The combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP) (E4/DRSP) is a novel oral contraceptive containing a fixed dose of E4 (14.2 mg) and DRSP (3 mg). The proposed study will address post-market requirements for E4/DRSP under section 505(o) in response to the Food and Drug Administration (FDA) request.
The primary objective of the study is to characterize and compare the risks of E4/DRSP with EE/DRSP and E4/DRSP with a pooled cohort of users of EE/LNG, EE/NETA, and EE/NGM combinations (non-DRSP-containing COCs) in a study population of actual users of these preparations under routine clinical practice. The main clinical outcome of interest is VTE.

Start Date01 Oct 2024

Sponsor / Collaborator

Estetra SRL

NCT06308614 / RecruitingPhase 2

A Phase 2, Randomized, Double-blind, Placebo-controlled Proof-of-Concept Study to Evaluate the Efficacy and Safety of Estetrol in Postmenopausal Subjects With Female Sexual Arousal Disorder

The goal of this clinical trial is investigating estetrol (E4) in women after menopause, suffering from sexual arousal disorder. The main question it aims to answer is: is 20 mg estetrol monohydrate effective in the treatment of sexual arousal disorder in women after their menopause. Participants will visit the clinic 7 times and complete a daily diary while receiving estetrol or placebo for 12 weeks. Placebo is a pill that looks the same as estetrol but has no active ingredient. Researchers will compare estetrol and placebo to see if estetrol has an effect on the sexual arousal of the participants.

Start Date29 Jan 2024

Sponsor / Collaborator

Estetra SRL

NCT06028555 / RecruitingNot ApplicableIIT

International Active Surveillance Study: Native Estrogen Estetrol (E4) Safety Study

Multinational, comparative, prospective, active surveillance study that follows two cohorts.
The primary objective of the study is to characterize and compare the risks of E4/Drospirenone (DRSP) with levonorgestrel-containing combined oral contraceptives (EE/LNG) in a study population that is representative of the actual users of these preparations. The main clinical outcome of interest is venous thromboembolism (VTE), specifically deep venous thrombosis (DVT) and pulmonary embolism (PE). Secondary objectives include measuring the occurrence of unintended pregnancy, assessing the risk of arterial thromboembolism (ATE), describing the drug utilization pattern, describing the baseline risk profile for VTE and ATE, and investigating outcomes associated with foetal exposure to E4/DRSP.

Start Date28 Jun 2023

Sponsor / Collaborator

Estetra SRL

100 Clinical Results associated with Estetrol

100 Translational Medicine associated with Estetrol

100 Patents (Medical) associated with Estetrol

215

Literatures (Medical) associated with Estetrol

01 Nov 2024·FERTILITY AND STERILITY

Efficacy and safety of the combination of estetrol 15 mg/drospirenone 3 mg in a cyclic regimen for the treatment of endometriosis-associated pain and objective gynecological findings: a multicenter, placebo-controlled, double-blind, randomized study

Article

Author: Hirakawa, Akihiro ; Harada, Tasuku ; Takayanagi, Toshiaki ; Nogami, Masayoshi ; Kobayashi, Takao ; Osuga, Yutaka ; Hirayama, Masashi ; Mochiyama, Takayuki ; Foidart, Jean-Michel

OBJECTIVE:

To evaluate the efficacy and safety of 24-week cyclic administration of estetrol (E4) (15 mg)/drospirenone (DRSP) (3 mg) in Japanese patients with endometriosis.

DESIGN:

A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

SETTING:

Twenty-five study centers in Japan.

PATIENT(S):

A total of 162 Japanese women diagnosed with endometriosis.

INTERVENTION(S):

Participants were randomly allocated to the E4/DRSP group or the placebo group. In the E4/DRSP group, participants were orally administered one tablet containing E4 (15 mg) and DRSP (3 mg) daily for 24 days, followed by one placebo tablet for 4 days for a hormone-free interval, constituting a 1-cycle regimen. One placebo tablet was administered once daily for 28 days to participants in the placebo group. The treatments were continued for six cycles (24 weeks) throughout the confirmatory period.

MAIN OUTCOME MEASURE(S):

Changes in visual analogue scale (VAS) scores for the most severe pelvic pain (lower abdominal and back pain) from baseline to six treatment cycles at the end of the confirmatory study period.

