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, MD1; Arthur Waldbaum, MD2; Samuel Lederman, MD3; Graeme L. Fraser, PhD4; Christopher Lademacher, MD, PhD5; Laurence Skillern, MD6; James Young5; Steven Ramael, MD4

1University of Colorado School of Medicine, Aurora, CO, USA; 2Downtown Women’s Healthcare, Denver, CO, USA; 3Altus Research, Lake Worth, FL, USA; 4OGEDA SA, subsidiary of Astellas Pharma, Inc., Gosselies, Belgium; 5Astellas Pharma US, Inc., Northbrook, IL, USA; 6Astellas 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)

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Vasomotor Symptoms (VMS) in Menopause

⚫ VMS (hot flashes and night sweats) are reported by up to 80% of women during

menopause in the US1,2 and persist for a median of 7.4 years3

⚫ Loss of thermoregulatory control in the area of the brain innervated by neurokinin 3

receptor (NK3R)-expressing neurons4,5 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 trial6

⚫ 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 treatments7,8

• 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 VESTAa Trial Objectives

PROs

• Evaluate the effect of different doses and dosing regimens
• n PROs

aThis study was named after the Roman goddess Vesta, goddess of the hearth, home, and family life.

Safety

• Evaluate the effect of different doses and dosing regimens
• n safety and tolerability
• Evaluate efficacy of doses and dosing regimens up to

90 mg BID on the frequency and severity of VMS using traditional VMS outcome measures

Primary Outcomes: VMS Frequency/ Severity

BID, twice daily.

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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/m2

Days –35 to –1

Screening period

• Screening visit (Visit 1)
• Collection of baseline VMS

frequency/severity data

• Must have ≥50 moderate to severe VMS

per week recorded on 7 consecutive days in the screening period to enter the trial

Randomization

Fezolinetant 15 mg BID Fezolinetant 30 mg BID Fezolinetant 60 mg BID Fezolinetant 90 mg BID Fezolinetant 30 mg QD Fezolinetant 60 mg QD Fezolinetant 120 mg QD Placebo

12-week treatment period

Follow-up (Visit 6)

Week 15

~3-week

follow-up

VMS frequency and severity recorded via electronic diary from screening through final study visit

BMI, body mass index; QD, once daily.

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Study Endpoints

• Mean change in frequency and severity of VMS per day from baseline to

weeks 4 and 12a

Coprimary Endpoints

• 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

minimum important difference (MID) and clinically important difference (CID) values, where available

• Menopause-Specific Quality of Life (MENQoL) questionnaire1,2
• Hot Flash-Related Daily Interference Scale (HFRDIS)3
• Greene Climacteric Scale (GCS)4

Secondary Endpoints

• Treatment-emergent adverse events (TEAEs), physical examinations, vital signs, laboratory tests
• 12-lead electrocardiogram parameters
• Plasma bone turnover marker concentrations
• Columbia-Suicide Severity Rating Scale

Safety Endpoints

aResults 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.

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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

aMost common reasons for discontinuation: withdrawal of consent (6.7%) and adverse events (AEs; 5.9%) bSafety population, unless otherwise specified. cValues are from efficacy analysis set; baseline is average frequency/severity of 24-hour VMS from 7 nonmissing days prior to day 1.

Parametersb Placebo (n=43) Fezolinetant 15 mg BID (n=45) 30 mg BID (n=43) 60 mg BID (n=45) 90 mg BID (n=44) 30 mg QD (n=43) 60 mg QD (n=45) 120 mg QD (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/m2, 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 African American Asian Other 30 (69.8) 10 (23.3) 2 (4.7) 1 (2.3) 37 (82.2) 8 (17.8) 31 (72.1) 12 (27.9) 28 (62.2) 15 (33.3) 1 (2.2) 1 (2.2) 36 (81.8) 8 (18.2) 31 (72.1) 11 (25.6) 1 (2.3) 34 (75.6) 10 (22.2) 1 (2.2) 30 (68.2) 13 (29.5) 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 mean (SD) Frequency/24 h Severity/24 h 9.7 (3.5) 2.5 (0.3) 11.1 (7.1) 2.5 (0.3) 9.9 (4.6) 2.4 (0.3) 9.5 (4.0) 2.5 (0.3) 9.3 (3.6) 2.4 (0.3) 11.2 (6.4) 2.4 (0.3) 9.4 (2.7) 2.4 (0.3) 9.7 (3.7) 2.5 (0.3)

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Reductions in Frequency of Moderate/Severe VMS with Fezolinetant vs Placebo

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.

