Endometrial Hyperplasia

Pictured: Front of FDA headquarters/Grandbrothers/Adobe Stock The FDA has approved Astellas’ fezolinetant, now to be marketed as Veozah, for the treatment of moderate to severe vasomotor symptoms in menopausal women, the company and regulator announced Friday. Vasomotor symptoms (VMS), also known as hot flashes or night sweats, are common occurrences during menopause, arising in 60% to 80% of women in the U.S. In turn, hot flashes lower quality of life and disrupt daily activities. Veozah, approved as an oral once-a-day 45-mg formulation, is the first antagonist of the neurokinin 3 (NK3) receptor approved for these menopausal symptoms, according to Astellas. The FDA did not give Veozah a boxed warning, but the drug’s label bears precautions for higher liver blood test values, as well as common side effects such as stomach pain, diarrhea, insomnia and back pain. Veozah uses a “novel mechanism of action” to address VMS at its root cause, Marci English, vice president and head of BioPharma Development at Astellas, said in the press release. Before menopause, the body maintains a strict balance between estrogen and neurokinin B (NKB) levels, which in turn leads to the healthy regulation of body temperature, as maintained by the hypothalamus. During menopause, however, estrogen concentrations drop and NKB becomes predominant, which disturbs the body’s temperature control system, giving rise to a host of uncomfortable symptoms collectively known as VMS. Veozah, an NK3 receptor blocker, works by preventing NKB from interacting with its corresponding receptor on hypothalamic neurons, which restores healthy temperature regulation in the body. Astellas supported its FDA bid for Veozah with data from the BRIGHT SKY clinical development program, which included three Phase III trials enrolling more than 3,000 participants in total. In February 2021, the company posted positive topline data from SKYLIGHT 1 and SKYLIGHT 2, two late-stage, double-blinded and placebo-controlled studies evaluating Veozah’s 30-mg and 45-mg doses over 52 weeks of treatment. Both studies met their co-primary endpoints, with both Veozah doses significantly reducing the frequency and severity of moderate to severe hot flushes versus placebo. SKYLIGHT 4, the third study under BRIGHT SKY, is likewise a double-blinded and placebo-controlled trial but is designed to evaluate the long-term safety of Veozah. Findings from this study, presented at the North American Menopause Society Annual Meeting in October 2022, showed both drug doses were safe through 52 weeks of follow-up, with most adverse events being mild or moderate in severity. SKYLIGHT 4 also found that incidence rates for endometrial malignancy and endometrial hyperplasia were within pre-specified limits. The FDA accepted fezolinetant’s New Drug Application in August 2022 and, following Astellas’ use of its priority review voucher, set a PDUFA date of February 2023. However, a few days before the target action date, the regulator extended the review window by three more months to allow for more time to assess the company’s data package. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

SKYLIGHT 4™ study results demonstrate the 52-week safety and tolerability of fezolinetant 30 mg and 45 mg once daily Pooled analyses will also be presented from SKYLIGHT 1™ and SKYLIGHT 2™ studies of fezolinetant, Astellas' investigational nonhormonal treatment for vasomotor symptoms (VMS) associated with menopause TOKYO, Oct. 12, 2022 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") will present 52-week results from the Phase 3 SKYLIGHT 4™ clinical study evaluating the safety and tolerability of fezolinetant, an investigational oral, nonhormonal compound being studied for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. The results will be featured in an oral presentation October 13 at The North American Menopause Society Annual Meeting. VMS, characterized by hot flashes and/or night sweats, are common symptoms of menopause.1,2 SKYLIGHT 4 results demonstrate the 52-week safety and tolerability of fezolinetant 30 mg and 45 mg once daily. Safety analyses demonstrated that both endometrial hyperplasia and endometrial malignancy were within pre-specified limits for fezolinetant-treated patients; reported treatment-emergent adverse events (TEAEs) were generally mild or moderate in severity; and headache and COVID-19 were the most common TEAEs, with similar incidences for fezolinetant and placebo. The frequency of elevated liver enzymes was low across groups, and elevations were generally asymptomatic, isolated, transient and resolved on treatment or soon after study drug discontinuation. "There is an