RESULT(S):

Estetrol/drospirenone showed changes in the mean VAS scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the 6-cycle treatment. The between-group difference was significant (-8.5 mm; 2-sided 95% confidence interval, -16.1 to -0.9 mm), showing superiority to placebo. The responder rates, ≥30% and ≥50% reductions in the VAS scores from baseline, were higher in the E4/DRSP group than in the placebo group: 53.2% vs. 29.6% and 36.4% vs. 12.3%. Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, and limited uterine mobility) were significantly improved by E4/DRSP treatment, and the proportions of stable and worsened participants were significantly lower than in the placebo group. Estetrol/drospirenone decreased the size of endometriomas and improved quality of life, on the basis of quality of life-related questionnaires and global impression scores. No safety concerns were observed with E4/DRSP treatment. Few differences were observed in the proportion of participants with hemostasis parameters outside the reference range between the E4/DRSP and placebo groups.

CONCLUSION(S):

Estetrol/drospirenone effectively treats endometriosis-associated pain and improves gynecological findings. Estetrol/drospirenone may be a safe, new option for endometriosis treatment with a potentially decreased risk of thromboembolic events.

CLINICAL TRIAL REGISTRATION NUMBER:

jRCT2011210027.

01 Nov 2024·FERTILITY AND STERILITY

Efficacy and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg combination in a cyclic regimen for the treatment of primary and secondary dysmenorrhea: A multicenter, placebo-controlled, double-blind, randomized study.

Article

Author: Mochiyama, Takayuki ; Osuga, Yutaka ; Hirakawa, Akihiro ; Hirayama, Masashi ; Takayanagi, Toshiaki ; Nogami, Masayoshi ; Kobayashi, Takao ; Harada, Tasuku ; Foidart, Jean-Michel ; Tayzar, Kyaw

OBJECTIVE:

To evaluate the efficacy and safety of the estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg combination in a cyclic regimen in Japanese women with primary and secondary dysmenorrhea.

DESIGN:

A 16-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study, followed by a 36-week, open-label, extension study.

SUBJECTS:

162 Japanese women with primary and secondary dysmenorrhea.

INTERVENTION:

Participants were randomly allocated to either the E4/DRSP group or the placebo group. In the E4/DRSP group, participants orally received one tablet containing E4 15 mg and DRSP 3 mg daily for 24 days, followed by a placebo tablet for 4 days, constituting one cycle. The placebo group was given one placebo tablet daily for 28 days. After 16 weeks, participants in the placebo group were switched to receive E4/DRSP for 36 weeks.

MAIN OUTCOME MEASURES:

Absolute change in the most severe total dysmenorrhea score from baseline to the end of the 16-week double-blinded period.

RESULTS:

E4/DRSP reduced the most severe total dysmenorrhea score by 2.3 points from baseline at week 16. The between-group difference was significant (-1.4, two-sided 95% confidence interval: -1.8 to -1.0), showing superiority to placebo (p<0.001). The responder rate, the proportion of participants who achieved a ≥2.0-point reduction in the most severe total dysmenorrhea score from baseline, was 64.3% in the E4/DRSP group, significantly higher than in the placebo group, 28.4%, (p<0.05). In the E4/DRSP group, visual analog scale scores for pelvic pain and dysmenorrhea symptoms during the menstrual bleeding periods were decreased by 44.2 mm and 42.3 mm, respectively, from baseline at week 16, significantly more than in the placebo group (p<0.001). Objective gynecological examinations suggested amelioration of pelvic tenderness, uterine mobility, and cul-de sac induration in the E4/DRSP group. E4/DRSP improved the quality of life-related questionnaires (interference with daily activities and sleeping) and global impression scores. Intermenstrual bleeding was the primary treatment-emergent adverse event in the E4/DRSP group, similar to combined oral contraceptives. There were no cases of venous thromboembolism and less impact on hemostasis parameters in the E4/DRSP group.

CONCLUSION:

E4/DRSP is an effective treatment for dysmenorrhea, offering a safe, new treatment option with potentially reduced thromboembolic risk.

01 Oct 2024·CONTRACEPTION

Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: A disproportionality analysis of the Eudravigilance database

Article

Author: Locquet, Médéa ; Beaudart, Charlotte ; Dogné, Jean-Michel ; Didembourg, Marie ; Tchimchoua, Babel Tsague ; Raskin, Lucie ; Douxfils, Jonathan

OBJECTIVES:

Pharmacovigilance data analysis can accelerate the identification of drug-related safety signals or reassure on the safety profile. This study evaluates the venous thromboembolism (VTE) risk of newer combined oral contraceptive (COC) formulations with natural estrogens, such as estradiol (E2) and estetrol (E4), using data from the EudraVigilance database.