• 55.0
• 74.3
• 75.8
• 80.2
• 86.9
• 75.1
• 77.7
• 76.9
• 100
• 90
• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD Change From Baseline to Week 12 in Frequency of Moderate/Severe VMS, % (SE)

* * * * * * *

Fezolinetant dose groups

• Fezolinetant reduced frequency of daily moderate/severe VMS vs placebo at week 12

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Responder Analyses for ≥50% Reduction in Moderate to Severe VMS Frequency at Last On-Treatment Week

*P<.05 for pairwise comparisons of fezolinetant vs placebo at last on-treatment week, with no adjustments for multiplicity

58.5 83.7 81.4 88.1 94.7 82.1 88.1 84.1

10 20 30 40 50 60 70 80 90 100 Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD Women (%) Achieving ≥50% Reduction in VMS at Last On-Treatment Week * * * * * * *

Fezolinetant dose groups

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LS Mean Change from Baseline in MENQoL Vasomotor Function Domain Score, Efficacy Analysis Seta

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.
• 1.8
• 2.3
• 2.4
• 3.2
• 3.0
• 3.5
• 3.4
• 3.8
• 3.6
• 4.4
• 1.9
• 2.9
• 2.4
• 3.3
• 2.8
• 3.6
• 5.0
• 4.5
• 4.0
• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 Week 4 Week 12 LS Mean (SE) Change from Baseline Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD

CID1 (−1.2)

Menopause-Specific Quality of Life Questionnaire, Vasomotor Function Domain Score

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LS Mean Change from Baseline in HFRDIS Score With Fezolinetant, Efficacy Analysis Seta

• 2.2
• 2.9
• 3.3
• 3.6
• 3.6
• 3.8
• 3.8
• 4.3
• 3.7
• 4.2
• 2.5
• 3.3
• 3.4
• 3.5
• 3.5
• 3.9
• 5.0
• 4.5
• 4.0
• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0

Week 4 Week 12 LS Mean (SE) Change from Baseline Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD

aThe LS means and standard errors are from an MMRM model with change from baseline as the dependent variable, 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. MID, minimum important difference.

• 1. Carpenter JS, et al. Menopause. 2017;24:877-85.

MID1 (−1.76)

Hot Flash Related Daily Interference Scale

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LS Mean Change from Baseline in GCS Vasomotor Symptom Score, Efficacy Analysis Seta,b

a No MID has been established in the published literature for the GCS vasomotor symptom score. bThe 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.

• 1.7
• 2.1
• 2.1
• 2.7
• 2.7
• 3.1
• 3.3
• 3.6
• 3.2
• 3.6
• 2.2
• 2.9
• 2.6
• 2.8
• 2.9
• 2.9
• 4.5
• 4.0
• 3.5
• 3.0
• 2.5
• 2.0
• 1.5
• 1.0
• 0.5

0.0 Week 4 Week 12 LS Mean (SE) Change from Baseline Placebo 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD

Greene Climacteric Scale, Vasomotor Symptom Score

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Fezolinetant 15 mg BID n=45 30 mg BID n=43 60 mg BID n=45 90 mg BID n=42 30 mg QD n=43 60 mg QD n=44 120 mg QD n=44 MENQoL-VMS Week 4 −0.6 (−1.4, 0.2) −1.2 (−2.0, −0.4) −1.6 (−2.4, −0.8) −1.9 (−2.7, −1.0) −0.1 (−0.9, 0.8) −0.7 (−1.5, 0.2) −1.0 (−1.8, −0.2) Week 12 −0.9 (−1.7, −0.1) −1.2 (−2.1, −0.4) −1.5 (−2.3, −0.7) −2.0 (−2.9, −1.2) −0.6 (−1.4, 0.3) −1.0 (−1.8, −0.2) −1.2 (−2.1, −0.4) HFRDIS Week 4 −1.1 (−2.0, −0.2) −1.4 (−2.3, 0.5) −1.6 (−2.5, −0.7) −1.5 (−2.4, −0.6) −0.3 (−1.1, 0.6) −1.2 (−2.0, −0.3) −1.3 (−2.2, −0.4) Week 12 −0.7 (−1.5, 0.2) −0.8 (−1.7, 0.03) −1.4 (−2.3, −0.5) −1.3 (−2.2, −0.4)

• 0.4

(−1.3, 0.5) −0.6 (−1.4, 0.3) −1.0 (−1.8, −0.1) GCS-VMS Week 4 −0.5 (−1.2, 0.2) −1.0 (−1.7, −0.3) −1.6 (−2.3, −0.9) −1.5 (−2.2, −0.8) −0.5 (−1.2, 0.2) −0.9 (−1.6, −0.2) −1.2 (−1.9, −0.5) Week 12 −0.5 (−1.2, 0.2) −1.0 (−1.7, −0.3) −1.5 (−2.2, −0.8) −1.5 (−2.2, −0.8) −0.8 (−1.5, −0.1) −0.7 (−1.4, −0.02) −0.8 (−1.5, −0.1)

LS Mean Difference (95% CI) Between Fezolinetant and Placebo in Patient-Reported Outcomes

