Oliver Martin Fischer

BAY 1002670: a novel, highly potent and selective progesterone receptor modulator for gynaecological therapies

STUDY QUESTION Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids? SUMMARY ANSWER The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids. WHAT IS KNOWN ALREADY PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes. STUDY, DESIGN, SIZE, DURATION The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue. PARTICIPANTS/MATERIAL, SETTING, METHODS BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P). MAIN RESULT AND THE ROLE OF CHANCE BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005). LIMITATIONS AND REASON FOR CAUTION Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far. WIDER IMPLICATIONS OF THE FINDING The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications. STUDY FUNDING/COMPETING INTEREST The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.

Tissue Remodeling and Nonendometrium-Like Menstrual Cycling Are Hallmarks of Peritoneal Endometriosis Lesions

We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.

Effects of dienogest on surgically induced endometriosis in rats after repeated oral administration.

Background: Dienogest demonstrates efficacy for lesion reduction and pain relief in clinical trials of endometriosis. The current study investigated an intraperitoneal animal model of endometriosis to further characterize the effects of dienogest. Methods: Endometrial-like lesions were induced in rats by autotransplantation of uterine tissue into the peritoneal cavity. Dienogest 0.3 or 1.0 mg/kg/day, danazol 100 mg/kg/day, or vehicle control were administered orally for 28 days. Changes in endometrial-like lesion size during treatment were assessed at laparotomy. Uterine horn weight was also measured as an index of the estrogenic effects of treatment. Results: Dienogest 0.3 mg/kg/day significantly reduced the total endometrial lesion area, with an effect equivalent to danazol 100 mg/kg/day. Unlike dienogest 1.0 mg/kg/day, dienogest 0.3 mg/kg/day had no effect on uterine horn weight, indicating an absence of estrogenic effects for this dose in rodents. Conclusion: Dienogest 0.3 mg/kg/day for 28 days demonstrated potent inhibitory activity on the growth of endometrial tissue in this model, providing supportive evidence for the efficacy of dienogest in lesion reduction.