Estetrol (E4), the first NEST™

Due to perceived safety and health concerns linked to hormone-related therapies, many women continue to avoid treatment for menopause symptoms or contraceptive solutions. Studies also underline the unmet need today for an estrogen with an improved benefit/risk profile. Preclinical and clinical research to date indicate that E4 could address this unmet need.

Estetrol (E4) is the first NEST™ : Native Estrogen acting Selectively in Tissues. Because of its unique mode of action, Mithra believes E4 has the potential to transform the Women’s Health Market, providing an improved side effect profile over current estrogens in key areas including oral contraception and menopause.

Today, Mithra is focused on the development of two late-stage E4-based products : Estelle^®, a 5th generation oral contraceptive, and Donesta^®, a next generation hormone therapy for VMS in menopause.

What is Estetrol (E4)?

Estetrol is a natural estrogen produced by the human foetus and passing in maternal blood at relatively high levels during pregnancy.

Unique potential

Thanks to its favorable pharmacodynamics and pharmacokinetics profile, its tolerability and its safety margin, E4 potentially represents a major breakthrough in various therapeutic fields of women’s health such as contraception and menopause. E4 also indicates applicability in areas outside of women’s health including hormone-dependant cancers, osteoporosis, neuro-protection and wound healing.

Mithra possesses a large number of patent families regarding Estetrol, from E4 synthesis to its use in a broad range of indications such as hormone-dependant cancer treatment (breast and prostate cancer in particular), dermatology (e.g. wound healing), neuroprotection and musculoskeletal pain.

Estetrol R&D Projects

Estelle^®

Contraception

Mithra’s lead product candidate, Estelle^®, is a Combined Oral Contraceptive (COC), composed of 15 mg Estetrol (E4) and 3 mg Drospirenone (DRSP).

Estelle® is currently in phase III clinical trials in Europe and in North America, under the name E4 Freedom (More info : www.e4freedom.com).

Donesta^®

Menopause

Donesta^® is a product candidate for a new generation of Hormone Therapy (HT), with the oral administration of Estetrol (E4) for Vasomotor Menopausal Symptoms (VMS) relief.

Donesta^® Phase II study, E4 Relief, recently yielded positive top-line results for VMS.

Projects pipeline

Pre-clinical

Phase I

Phase II

Phase III

Registration

Estelle®

Donesta®

Estetrol Videos

About Estetrol

Discover the history of Estetrol

Essenscia Innovation Award 2016

Presentation of Estetrol by Prof. Jean-Michel Foidart

Estetrol Interview

Estetrol for Oral Contraception, 16th World Congress of Human Reproduction, Berlin, 2015

F.A.Q.

What are the effects of oestrogens ?

Oestrogens refer to a group of hormones that play an essential role in the growth and development of female sexual characteristics and the reproductive process. Oestrogens circulate in the bloodstream and bind to oestrogen receptors on cells in targeted tissues, affecting not only the breast and uterus, but also the brain, bone, liver, heart and other tissues. Furthermore, they control growth of the uterine lining during the first part of the menstrual cycle, cause changes in the breast during adolescence and pregnancy and regulate various other metabolic processes, including bone growth and cholesterol levels.

Overall, natural oestrogens are mainly produced in the ovaries, adrenal glands and fat tissues. The three major naturally occurring oestrogens in women are:

Estrone (E1), the predominant oestrogen in menopausal women, is produced primarily in the ovaries
Estradiol (E2), the most abundant in women of reproductive age, is the predominant oestrogen in pre-menopausal women and is produced primarily in the ovaries
Estriol (E3) is produced by the placenta during pregnancy.

Most current marketed drugs containing oestrogen consist of E2 and ethinylestradiol (EE), the latter is a potent synthetic oestrogen derivative from E2.

What are clinical trials?

Pharmaceutical companies perform clinical research studies to advance science and treatment options.

When a new molecular compound is discovered or selected and has a potential improvement for patient health, it goes through laboratory testing during pre-clinical development. Once pre-clinical tests show promising results, the next step is clinical trials on humans. The goal/purpose of clinical trials is to learn more about safety and efficacy of medications to determine whether they can be made available to the public.

Thousands of volunteers all around the world take part in well-controlled clinical research studies every year. These are carefully monitored under strict government regulations.

What are the phases of a clinical trial?

A medical product development is a long and expensive process that can take more than ten years until approval. It is divided in consecutive phases:

Phase I : The goal of Phase 1 studies is to evaluate how the drug interacts with the human body, the side effects associated with increased dosages, and could also gather early information about how effective it is and determine the drug administration which have limited risk and a maximum of possible benefits. These trials are conducted on healthy volunteers (tens). After Phase 1 and in case of good safety profile, the product can go through Phase II.

Phase II : The goal of Phase 2 studies is to determine the optimal dosing of the medicinal product and to test the efficacy and complete the safety data. These trials are conducted on few hundred patients. If the evidence of effectiveness is shown, the Phase III can start.

Phase III : The goal of Phase 3 studies is to confirm previous results with the new medicinal product in order to show the efficacy and evaluate the efficacy/tolerance to a specific population. These trials are done on several hundred up to thousands patients.

Complete dossier and results are then submitted to the competent health authorities (as for example the European Agency of Medicines (EMA) in Europe or the FDA (US Food & Drug Administration) in the US) and in case of marketing license authorization, the new medicinal product is brought to market.

Phase IV : Once on the market, Phase 4 studies are carried out for post-marketing safety monitoring with close watch on the side effects : it is pharmacovigilance.