Mithra (Euronext Brussels: MITRA), a company dedicated to Women’s Health, today announced positive topline safety results from the Phase 3 Donesta® pivotal E4 COMFORT clinical trial in the United States and Canada aiming at evaluating the efficacy and safety of Donesta® for the treatment of Vasomotor Symptoms (VMS) in post-menopausal women. Donesta® is Mithra’s next generation orally-administered Estetrol (E4)-based hormone therapy product candidate.
Phase 3 North American Study topline safety results support overall good safety profile of Donesta®, Mithra’s next generation Estetrol (E4)-based product candidate for menopause, as consistently demonstrated in previous E4 studies.
Topline safety results were demonstrated for the treatment of post-menopausal women aged 40-65 years with moderate to severe vasomotor symptoms with key secondary endpoints achieved, including E4’s beneficial effect on cholesterol profile and on bone turnover biomarkers. These highlights will be presented during the webcast dedicated to Mithra’s 2022 full year results.
These results will support the filing with U.S. regulatory agency anticipated by end of H1 2023 for a market authorization in H1 2024, whereas primary safety data are anticipated in H1 2024 for Europe with a market authorization in H1 2025.
Full dataset analysis is still in progress
The Phase 3 Clinical Program carried out in 2,550 postmenopausal women (1) (40-65 years) includes two pivotal studies: one in North America (C302) and a second in 14 countries in Europe, Latin America and Russia (C301). Both trials are randomized, multicentre, double-blind, placebo-controlled trials. Early 2022, Mithra announced the topline efficacy results of both trials, which demonstrated a meaningful reduction in VMS from baseline and compared to placebo with all co-primary efficacy endpoints statistically (all p<0.05) met (2).
Topline safety results
Previous E4 studies have demonstrated the overall’s safety profile of Estetrol. Whereas the full dataset analysis is still in progress, these topline safety results not only confirm Donesta®’s safety profile in the treatment of VMS, but also delineate further E4’s unique benefit/risk profile for postmenopausal women.
In the C302 trial, safety data were captured up to 12 months of treatment either with the 15 mg and 20 mg E4 doses compared to placebo (efficacy part) or open-label with the 20 mg E4 dose (safety part). These topline safety results, evaluated general safety and secondary endpoints such as health-related quality of life, treatment satisfaction, lipid and glucose metabolism and endometrial safety in hysterectomized and non-hysterectomized women.
Key secondary endpoints
Among the highlights of these results, the study confirmed previous clinical and biochemical evidence with minimal changes in hemostasis parameters and hepatic markers, E4’s positive influence on bone turnover markers and beneficial effect on cholesterol profile. These results contribute to showcase the unique profile of E4.
At a daily dose of 15 mg or 20 mg, Donesta® was well tolerated in hysterectomized women. In nonhysterectomized women, as expected for an estrogen administered alone, endometrial proliferation was observed and confirmed the need of adding a progestogen to curb related events in this population. Therefore, once the estrogen was first administrated and followed with the administration of progesterone, endometrial thickening was, partially to completely, reversed within a two-week treatment. Most of the treatment emergent adverse events were mild or moderate in intensity.
Update on European study (C301)
The European study C301 is still ongoing with primary safety data anticipated for H1 2024. Barring any unforeseen event, Mithra confirms its ambition to achieve marketing authorization for Donesta® in H1 2024 for the United States and in H1 2025 for Europe. A marketing authorization that was initially anticipated in Q4 2024 and moved to H1 2025 owing to a slow recruitment.
Graham Dixon, CSO Mithra Women’s Health, commented: “These safety results show Donesta®’s complete profile to safely and effectively treat menopausal symptoms. At the beginning of 2024, the European study (C301) should reinforce the unique safety profile of E4, supporting further the fantastic therapeutic potential of this molecule. After having successfully signed the licence agreement with Gedeon Richter for the commercialization of Donesta® in Europe, these topline safety results will support the upcoming regulatory filing process and bring us closer to a marketing authorization in North America.”
(1) Considering recruitment extension of the C301 endometrial safety study
(2) Mithra’s press release, 14/04/2022