unmet need for safe and effective nonhormonal treatment options for VMS associated with menopause, which can adversely impact daily quality of life," said Genevieve Neal-Perry, M.D., Ph.D., Chair, UNC School of Medicine Department of Obstetrics and Gynecology. "The SKYLIGHT 4 study results demonstrate the long-term safety and tolerability of fezolinetant, providing further support for its potential use as a treatment for VMS." In addition, pooled efficacy data from SKYLIGHT 1™ and SKYLIGHT 2™ evaluating early response to fezolinetant, its impact on sleep and treatment response analyzed by race will be presented. "Results of the SKYLIGHT 4 study and the pooled analyses from the SKYLIGHT 1 and 2 studies provide further insights into the safety and effectiveness of fezolinetant," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas. "Through our clinical development program, we are excited to further characterize the clinical profile of fezolinetant for women who experience hot flashes as part of menopause." Fezolinetant is an investigational selective neurokinin 3 (NK3) receptor antagonist and is not approved for use anywhere in the world. New Drug and Marketing Authorization applications for fezolinetant are under review in the U.S. and Europe, respectively. If approved, fezolinetant would be a first-in-class, nonhormonal treatment option to reduce the frequency and severity of moderate to severe VMS associated with menopause. Astellas will also present three abstracts examining the association between VMS and weight gain, sleep quality and work productivity. Following are all of Astellas' presentations at NAMS 2022: SKYLIGHT Data at NAMS Astellas VMS Data at NAMS About the BRIGHT SKY™ Phase 3 Program The BRIGHT SKY pivotal trials, SKYLIGHT 1™ (NCT04003155) and SKYLIGHT 2™ (NCT04003142), enrolled over 1,000 women with moderate to severe VMS. The trials are double-blinded, placebo-controlled for the first 12 weeks followed by a 40-week treatment extension period. Women were enrolled at over 180 sites within the U.S., Canada and Europe. SKYLIGHT 4™ (NCT04003389) is a 52-week double-blinded, placebo-controlled study designed to investigate the long-term safety of fezolinetant. For SKYLIGHT 4, over 1,800 women with VMS were enrolled at over 180 sites within the U.S., Canada and Europe. About VMS Associated with Menopause VMS, characterized by hot flashes (also called hot flushes) and/or night sweats, are common symptoms of menopause.1,2 In the U.S., about 60% to 80% of women experience these symptoms during or after the menopausal transition and, worldwide, more than half of women 40 to 64 years of age experience VMS.3,4,5,6 VMS can have a disruptive impact on women's daily activities and overall quality of life.1 About Fezolinetant Fezolinetant is an investigational oral, nonhormonal therapy in clinical development for the treatment of moderate to severe VMS associated with menopause. Fezolinetant works by blocking neurokinin B (NKB) binding on the kisspeptin/neurokinin/dynorphin (KNDy) neuron to moderate neuronal activity in the thermoregulatory center of the brain (the hypothalamus) to reduce the frequency and severity of moderate to severe VMS associated with menopause.7,8,9 The safety and efficacy of fezolinetant are under investigation and have not been established. There is no guarantee the agent will receive regulatory approval or become commercially available for the uses being investigated. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at . Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. References 1 Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47. 2 Jones RE, Lopez KH, eds. Human Reproductive Biology. 4th ed. Waltham, MA: Elsevier, 2014:120. 3 Makara-Studzinska MT, Krys-Noszczyk KM, Jakiel G. Epidemiology of the symptoms of menopause - an intercontinental review. Przegl Menopauzalny [Menopause Rev]. 2014;13:203-211. 4 Gold EB, Colvin A, Avis N, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health. 2006;96:1226-1235. 5 Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21:924-932. 6 Williams RE, Kalilani L, DiBenedetti DB, et al. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States. Climacteric. 2008;11:32-43. 7 Depypere H, Timmerman D, Donders G, et al. Treatment of menopausal vasomotor symptoms with fezolinetant, a neurokinin 3 receptor antagonist: a phase 2a trial. J Clin Endocrinol Metab. 2019;104:5893-5905. 8 Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27:382-392. 9 Fraser GL, Hoveyda HR, Clarke IJ, et al. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderate levels of ovarian hormones throughout the menstrual cycle. Endocrinology. 2015;156:4214-4225. SOURCE Astellas Pharma Inc.