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Parameters, Safety Population Placebo (n=43) Fezolinetant 15 mg BID (n=45) 30 mg BID (n=43) 60 mg BID (n=45) 90 mg BID (n=44) 30 mg QD (n=43) 60 mg QD (n=45) 120 mg QD (n=44) TEAEs, n (%) 21 (48.8) 20 (44.4) 18 (41.9) 21 (46.7) 19 (43.2) 23 (53.5) 28 (62.2) 22 (50.0) Serious TEAEs, n (%) 1 (2.2)a Treatment-related serious TEAEs, n (%) Deaths, n Severe TEAEs, n (%) 1 (2.3) 1 (2.3) 2 (4.4) 1 (2.3) Treatment-related severe TEAEs, n (%) 1 (2.3)b 1 (2.2)c All treatment-related TEAEs, n (%) 3 (7.0) 1 (2.2) 9 (20.9) 8 (17.8) 9 (20.5) 10 (23.3) 12 (26.7) 11 (25.0) TEAEs in ≥5% in any treatment arm Headache 2 (4.7) 3 (6.7) 2 (4.7) 2 (4.4) 1 (2.3) 6 (14.0) 3 (6.7) 4 (9.1) Nausea 1 (2.3) 1 (2.2) 3 (7.0) 3 (6.7) 1 (2.3) 2 (4.7) 3 (6.7) 2 (4.5) Urinary tract infection 1 (2.3) 2 (4.4) 1 (2.3) 2 (4.4) 2 (4.5) 2 (4.7) 2 (4.4) 3 (6.8) Diarrhea 1 (2.3) 1 (2.3) 2 (4.4) 2 (4.5) 1 (2.3) 3 (6.7) 2 (4.5) Upper respiratory tract infection 1 (2.3) 2 (4.4) 1 (2.3) 1 (2.2) 1 (2.3) 3 (7.0) 1 (2.2) 1 (2.3) Fatigue 1 (2.2) 1 (2.3) 1 (2.2) 2 (4.5) 3 (6.7) 1 (2.3) Viral upper respiratory tract infection 2 (4.4) 1 (2.3) 1 (2.2) 3 (6.8) Sinusitis 3 (6.7) 1 (2.3) 2 (4.4) Cough 1 (2.2) 1 (2.2) 3 (6.7)

Treatment-Emergent Adverse Events

• TEAE rates were comparable across all groups, and events were mostly mild and moderate

aSquamous cell carcinoma of the skin. bLiver function test increased. cDrug-induced liver injury.

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Other Safety Parameters of Interest

• Liver enzymes
• All patients were asymptomatic; no cases of bilirubin >2×ULN and therefore no cases of Hy’s law
• Elevated liver enzyme levels rapidly returned to baseline after discontinuation of fezolinetant
• 2 patients with raised liver enzyme levels who did not immediately discontinue therapy had a clear trend toward

normalization of liver transaminases while maintained on treatment

• No other clinically meaningful changes were noted in vital signs, laboratory tests, electrocardiogram

parameters, or plasma bone marker concentrations

• Columbia-Suicide Severity Rating Scale reflected no evidence of suicidal ideation or behavior at week 12

Parameter Criteria Placebo Fezolinetant 15 mg BID 30 mg BID 60 mg BID 90 mg BID 30 mg QD 60 mg QD 120 mg QD Patients, n 42 43 41 41 40 41 43 42 AST or ALT, n (%) >3×ULN >5×ULN >8×ULN 1 (2.4) 3 (7.3) 1 (2.4) 1 (2.4) 2 (5.0) 2 (5.0) 1 (2.5) 1 (2.3) 1 (2.3) 1 (2.3) 2 (4.8) 1 (2.4)

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Conclusions

• Frequency of VMS was reduced by most dose levels of fezolinetant given either QD or BID
• A larger percentage of women had a ≥50% reduction in VMS frequency for most doses of fezolinetant

compared with placebo

• Reductions in VMS frequency were accompanied by clinically meaningful changes in PROs
• All doses of fezolinetant improved HFRDIS and MENQoL scores at weeks 4 and 12
• GCS-VMS domain scores were improved for most fezolinetant doses relative to placebo at weeks 4 and 12
• TEAE rates were similar across all fezolinetant groups; events were mostly mild or moderate
• Thus, fezolinetant, a centrally acting, nonhormonal therapy, has the potential to be a well-

tolerated and effective treatment for moderate to severe VMS associated with menopause, which could translate into meaningful improvements in QOL

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Funding and Acknowledgments

• This study was sponsored by OGEDA SA (Gosselies, Belgium), a wholly owned

subsidiary of Astellas Pharma, Inc.

• Medical writing and editorial support were provided by Echelon Brand

Communications, LLC (Parsippany, NJ), an OPEN Health company, and funded by Astellas Pharma, Inc.

• Hamid Hoyeda contributed to fezolinetant development

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