STUDY DESIGN:

We conducted a disproportionality reporting rate analysis of VTE events associated with various COC formulations by extracting individual case reports from EudraVigilance database up to July 28, 2024. The study compared the proportionality reporting rate between natural estrogen-based COCs (E2 and E4) and conventional synthetic estrogen-based COCs (ethinylestradiol [EE]), with a comparison to EE-levonorgestrel.

RESULTS:

The analysis revealed that COCs containing natural estrogens exhibited significantly lower proportionality reporting rates for thrombotic events compared to EE-based COCs. Specifically, E4-drospirenone (E4-DRSP) showed the lowest proportionality reporting rate (0.12), similar to progestin-only pills. EE-DRSP had the highest proportionality reporting rate (2.25), suggesting an increased thrombotic risk.

CONCLUSIONS:

The study supports the safer thrombotic profile of natural estrogen-based COCs, particularly E2 and E4 formulations, over synthetic estrogen-based COCs containing EE. These findings support the hypothesis that E2- and E4-based pills are safer than EE-based pills, aligning with a shift toward safer contraceptive options in clinical practice.

IMPLICATIONS:

Natural estrogens such as E2 and E4 may emerge as safer alternatives to synthetic estrogens like EE, particularly when combined with progestins like DRSP. This multilevel evidence underscores the importance of evidence-based prescribing practices to enhance patient safety and minimize thrombotic risks associated with COC use.

News (Medical) associated with Estetrol

12 Jun 2024

·www.pharmaceutical-technology.com

Bankrupt Mithra cashes in on remaining assets for $188.2m

Mithra’s efforts to extend its cash runway earlier this year were unsuccessful. Image credit: Shutterstock/Nudphon Phuengsuwan. A day after filing for bankruptcy, Mithra has sold its share in two of its daughter pharmaceutical companies along with rights to its female hormone drug portfolio for €175m ($188.2m). Recommended Buyer's Guides Buyer's Guide Leading Guide to Packaging Materials, Containers and Containment Services for the Pharmaceutical Industry Buyer's Guide Leading Guide to Compliance Software for the Pharmaceutical Industry The deal saw Budapest-headquartered pharma company Gedeon Richter buy all of Mithra’s shares in Neuralis and Estetra – both subsidiaries of the struggling women’s health pharmaceutical company. Gedeon Richter also gained assets related to the manufacturing of estetrol. The funds, after deduction of financial debts, will be used to repay Mithra’s creditors, meaning the sale does not create any value for the shareholders of Mithra Pharmaceuticals , according to a 10 June press release. Belgium-based Mithra has faced severe financial difficulties in the past few years with share prices tanking by more than 90%. Efforts to extend its cash runway , which included raising $13.7m by selling its stake in Mayne Pharma , were unsuccessful, forcing the company to file for bankruptcy and siphon off its remaining holdings. The transfer will see Gedeon Richter gain rights to Mithra’s Estelle (estetrol-E4 / drospirenone), marketed as Nextstellis and Drovelis in the US and EU respectively. Estelle netted Mithra €2.6m in the first half of 2023. See Also: NPX-267 by NextPoint Therapeutics for Triple-Negative Breast Cancer (TNBC): Likelihood of Approval NPX-267 by NextPoint Therapeutics for Non-Small Cell Lung Cancer: Likelihood of Approval Gedeon Richter will also take on development duties for Mithra’s menopause treatment candidate Donesta which produced positive topline Phase III results in mid-2023. The orally administered estetrol (E4) hormone therapy is slated for US approval in 2024 and EU approval in 2025. Mithra said that “all 49 members of the personnel engaged by the transferred entities will be able to pursue their activities with Gedeon Richter,” along with 17 other employees who have been offered jobs by the latter company. Two of Mithra’s other properties – Novalon, a long-acting drug specialist entity it acquired in 2015, and a contract development and manufacturing organisation (CDMO) facility – remain unaffected by the deal with Gedeon Richter and stay under protection. Mithra said it expects offers to come in by mid-month subject to judicial protection measures being extended. In a statement released on 10 June announcing bankruptcy filing, Mithra stated its employees’ research and future progress “will outlive Mithra and will continue under a different banner from now on. We all hope that these efforts will lead to the development of new solutions that will benefit as many people as possible.”

