Novel Evaluation With QGC001 in Hypertensive Overweight Patients of Multiple Ethnic origins Efficacy and Safety of a Novel Antihypertensive Pharmacotherapeutic Approach in a High-Risk, Diverse Population K.C. Ferdinand, F. Balavoine, B. Besse, H.R. Black, S. Desbrandes, H.C. Dittrich, S.D. Nesbitt .
Disclosures • Keith C. Ferdinand is a consultant for Novartis, Amgen, Sanofi, Boehringer Ingelheim, Janssen, Quantum Genomics • Henry R. Black is a consultant for Akcea Therapeutics, Takeda and Quantum Genomics • Howard C. Dittrich ch is a consultant for Quantum Genomics • Shawna D. Nesbitt is a consultant for Relypsa and Quantum Genomics • Fabrice are full-time Balavoine, Bruno Besse, Stephanie Desbrandes employees of Quantum Genomics 2
Background • Hypertension (HTN) is controlled in 48.3% of patients in the U.S. • Uncontrolled HTN is higher in obese, black and other minority patients • Salt-sensitivity, low renin levels and sympathetic nervous system overactivity are associated with diminished response to ACE-I/ARB monotherapy and resistant HTN • Obesity rate is increasing (30.5% in 1999-2000 vs 39.6% in 2015-2016) • Obesity is more common in Blacks (46.8%) and Hispanics (47.0%) than in Whites (37.9%) • The risk of resistant HTN is increased by 5 fold with obesity 1 NCHS data brief N°289, Oct 2017; 2 Carey R. et al., Hypertension. 2018;72:0000; 3 Helmer A et al., Annals of Pharmacology 2018 1-9; 4 The State of Obesity 2018; 5 Jordan J, et al., J Hypertens 2007, 25(4):897–900; 6 Bramlage P, et al., Am J Hypertens 2004, 17(10):904–910 3
Firibastat: Mechanism of Action • Angiotensin III is one of the main effective peptide of the brain renin angiotensin system, exerting tonic stimulatory control over BP • Firibastat (QGC001/RB150) is an orally active brain penetrating pro-drug of EC33, a selective and specific aminopeptidase A (APA) inhibitor Brain firibastat 2 x EC33 reductases Vasopressin release APA Sympathetic nerve activity x Angio II Angio III Baroreflex activation APA = Aminopeptidase A Blood pressure Angio II = Angiotensin II Angio III = Angiotensin III 1 Bodineau et al., Hypertension, 2008. 2 Marc et al., Hypertension, 2012. 3 Huang et al., Cardiovascular Research, 2013 4 4
Firibastat: Pharmacokinetic and Pharmacodynamic Aspects In Rat: • Has no effect on BP in normotensive rats • Is more effective in DOCA-salt rats than in SHRs suggesting efficacy in salt-dependant HTN In Human: • Tmax 3-5 h • Half-life: 2.2 h • Steady state: 4 days • No effect on BP , HR and eGFR in normotensive volunteers • Phase 2a: BP decreases in hypertensive patients (N=34) 1 Bodineau et al., Hypertension, 2008; 2 Marc et al., Hypertension, 2012; 3 Balavoine et al., Clin. Pharmacokinet., 2014; 4 Azizi et al., Hypertension (submitted) 5
Main Entry Criteria Main inclusion criteria • Primary HTN (SBP: 145-170 mmHg and DBP<105 mmHg after 2-week wash-out) • BMI: 25-45 kg/m² • At least 50% self-identified Blacks or Hispanics Main exclusion criteria • eGFR rate<45ml/min/1.73m 2 • T1D or T2D with A1C>8% or treated with short-acting insulin or sodium-glucose cotransporter 2 inhibitors T1D: type 1 diabetes mellitus; T2D: type 2 diabetes mellitus 6
Phase 2b NEW-HOPE Study design U.S. Multicenter open-label trial AOBP: Automated Office Blood Pressure Clinicaltrials.gov : NCT03198793 7
NEW-HOPE Protocol: Automated Office Blood Pressure (AOBP) • 5 minutes rest in seated position • Back supported in a quiet room • No talking • Legs uncrossed on the floor throughout the measurements • 6 measurements at 1-minute intervals • First measurement automatically discarded and • Next 5 measurements averaged. • AOBP highly correlates with daytime ABP *ABP: Ambulatory Blood Pressure 1 NEW-HOPE Protocol QGC001/2QG02; 2 Myers MG, Matangi M, Kaczorowski J., J Clin Hypertens. 2018;00:1–7. 8
Phase 2b NEW-HOPE Study Endpoints Primary endpoint: • Systolic automated office BP (AOBP) 8-week change from baseline Secondary endpoints: • Diastolic AOBP 8-week change from baseline • Percentage of controlled subjects (i.e. AOBP ≤ 140/90 mmHg after 8 weeks) • Systolic and diastolic ambulatory BP (ABP) • Safety *ABP: Ambulatory Blood Pressure 9
