO), estrone (E1), estradiol (E2), estriol (E3) and ethinylestradiol (EE). During oral administration, E4 acts an oestrogen at vaginal, uterine and bone level, demonstrating a profile “which preserves the hepatic environment”. Furthermore, E4 eliminates hot flushes and prevents ovulation. More surprisingly, E4 acts as an oestrogen antagonist in breast tissue. In a validated rat model, it was shown to be able to prevent the development of breast tumours and eliminate pre-existing breast tumours in the presence of estradiol (E2).
“The key characteristic of Estetrol is its differentiated action mechanism according to tissue. This is known as ‘SERM’ (selective oestrogen receptor modulator),” explains Herjan Coelingh Bennink, CEO of Pantarhei Bioscience. “Estetrol acts both as a relatively potent oestrogen on certain types of tissue such as the vaginal mucosa, bone and brain – which explains the effect on hot flushes and inhibition of ovulation –, whereas it has a neutral effect on other types of tissue such as the liver – hence the fact that it does not stimulate coagulation and does not increase the risk of thrombosis and embolism. Lastly, it has an anti-oestrogen effect on breast tissue. We therefore have access to an oestrogen without any negative consequences on coagulation and which does not appear to have any consequences on breast cancer”.
Result of clinical studies
Studies have shown that, once administered to post-menopausal women, E4 effectively reduces the frequency of hot flushes and nocturnal sweating. The results of phase 1 studies also prove that E4 does not appear to stimulate breast cancer and could even exert an inhibitory effect. Lastly, E4 has a positive action on bone metabolism and could therefore be used in the context of the prevention or treatment of osteoporosis. These results support the development of hormone replacement therapy (HRT) containing E4 in the hope of maintaining the current benefits of HRT (reduction in hot flushes, improvement in bone quality and quality of life) while reducing the risk profile (cardiovascular disease, thrombosis, embolism and breast cancer).
About the menopause
“Estetrol is very promising in the field of the menopause: It relieves vasomotor symptoms, unpleasant hot flushes and, at low doses, stimulates keratinocyte proliferation in the vaginal mucosa, which makes it a potential treatment for vaginal atrophy and urogenital complaints (micturition disorders, dyspareunia, and vaginal dryness). Until now, short-term studies have been conducted, with small numbers of women, but are generating positive results. The next step is to investigate for the ideal dose (phase II studies), which will be followed by a study including a larger number of female patients. In order to implement and finance this development, we have found Mithra to be a solid partner, recognised in the field of women’s health,” explains Herjan Coelingh Bennink, CEO of Pantarhei Bioscience.
About Pantarhei Bioscience
Pantarhei Bioscience is a Dutch pharmaceutical company created in 2001, specialising in the development of innovative therapeutic approaches in the fields of women’s health and cancer therapies. Guided by a clear goal for innovation, the company develops and patents totally innovative therapeutic concepts based on existing compounds. An innovative vision is applied throughout preclinical and clinical studies, until proof of the clinical feasibility of the concept is achieved, and the next step is always entrusted to a partner.
 1. Visser M, Coelingh Bennink HJT. Clinical applications for estetrol. J Reproductionsmed Endocrinol 2010;7(Sonderheft 1):56-60.