Phase 3AcquisitionClinical Result

28 May 2024

·www.globenewswire.com

Mithra postpones its annual general meeting

Liege, Belgium, 28 May 2024 – 15:00 CEST – Mithra (Euronext Brussels: MITRA), a company dedicated to women’s health, today announces that in the context of the monetization process and the uncertainties related thereto, Mithra postpones its Annual General Shareholders’ Meeting, previously planned for 30 May 2024, to a later date to be determined. Background Information: On 5 March 2024, Mithra announced the launch of a comprehensive monetization process, exploring potential sales of selected assets, notably Estetra SRL, and potentially the entire business. Additionally, Mithra announced the entry into a secured bridge loan facility (“the Facility”) for an amount of up to EUR 13.5 million to be drawn in multiple tranches upon the satisfaction of certain milestones, as well as an uncommitted EUR 5 million "accordion" facility (which could be used once the committed amount has been fully drawn and only if the lenders consent). The lenders under the Facility consist of funds managed by Highbridge Capital Management, LLC and funds managed by Whitebox Advisors, LLC. The monetization process for Mithra’s CDMO and Novalon SA assets are proceeding under court protection measures from the Liege Company Courts. The Mithra CDMO asset in Flemalle, Belgium was granted “Transfer under Judicial Supervision” with court-designated trustees to oversee negotiations with potential bidders and select the best offer while safeguarding the interests of the company, its creditors, and its employees. The Judicial reorganization proceedings to restructure the debt of Novalon SA, Mithra’s complex therapeutics business, involves reaching an amicable agreement with some creditors and implementing a court-sanctioned debt-restructuring plan therewith. The protection measures are expected to remain in effect until 19 June 2024. For more information, please contact: Mithra Pharmaceuticals SAAlex Sokolowski, PhDHead of IR & Communicationsinvestorrelations@mithra.com +32 (0)4 349 28 22 Frédérique Depraetere Communications Directorinfo@mithra.com+32 (0)4 349 28 22 About Mithra Mithra Pharmaceuticals SA (Euronext: MITRA) is a Belgian biopharmaceutical company dedicated to transforming women’s health by offering new choices through innovation, with a particular focus on contraception and menopause. Mithra’s goal is to develop products offering better efficacy, safety and convenience, meeting women’s needs throughout their life span. Mithra explores the potential of the unique native estrogen estetrol in a wide range of applications in women health and beyond. After having successfully launched the first estetrol-based product in 2021, the contraceptive pill ESTELLE®, Mithra is now focusing on its second product DONESTA®, the next-generation hormone therapy. Mithra also offers partners a complete spectrum of solutions from early drug development, clinical batches and commercial manufacturing of complex polymeric products (vaginal ring, implants) and complex liquid injectables and biologicals (vials, pre-filled syringes or cartridges) at its technological platform Mithra CDMO. Active in more than 100 countries around the world, is headquartered in Liège, Belgium. www.mithra.comESTELLE® and DONESTA® are registered trademarks of Mithra Pharmaceuticals or one of its affiliates. Important informationThe contents of this announcement include statements that are, or may be deemed to be, "forward-looking statements". These forward-looking statements can be identified by the use of forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. By their nature, forward-looking statements involve risks and uncertainties, and readers are cautioned that any such forward-looking statements are not guarantees of future performance. The Company's actual results may differ materially from those predicted by the forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law.

29 Apr 2024

·www.globenewswire.com

Mithra updates on offers received in the context of its monetization process and on its Annual Report 2023

