Effect of the Neurokinin 3 Receptor Antagonist Fezolinetant on - PowerPoint PPT Presentation

Effect of the Neurokinin 3 Receptor Antagonist Fezolinetant on Menopausal Vasomotor Symptoms and Patient-Reported Outcomes: Results of a Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging Study (VESTA) Nanette Santoro, MD 1 ; Arthur Waldbaum, MD 2 ; Samuel Lederman, MD 3 ; Graeme L. Fraser, PhD 4 ; Christopher Lademacher, MD, PhD 5 ; Laurence Skillern, MD 6 ; James Young 5 ; Steven Ramael, MD 4 1 University of Colorado School of Medicine, Aurora, CO, USA; 2 Downtown Women’s Healthcare, Denver, CO, USA; 3 Altus Research, Lake Worth, FL, USA; 4 OGEDA SA, subsidiary of Astellas Pharma, Inc., Gosselies, Belgium; 5 Astellas Pharma US, Inc., Northbrook, IL, USA; 6 Astellas Pharma Europe Ltd, Chertsey, UK

Author Disclosures ⚫ N. Santoro: OGEDA (consultant) , Menogenix, Inc. (scientific Advisory Board, stock options, SBIR co-investigator) ⚫ A. Waldbaum: Radius Health, Inc., OGEDA, Mitsubishi Pharma, Menogenix, Endoceutics, and Shionogi (grant recipient) ⚫ S. Lederman: Altus Research (consultant) ⚫ G.L. Fraser: OGEDA SA (former employee), Astellas Pharma (consultant) ⚫ C. Lademacher: Astellas Pharma (employee) ⚫ L. Skillern: Astellas Pharma (former employee) ⚫ J. Young: Astellas Pharma (employee) ⚫ S. Ramael: OGEDA (former employee) 2

Vasomotor Symptoms (VMS) in Menopause ⚫ VMS (hot flashes and night sweats) are reported by up to 80% of women during menopause in the US 1,2 and persist for a median of 7.4 years 3 ⚫ Loss of thermoregulatory control in the area of the brain innervated by neurokinin 3 receptor (NK3R)-expressing neurons 4,5 is believed to cause VMS ⚫ Fezolinetant, an oral NK3R antagonist, markedly reduced frequency and severity of moderate to severe menopausal VMS and was well-tolerated over 12 weeks in a recent randomized controlled trial 6 ⚫ Patient-reported outcomes (PROs) help quantify the value patients place on symptoms and outcomes and are becoming an increasingly important component of the assessment of new treatments 7,8 1. Gold EB, et al. Am J Public Health . 2006;96:1226-35. 2. Freeman EW, et al. Menopause . 2014;21:924-32. 3. Avis NE, et al. JAMA Intern Med . 2015;175:531-9. 4. Mittelman-Smith MA, et al. Proc Natl Acad Sci. 2012;109:19846-51. 5. Rance NE, et al. Front Neuroendocrinol . 2013;34:211-27. 6. Depypere H, et al. J Clin Endocrinol Metab. 2019; doi: 10.1210/jc.2019-00677. 7. Craig BM, et al. Value Health . 2016;19:158-66. 8. Gregory KD, et al. OBG Manag . 2018;30:18-23,48 (available at: https://www.mdedge.com/obgyn/article/159650/practice-management/role-patient-reported-outcomes-womens-health/page/0/1). 3

Fezolinetant: Phase 2b VESTA a Trial Objectives • Evaluate efficacy of doses and dosing regimens up to 90 mg BID on the frequency and severity of VMS using Primary traditional VMS outcome measures Outcomes: VMS Frequency/ Severity • Evaluate the effect of different doses and dosing regimens on PROs PROs • Evaluate the effect of different doses and dosing regimens on safety and tolerability Safety a This study was named after the Roman goddess Vesta, goddess of the hearth, home, and family life. BID, twice daily. 4

Study Design and Population • Phase 2b randomized, placebo-controlled, double-blind, multicenter trial (NCT03192176) conducted in the US • Postmenopausal women >40 –65 years old with ≥50 moderate to severe VMS/ wk and BMI 18‒38 kg/m 2 12-week treatment period ~ 3-week Fezolinetant 15 mg BID Days – 35 to – 1 follow-up Fezolinetant 30 mg BID Screening period Fezolinetant 60 mg BID Randomization • Screening visit (Visit 1) Week 15 • Collection of baseline VMS Fezolinetant 90 mg BID Follow-up frequency/severity data Fezolinetant 30 mg QD • Must have ≥50 moderate to severe VMS (Visit 6) per week recorded on Fezolinetant 60 mg QD 7 consecutive days in the screening period Fezolinetant 120 mg QD to enter the trial Placebo VMS frequency and severity recorded via electronic diary from screening through final study visit BMI, body mass index; QD, once daily. 5

Study Endpoints Coprimary • Mean change in frequency and severity of VMS per day from baseline to Endpoints weeks 4 and 12 a • Responders: Women with reduction of ≥50% from baseline in frequency of moderate to severe VMS • PROs: Change in PRO scores from baseline to weeks 4 and 12, in relation to published Secondary minimum important difference (MID) and clinically important difference (CID) values, Endpoints where available • Menopause-Specific Quality of Life (MENQoL) questionnaire 1,2 • Hot Flash-Related Daily Interference Scale (HFRDIS) 3 • Greene Climacteric Scale (GCS) 4 • Treatment-emergent adverse events (TEAEs), physical examinations, vital signs, laboratory tests • 12-lead electrocardiogram parameters Safety Endpoints • Plasma bone turnover marker concentrations • Columbia-Suicide Severity Rating Scale a Results of coprimary endpoints were presented previously (Fraser G, et al. J Endocr Soc. 2019;3(Suppl 1):OR33-6) and will not be emphasized in the current presentation. 1. Hilditch JR, et al. Maturitas. 1996;24:161-175. 2. Lewis JE, et al. Maturitas. 2005;50:209-221. 3. Carpenter JS. J Pain Symptom Manage. 2001;22:979-989. 4. Greene JG. Maturitas. 1998;29:25-31. 6

