Donesta (estetrol) / Mithra, Pantarhei - LARVOL DELTA

Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1. (PubMed, J Clin Med) - "IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • IGF1

Role of membrane estrogen receptor alpha on the positive feedback of estrogens on Kisspeptin and GnRH neurons. (PubMed, eNeuro) - "Interestingly, the absence of activation of Kp and GnRH neurons is alleviated in both models by progesterone (P). Collectively the results of these two approaches converge to provide evidence that membrane estrogen signaling contributes to this key event for the central regulation of reproduction."

Journal • ER

Impact of Estetrol Combined with Drospirenone on Blood Coagulation and Fibrinolysis in Patients with Endometriosis: A Multicenter, Randomized, Open-Label, Active-Controlled, Parallel-Group Study. (PubMed, Clin Appl Thromb Hemost) - "Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090)."

Clinical • Journal • Cardiovascular • Endometriosis • Gynecology • Venous Thromboembolism • Women's Health • PROS1

Estetrol/drospirenone oral contraceptive impact on lipid parameters in 40-50 year olds (NAMS 2024) - "Changes in total cholesterol, LDL, HDL and triglyceride levels from baseline to end of treatment in a phase 3 contraceptive trial of estetrol/drospirenone were minimal and did not differ between participants 40-50 years and 16-39 years. These results support that estetrol/drospirenone has a negligible impact on lipid parameters in primarily healthy older users."

Dyslipidemia • ER

Efficacy of Estetrol (E4) for Menopausal Vasomotor Symptoms: Results from a Phase 3 Randomized, Double-Blind, Placebo-Controlled Tria (NAMS 2024) - P3 | "E4 15 mg and 20 mg significantly reduces the frequency of VMS compared to placebo by week 4 with ongoing and further reductions up to week 12. E4, reduced frequency and severity of VMS in the US and Canadian population and offers a promising new treatment option for symptomatic PM women."

Clinical • P3 data • ER

Benefits of Estetrol (E4) on Patient-Reported Outcome Measures in Postmenopausal Women: Results from a Phase 3 Trial (NAMS 2024) - P3 | "E4-treated postmenopausal women reported a general improvement in their health-related quality of life, with s significant differences compared to placebo observed for the total MENQOL score and the vasomotor domain score. Additionally, most women treated with E4 20mg reported clinically important improvement of their symptoms, compared to those treated with placebo."

Clinical • P3 data • Patient reported outcomes

Bleeding patterns with use of an oral contraceptive containing estetrol and drospirenone in older participants from two phase-3 clinical trials (NAMS 2024) - "We found no overall differences in scheduled and unscheduled bleeding/spotting or bleeding-related TEAEs across 12 cycles of estetrol/drospirenone use in participants 40-50 years compared to 16-39 years. These results demonstrate positive bleeding outcomes with estetrol/ drospirenone use in older combined oral contraceptive users."

Clinical • P3 data • Gynecology • Hematological Disorders

Bone Turnover in Postmenopausal Women: Evaluating the Impact of Estetrol (E4) From a Randomized Placebo-Controlled Phase 3 Trial (NAMS 2024) - P3 | "E4 treatment is associated with a reduction of the biomarkers CTX-1 and PINP which is indicative of reduced bone turnover. E4 has a potentially beneficial effect on maintenance of bone strength and therefore, prevention of osteoporosis in postmenopausal women."

Clinical • P3 data • Osteoporosis • Rheumatology

Efficacy and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg combination in a cyclic regimen for the treatment of endometriosis-associated pain and objective gynecological findings: A multicenter, placebo-controlled, double-blind, randomized study. (PubMed, Fertil Steril) - "E4/DRSP effectively treats endometriosis-associated pain and improves gynecological findings. E4/DRSP may be a safe, new option for endometriosis treatment with a potentially reduced risk of thromboembolic events."

Clinical • Journal • Back Pain • Cardiovascular • Endometriosis • Gynecology • Musculoskeletal Pain • Pain • Women's Health

Effects of E4/DRSP on self-reported physical and emotional premenstrual and menstrual symptoms: data from the phase 3 clinical trial in Europe and Russia. (PubMed, Eur J Contracept Reprod Health Care) - P3 | "E4/DRSP starters experienced significant improvements in the domains Pain, Water Retention and Negative Affect particularly benefiting those with more severe baseline symptoms. Switchers showed minimal changes."

Journal • P3 data • Back Pain • Fatigue • Pain

The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males. (PubMed, J Endocr Soc) - "Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public."

Journal • Review • Cardiovascular • Fatigue • Genito-urinary Cancer • Musculoskeletal Pain • Oncology • Osteoporosis • Prostate Cancer • Solid Tumor

Anti-ageing effects of Estetrol on the skin: Protection from cellular senescence and restoration of dermal architecture (ENDO 2024) - "Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Estetrol/GPER/SERPINB2 transduction signaling inhibits the motility of triple-negative breast cancer cells. (PubMed, J Transl Med) - "Overall, our results provide new insights into the mechanisms through which E4 can halt migratory and invasive features of TNBC cells."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Evaluating the toxicity of estetrol, 17α-ethinylestradiol, and their combination with drospirenone on zebrafish larvae: A behavioural and proteomic study. (PubMed, Aquat Toxicol) - "These findings suggest that E4-based combined oral contraceptives present a more favourable environmental profile than EE2-based contraceptives, particularly during the early developmental stages of fish."