Mithra has received binding offers for selected assets, including Estetra SRL, as part of its monetization process. As it stands, the aggregate amount of these offers is insufficient to ensure full repayment of all creditors of Mithra, and, therefore, the offers do not allow to create value for Mithra’s shareholders at the present time.Mithra has requested the suspension of trading of its shares on Euronext Brussels pending continuing negotiations with offering parties.Mithra postpones the publication of its Annual Report 2023 to a later date due to the current circumstances to reflect a situation in discontinuity. LIEGE, Belgium, April 29, 2024 (GLOBE NEWSWIRE) -- Mithra (Euronext Brussels: MITRA), a company dedicated to women’s health, announces that it has received several binding offers1 for selected Mithra assets (particularly Estetra SRL) during the week of 22 April 2024, as part of its ongoing monetization process— first announced on 05 March 2024. In collaboration with Stifel Investment Bank and other expert advisors, Mithra is diligently analyzing these offers, which include all shares in Estetra SRL and certain other activities and assets within the Mithra group. Mithra continues to seek potential buyers for all its activities and assets (i.e., Mithra CDMO, Novalon, Mithra R&D, Neuralis, Mithra parent co.). As it stands, the aggregate amount of these offers is insufficient to ensure full repayment of all creditors of Mithra. Therefore, the offers received will not create value for the shareholders of Mithra. Mithra remains committed to negotiating with the offering parties to enhance the value offered, acting in the best interest of all stakeholders. The Company is also considering taking appropriate action, including continuing negotiations for the relevant assets under court proceedings (as is the case for other assets of the Mithra group), to advance these discussions further if necessary. Consequently, Mithra has requested the Financial Services and Markets Authority (FSMA) to suspend trading of the Company’s shares on Euronext Brussels pending the on-going negotiations. Mithra remains committed to executing its monetization process with diligence and transparency representing the interests of all stakeholders and will continue providing timely updates to the market and stakeholders as appropriate. Additionally, Mithra will postpone the publication of its Annual Report 2023 (originally scheduled for 30 April 2024) as it was prepared based on a going concern assumption. Instead, considering the recent events, an annual report will be prepared and published for Mithra reflecting a situation "in discontinuity" at a later date, which will be announced in a subsequent communication. About MithraMithra Pharmaceuticals SA (Euronext: MITRA) is a Belgian biopharmaceutical company dedicated to transforming women’s health by offering new choices through innovation, with a particular focus on contraception and menopause. Mithra’s goal is to develop products offering better efficacy, safety and convenience, meeting women’s needs throughout their life span. Mithra explores the potential of the unique native estrogen estetrol in a wide range of applications in women health and beyond. After having successfully launched the first estetrol-based product in 2021, the contraceptive pill ESTELLE®, Mithra is now focusing on its second product DONESTA®, the next-generation hormone therapy. Mithra also offers partners a complete spectrum of solutions from early drug development, clinical batches and commercial manufacturing of complex polymeric products (vaginal ring, implants) and complex liquid injectables and biologicals (vials, pre-filled syringes or cartridges) at its technological platform Mithra CDMO. Active in more than 100 countries around the world, is headquartered in Liège, Belgium. www.mithra.com ESTELLE® and DONESTA® are registered trademarks of Mithra Pharmaceuticals or one of its affiliates. Important informationThe contents of this announcement include statements that are, or may be deemed to be, "forward-looking statements". These forward-looking statements can be identified by the use of forward-looking terminology, including the words "believes", "estimates," "anticipates", "expects", "intends", "may", "will", "plans", "continue", "ongoing", "potential", "predict", "project", "target", "seek" or "should", and include statements the Company makes concerning the intended results of its strategy. By their nature, forward-looking statements involve risks and uncertainties, and readers are cautioned that any such forward-looking statements are not guarantees of future performance. The Company's actual results may differ materially from those predicted by the forward-looking statements. The Company undertakes no obligation to publicly update or revise forward-looking statements, except as may be required by law. 1 subject to certain / customary conditions

Drug Approval

100 Deals associated with Estetrol

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KEGG	Wiki	ATC	Drug Bank
D11513	Estetrol	-	DB12235

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Menopausal symptoms	Phase 3	US	Estetra SRL	27 Sep 2019
Menopausal symptoms	Phase 3	CA	Estetra SRL	27 Sep 2019
Vasomotor symptom	Phase 3	US	Estetra SRL	27 Sep 2019
Vasomotor symptom	Phase 3	CA	Estetra SRL	27 Sep 2019
Menopausal syndrome	Phase 3	-	Mithra Pharmaceuticals SA	-
Hot Flashes	Phase 2	BE	Donesta Bioscience BV	01 May 2016
Contraception	Phase 2	FI	Estetra SRL	01 Sep 2010

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02720224 (CTgov)	Phase 1	Contraception	6	Estetrol	xyeqtkbpvk(ptoumenqvu) = vfyxqhwdzb txsdbyrqfx (euqmjnofdp, lritafmxcw - gcrijnetce) View more	-	10 Dec 2018

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