Disposition, Demographics, and Baseline Characteristics • Screened N=992; randomized N=356; treated (safety population) n=352; efficacy analysis set n=349; completers n=287 (81%) a Fezolinetant 15 mg 30 mg 60 mg 90 mg 30 mg 60 mg 120 mg Placebo BID BID BID BID QD QD QD Parameters b (n=43) (n=45) (n=43) (n=45) (n=44) (n=43) (n=45) (n=44) Age, y, mean (SD) 54.8 (5.5) 53.7 (5.0) 53.9 (3.8) 54.6 (5.0) 54.9 (4.0) 52.7 (3.8) 55.0 (4.9) 56.8 (4.4) BMI, kg/m 2 , mean (SD) 27.3 (4.8) 29.3 (4.3) 28.3 (4.0) 29.1 (5.2) 27.3 (4.6) 28.8 (4.0) 28.3 (4.4) 28.8 (4.9) Race, n (%) White 30 (69.8) 37 (82.2) 31 (72.1) 28 (62.2) 36 (81.8) 31 (72.1) 34 (75.6) 30 (68.2) African American 10 (23.3) 8 (17.8) 12 (27.9) 15 (33.3) 8 (18.2) 11 (25.6) 10 (22.2) 13 (29.5) Asian 2 (4.7) 0 0 1 (2.2) 0 0 0 0 Other 1 (2.3) 0 0 1 (2.2) 0 1 (2.3) 1 (2.2) 1 (2.3) Ethnicity, n (%) Hispanic/Latino 15 (34.9) 16 (35.6) 9 (20.9) 13 (28.9) 10 (22.7) 17 (39.5) 12 (26.7) 9 (20.5) Baseline VMS, c Frequency/24 h 9.7 (3.5) 11.1 (7.1) 9.9 (4.6) 9.5 (4.0) 9.3 (3.6) 11.2 (6.4) 9.4 (2.7) 9.7 (3.7) mean (SD) Severity/24 h 2.5 (0.3) 2.5 (0.3) 2.4 (0.3) 2.5 (0.3) 2.4 (0.3) 2.4 (0.3) 2.4 (0.3) 2.5 (0.3) a Most common reasons for discontinuation: withdrawal of consent (6.7%) and adverse events (AEs; 5.9%) b Safety population, unless otherwise specified. c Values are from efficacy analysis set; baseline is average frequency/severity of 24-hour VMS from 7 nonmissing days prior to day 1. 7

Reductions in Frequency of Moderate/Severe VMS with Fezolinetant vs Placebo • Fezolinetant reduced frequency of daily moderate/severe VMS vs placebo at week 12 Fezolinetant dose groups Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD Frequency of Moderate/Severe VMS, % (SE) 0 Change From Baseline to Week 12 in -10 -20 -30 -40 -50 -60 -55.0 -70 -80 -74.3 -76.9 -75.1 -90 -75.8 -77.7 -80.2 * * * * -86.9 * -100 * * Coprimary Efficacy Endpoints • Frequency: Least squares (LS) mean differences of −1.9 to −3.5 at week 4 and −1.8 to −2.6 at week 12 (all P <.05) • Severity: LS mean differences of −0.4 to −1.0 at week 4 (all P <.05) and −0.2 to −0.6 at week 12 ( P <.05, 60 and 90 mg BID and 60 mg QD) *P <.05 for all pairwise comparisons of fezolinetant vs placebo at weeks 4 and 12, with no adjustments for multiplicity. 8

Responder Analyses for ≥50% Reduction in Moderate to Severe VMS Frequency at Last On-Treatment Week * 100 94.7 * Women (%) Achieving ≥50% Reduction * 88.1 88.1 * * * in VMS at Last On-Treatment Week * 90 84.1 83.7 82.1 81.4 80 70 58.5 60 50 40 30 20 10 0 Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD Fezolinetant dose groups * P <.05 for pairwise comparisons of fezolinetant vs placebo at last on-treatment week, with no adjustments for multiplicity 9

LS Mean Change from Baseline in MENQoL Vasomotor Function Domain Score, Efficacy Analysis Set a Menopause-Specific Quality of Life Questionnaire, Vasomotor Function Domain Score Week 4 Week 12 0.0 Placebo LS Mean (SE) Change from Baseline -0.5 15 mg BID -1.0 30 mg BID CID 1 (−1.2) 60 mg BID -1.5 90 mg BID -2.0 -1.8 30 mg QD -1.9 -2.5 -2.3 60 mg QD -2.4 -2.4 -3.0 120 mg QD -2.8 -2.9 -3.5 -3.0 -3.2 -3.3 -3.4 -4.0 -3.5 -3.6 -3.6 -3.8 -4.5 -4.4 -5.0 a The LS means and standard errors are from an MMRM model with change from baseline as the dependent variable and the treatment group, visit and smoking status as factors and baseline measurement as a covariate as well as interaction of treatment by week and an interaction of baseline measurement by week. CID, clinically important difference 1. Bushmakin AG, et al. Menopause. 2014;21(8):815-22. 10