Journal

Safety, compliance and pharmacokinetics of E4/DRSP in post-menarchal female adolescents (ESCRH 2024) - P3 | "This study will provide crucial insights into E4/DRSP's safety, compliance, and bleeding profiles in post-menarchal adolescents, commonly prescribed COC for non-contraceptive purposes."

Clinical • Compliance • PK/PD data • Women's Health

Safety and tolerability of the Estetrol/Drospirenone contraceptive pill in starters compared to switchers (ESCRH 2024) - P3 | "The total incidence of adverse events in E4/DRSP starters and true new starters is notably lower than that observed in switchers, additionally AEs dysmenorrhea, viral upper respiratory tract infections and acne were reported more frequently in switchers. These findings reinforce the favourable safety profile of E4/DRSP in the starter group. Conflict details: KGD is ad hoc advisory board member and speaker for Organon (MSD), Bayer, Exelgyn, Actavis, Gedeon Richter, Mithra, Exeltis, Ferring, Natural Cycles, Azanta, Gynuity, Obseva MedinCell, Cirqle, Addeira and HRA-Pharma, member of the ICCR, Population council and Director of a WHO collaborating centre for research in Human Reproduction and investigator of ongoing NICHD male contraception trial."

Clinical • Acne Vulgaris • CNS Disorders • Depression • Infectious Disease • Nephrology • Pain • Psychiatry • Respiratory Diseases • Women's Health

Estetrol/drospirenone versus 17α-ethinylestradiol/drospirenone: An extended one generation test to evaluate the endocrine disruption potential on zebrafish (Danio rerio). (PubMed, Environ Int) - "In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (∼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation. Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP."

Journal

EFFECTS OF ESTETROL ON MITOCHONDRIAL FUNCTIONS IN CELLULAR MODELS OF ALZHEIMER'S DISEASE (ADPD 2024) - "The data indicate that E4 is able to modulate cellular bioenergetics with an overall similar or, for some parameters, better efficacy than E2. E4 and E2 treatment showed better efficacity in the cellular model of AD-related tauopathy than in the model of amyloidopathy. This statement must be verified with further experiments."

Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • APP

Low thrombin generation in postmenopausal women using estetrol. (PubMed, Climacteric) - P2 | "After 12 weeks of treatment, all treatment groups showed a mean thrombogram (±95% confidence interval [CI] of the mean) within the reference ranges, that is, the 2.5th-97.5th percentile of all baseline thrombograms (n = 168), as well as for TGA parameters. The intake of E4 15 mg for 12 weeks led to significant but not clinically relevant changes compared to baseline as the mean values (±95% CI of the mean) remained within reference ranges, demonstrating a neutral profile of this estrogen on hemostasis."

Journal • ER

Role of membrane estrogen receptor alpha (ERα) in the rapid regulation of male sexual behavior. (PubMed, J Neuroendocrinol) - "In conclusion, the shift in timing at which the effect of E4 is observed in mice lacking mERα suggests a role for mERα in the regulation of rapid effects of neuroestrogens on sexual performance, thus providing the first demonstration that E4 acts as an antagonist of a mER in the brain. The persisting effect of ATD on behavior in C451A-ERα mice also suggests the implication of another ER."

Journal • ER

The benefits of estetrol addition to drospirenone for contraception. (PubMed, AJOG Glob Rep) - "Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years...Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively...The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters."

Journal • Cardiovascular

Mithra prices private placement to raise EUR 20 million in equity (GlobeNewswire) - "Mithra Pharmaceuticals SA...announces today that it entered into a definitive agreement to raise EUR 20 million in gross proceeds via a private placement of 10 million new ordinary shares at an issue price of EUR 2.00 per share, representing a 17% discount to the closing share price on 23 August 2023 (the 'Private Placement')...Under the terms of the Private Placement, the Investor committed to subscribe for 10 million new shares of the Company....'The proceeds will be used to advance development of our promising portfolio of medicines as we execute on our strategy to become a global leader in women’s health. In particular, the funds will support the filing for approval of Donesta®, our next generation Estetrol®-based hormone therapy product candidate in the U.S., as well as other development and corporate expenses.'"

Financing • Breast Cancer • CNS Disorders • Endometriosis • Genito-urinary Cancer • Migraine • Oncology • Pain • Prostate Cancer • Solid Tumor • Women's Health

Estetrol Is Safe and Well Tolerated during Treatment of Hospitalized Men and Women with Moderate COVID-19 in a Randomized, Double-Blind Study. (PubMed, J Clin Med) - P2 | "The primary efficacy endpoint of improvement in COVID-19 (percentage of patients recovered at day 28) between the placebo and E4 arms was not met. E4 was well tolerated, with no safety signals or thromboembolic events, suggesting that postmenopausal women can safely continue E4-based therapy in cases of moderate COVID-19 managed with SoC."

Clinical • Journal • Cardiovascular • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Estetrol Prolongs Anagen in Healthy Female Scalp Hair Follicles by Positively Modulating Dermal Papilla Functions and Generation of Progenitor Stem Cells Ex Vivo (ENDO 2023) - "Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Preclinical • Alopecia • ALPL • CD34 • ER • VCAN

Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment. (PubMed, Int J Mol Sci) - "Measurements of the circulating concentration of E4 in mice revealed that the mouse equivalent dose necessary to mimic human treatment does not fit with the allometric prediction. In conclusion, this study highlights the importance of precise definition of the most appropriate dose and route of administration to utilize when developing predictive preclinical animal models to mimic or anticipate specific human treatment."

Journal • Preclinical