VVA : new therapeutic options? BMS october 2017 A Pintiaux

Disclosures Member of the european board of TEVA without personal gain No conflict of interest for this presentation

VVA Vulvar and vaginal atrophy (VVA) is a chronic and progressive medical condition that develops because of the decline of estrogen levels. Symptoms : vaginal dryness, irritation and dyspareunia increased urinary frequency, urgency, and urge incontinence Approximately 50% of postmenopausal women suffer from VVA symptoms Local vaginal estrogens represent the current standard of care for treatment of symptomatic VVA and are effective in alleviating symptoms of moderate -to-severe VVA.

For symptomatic vaginal atrophy that does not respond to self-care measures, estrogen treatment is the standard of care, typically with vaginally administered local estrogens.

VVA : Some significant barriers to treatment lack of knowledge about VVA reluctance to discuss symptoms with healthcare professionals safety concerns for hormonal or non hormonal treatment ( endocrine disruptors in some vaginal preparations) Contraindications to estrogen use and inconvenience Parish SJ, Nappi RE, Krychman ML, et al. Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy. Int J Womens Health 2013;5:437 47 North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013;20:888 902 Palacios S, Castelo-Branco C, Currie H, et al. Update of managementof genitourinary syndrome of menopause. A practical guide. Maturitas 2015;82:308 13

The estrogen selective estrogen receptor modulator (SERM) ospemifene A new oral therapy option for postmenopausal women with moderate or severe VVA Ospemifene acts by exerting a tissue-specific effect, including an estrogen agonist effect on the vaginal epithelium The efficacy and safety of ospemifene were established in 30 clinical trials, with 2471 subjects Cui Y, Zong H, Yan H, Li N, Zhang Y. The efficacy and safety of ospemifene in treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy: a systematic review and meta-analysis. J Sex Med 2014; 11: 487-97.

New oral therapy option for postmenopausal women A combined analysis of two phase III trials reported improvement in dyspareunia and vaginal dryness in three-quarters of women compared with 50% to 60% who received the placebo. Ospemifene has recently been approved by the European medicines Agency (EMA) to treat moderate-to-severe VVA in postmenopausal women who are not subject to local vaginal estrogen therapy. Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010; 17: 480-6. Nappi RE, Panay N, Bruyniks N, Castelo-Branco C, De Villiers TJ, Simon JA. The clinical relevance of the effect of ospemifene on symptoms of vulvar and vaginal atrophy. Climacteric 2015; 18: 233-40.

Molecular Biology : Ospemifene Triphenylethylene derivative, structurally similar to tamoxifen, but without the 2- (dimethylamino)ethoxy region Removal of this region is associated with reduced agonistic activity in the uterus, and no effects on agonist activity in bone or the cardiovascular system The binding affinity of ospemifene for ER a and ER b was evaluated in a competitive binding assay ; ospemifene displaced labeled 17 - estradiol in a concentration-dependent manner B.S. Komm, S. Mirkin / Journal of Steroid Biochemistry & Molecular Biology 143 (2014) 207 222

Pharmacology Following oral administration, ospemifene reaches the peak median serum concentration in approximately 2 hours in fasting postmenopausal women. The bioavailability of ospemifene is increased two- to three-fold by food intake, hence it is recommended to be taken with food. Steady state concentrations were observed after 7 days. Ospemifene is metabolized by cytochrome P450 (CYP450) enzymes in the liver, and it has a half-life of 26 hours. Excreted in the feces (75%) and urine. In vivo experiments demonstrated that the metabolism of ospemifene was induced by rifampin and was inhibited by ketoconazole or fluconazole. Jae Jun Shin and Seul Ki KimJournal of Menopausal Medicine 2017;23:79-84 Koskimies P, Turunen J, Lammintausta R, Scheinin M.Single-dose and steady-state pharmacokinetics of ospemifene, a selective estrogen receptor modulator, in postmenopausal women. Int J Clin Pharmacol Ther 2013; 51: 861-7.

Preclinical AND Clinical Data Breast Bone Endometrium

Bone Endometrium Brain

Prevention of recurrent lower urinary tract infections in postmenopausal women with genitourinary syndrome: outcome after 6 months of treatment with ospemifene. Thirty-nine patients were enrolled in the study. Two patients experienced one new UTI episode and the mean number of positive urine culture decreased significantly after 6 months (3.65 ± 2.12 vs 0.25 ± 0.17, p <.0001). The mean number of urinary infection symptoms decreased significantly after treatment; dysuria reduced (4.76 ± 2.45 vs 0.89 ± 1.12). Schiavi MC, Gynecol Endocrinol. 2017

Effects of ospemifene on vaginal epithelium of post-menopausal women. Thirty-two post-menopausal women undergoing surgical procedures were enrolled. Sixteen subjects taking ospemifene at the time of inclusion (OSP) were compared to 16 subjects not taking any hormone (CTL). OSP group showed thicker vaginal epithelium (349 ± 64 vs. 245 ± 53 μm, p <.001), higher proliferation index (212 ± 47 vs. 127 ± 28 Ki-67 + cells/mm, p <.001), higher epithelial (27.3 ± 3.1 vs. 20.6 ± 2.9 score, p <.001) and stromal (26.6 ± 4.9 vs. 20.6 ± 2.6 score, p <.001) ERα expression when compared to the CTL group. In postmenopausal women affected by VVA, 1 month intake of ospemifene is associated with an increased maturation, and ERα expression of the vaginal mucosa. Alvisi S, Gynecol Endocrinol. 2017

N. Bruyniks, N. Biglia, S. Palacios & A. O. Mueck (2017): Systematic indirect comparison of ospemifene versus local estrogens for vulvar and vaginal atrophy, Climacteric, DOI: 10.1080/13697137.2017.12847 80

Safety In clinical trials with postmenopausal women, ospemifene had no adverse effects on the breast, and mammograms performed after 52 weeks of ospemifene were normal in all subjects of all groups. In a phase III trial of postmenopausal women,with a treatment period of 12 weeks, taking either ospemifene 30 mg or 60 mg or placebo : minimal change in the endometrial thickness, and their endometrial biopsy showed no cases of endometrial hyperplasia or carcinoma. Extension studies demonstrated no significant endometrial changes associated with the use of ospemifene for at least up to 1 year of treatment. The FDA concluded that ospemifene 60 mg per day was generally safe. Simon JA, Lin VH, Radovich C, Bachmann GA. One-yearlong-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause 2013; 20: 418-27. Simon J, Portman D, Mabey RG, Jr. Long-term safety ofospemifene (52-week extension) in the treatment of vulvar and vaginal atrophy in hysterectomized postmenopausal women. Maturitas 2014; 77: 274-81. Portman DJ, Bachmann GA, Simon JA. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013; 20: 623-30.

Side effects Hot flashes were the most frequently reported side effects of ospemifene, with reported occurrence of 2% in the placebo group and 7.2% in the ospemifene group The incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per 1,000 women, respectively, in the ospemifene group and 1.04 and 0 per 1,000 women, respectively, in the placebo group. The incidence of deep vein thrombosis was 1.45 per 1,000 women in the ospemifene group and 1.04 per 1,000 women in the placebo group. Cui Y, Zong H, Yan H, Li N, Zhang Y. The efficacy and safety of ospemifene in treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy: a systematic review and meta-analysis. J Sex Med 2014; 11:487-97 Shionogi Inc. Osphena : prescribing package insert. Florham Park, NJ: Shionogi Inc.;2015.

Archer D, Menopause, Vol. 24, No. 10, 2017

Repurposing ospemifene for potentiating an antigen-specific immune response. Ospemifene induced expression of the key TH1 cytokines interferon gamma and interleukin-2 in vitro, which may be mediated by stimulating T-cells through phosphoinositide 3-kinase and calmodulin signaling pathways. In combination with an antigen-specific peptide cancer vaccine, ospemifene increased antigenspecific immune response and increased cytotoxic T-lymphocyte activity in tumor-bearing and nontumor-bearing mice. The pretreatment, intermittent, and chronic dosing schedules of ospemifene activate naive T-cells, modulate antigeninduced tolerance and reduce tumor-associated, pro-inflammatory cytokines, respectively. CONCLUSIONS: Taken together, ospemifene's dose response and schedule-dependent immune modulating activity offers a method of tailoring and augmenting the efficacy of previously failed antigen-specific cancer vaccines for a wide range of malignancies. Kao CJ, Menopause. 2017

DHEA

Oral DHEA for postmenopausal women: A review of the evidence little convincing data to support the use of oral DHEA therapy in healthy aging individuals to improve conditions synonymous with normal aging such as reduced sexual function or diminished wellbeing no serious adverse effects have been reported in short term studies insufficient documentation on the effect of DHEA on the breast and the endometrium Labrie and others have investigated the effects of DHEA on mammary tissue extensively in vitro and rodent model and consistently report an inhibitory effect on mammary carcinoma development Endometrial thickness did not increase in postmenopausal women during a 6-month study of 25mg oral DHEA daily or in a 12-month study of 50mg oral DHEA daily M. Panjari, S.R. Davis / Maturitas 66 (2010) 172 179

Effect of intravaginal DHEA in postmenopausal women a daily dose of one ovule of the following DHEA concentrations: 0.0%, 0.5%, 1.0% or 1.8% after 7 days of treatment, the maturation value of the vaginal epithelial cells was significantly increased while the vaginal ph was significantly decreased at all DHEA doses serum concentrations of estradiol and testosterone remained within the values found in normal postmenopausal women at all DHEA doses similar observations were made for serum androstenedione, estrone, estrone-sulfate and DHEA-sulfate. DHEA is transformed into both androgens and estrogens in the vagina and permits to exert benefits on all the three layers of the vaginal wall. F. Labrie et al. / Journal of Steroid Biochemistry & Molecular Biology 111 (2008) 178 194

Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance) Postmenopausal women with a history of breast or gynecologic cancer who had completed primary treatment, had no evidence of disease, and reported at least moderate vaginal symptoms were eligible Four hundred sixty-four women were randomized. Women could be on tamoxifen or an AI for at least 8 weeks, without plans to change treatment during the study. Women were not eligible for the study if they had prior pelvic surgery resulting in anatomical changes, had prior radiation to the pelvis, active vaginal infections, or had used any hormonal product (including soy or any compounded hormones) in the preceding 4 weeks. Debra L. Barton & Charles L. Loprinzi, Support Care Cancer 2017

Debra L. Barton & Charles L. Loprinzi, Support Care Cancer 2017

Belgian Menopause Society