560 subjects 816 subjects screened ineligible (Mainly due to BP 256 subjects enrolled level) 254 subjects * All patients who took at least one 36 (14.1%) subjects Intent-to-treat* capsule and with at least one post- withdrew baseline blood pressure assessment population - 17 (6.6%) adverse events - 5 (2.0%) consent withdrawn - 5 (2.0%) lost to follow-up 250mg BID: 37 subjects (14%) - 2 (0.8%) non-compliance 218 subjects completed 500mg BID: 178 subjects (70%) - 2 (0.8%) severe hypertension 500mg BID+HCTZ: 39 subjects (15%) study on treatment (per-protocol) 10
Baseline characteristics N=254 Age, mean (SD), y 58.3 (10.0) Age ≥ 65, n (%) 67 (26.4%) Women, n (%) 116 (45.7%) Self-identified minorities*, n (%) 136 (53.5%) Blacks, n (%) 96 (37.8%) Weight, mean (SD), kg 95.0 (17.0) BMI, mean (SD), kg/m² 33.0 (5.2) Obese, n (%) 166 (65%) T2D, n (%) 71 (27.9%) eGFR, mean (SD), ml/min/1.73m² 87.7 (18.4) * Minorities: Black or Hispanic 11
Baseline characteristics N=254 Systolic AOBP, mean (SD), mmHg 153.9 (7.2) Diastolic AOBP, mean (SD), mmHg 91.5 (8.4) Systolic daytime ABP, mean (SD), mmHg 151.2 (13.2) Diastolic daytime ABP, mean (SD), mmHg 87.3 (9.4 ) Anti-hypertensive treatment before inclusion Untreated, n (%) 57 (22%) 1 drug, n (%) 111 (43.7%) 2 drugs, n (%) 79 (31%) 3 drugs, n (%) 7 (3%) 12
Primary Endpoint: change to week 8 in systolic AOBP 153.9±7.2 Change at day 56 P value* N=254 -9.7 mmHg <0.0001 95% CI [-10.9 , -7.4 ] 144.3*±14.2 N=254 7 14 28 56 *ITT population-LOCF LOCF: Last observation carried forward 95% CI : 95% confidence interval 13
Multivariate analysis on change from baseline in systolic AOBP • Multivariate analysis, parameters include: baseline systolic AOBP, age, BMI, gender, race, sites • The only significant predictive factor is baseline systolic AOBP 14
BP endpoints by AOBP Baseline Day 56 Change P value Systolic AOBP, mean (SD), mmHg 153.9 (7.2) 144.3 (14.2) -9.7 (14.4) <0.0001 Diastolic AOBP, mean (SD), mmHg 91.5 (8.4) 87.2 (10.6) -4.3 (9.4) <0.0001 Further data will be analyzed to document 24h BP, daytime ABP and nocturnal ABP. 15
Systolic AOBP change across sub-groups p value for interaction -7 16
Firibastat effectiveness in black and non-black patients N=158 N=96 days 7 14 28 56 17
Firibastat effectiveness in black and non-black patients Black Non-Black N= 96 N= 158 Age, mean (SD), y 57.2 (8.5) 59.0 (10.6) BMI, mean (SD), kg/m² 34.3 (5.1) 32.2 (5.1) Systolic AOBP, mean (SD), mmHg 153.8 (7.1) 154.0 (7.3) Change in systolic AOBP (mmHg) -10.5 (14.7) -9.1 (14.2) p<0.0001 p<0.0001 18
Safety Events Patients (%) N= 255 Treatment-emergent adverse events (TEAE) 107 (42%) Related TEAEs 61 35 (14%) • Headache 11 10 (4%) • Skin reaction 9 7 (3%) Adverse event leading to discontinuation 25 19 (7.5%) • Skin reaction 3 • Headache 4 • Hypertension 3 • Dizziness 5 • Diarrhea 3 • Others 7 Serious adverse event 5 5 (2%) Serious related Adverse event 1 1 (0.4%) • Erythema multiforme 1 19
Laboratory tests Baseline Day 56 Change Potassium (mmol/l), mean (SD) 4.38 (0.4) 4.36 (0.5) -0.03 Sodium (mmol/l), mean (SD) 139.3 (2.5) 139.0 (2.3) -0.2 Blood glucose (mg/dl), mean (SD) 112 (34) 117 (44) +3.5 Creatinine mg/dl, mean (SD) 0.91 (0.2) 0.91 (0.2) 0.0 ALT UI/l, mean (SD) 21.8 (16.5) 25.1 (16.3) +3.7 AST UI/l, mean (SD) 19.1 (9.7) 21.1 (11.3) +2.3 ALT: alanine aminotransferase AST: aspartate aminotransferase 20
NEW-HOPE: Study Limitations • Open-label, with no placebo or control group (this choice endorsed by the FDA) • Placebo use has: - Ethical concerns in a high-risk population - Physician/subjects concerns, limiting subject recruitment - Potential exclusion of subjects with more severe disease targeted for the study • AOBP (and not ABP) as primary endpoint • However, AOBP known to highly correlate with daytime ABP • 2 month-treatment period • Self-identified race/ethnicity • 2 week-wash-out period 1 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 2 Myers MG, Matangi M, Kaczorowski J. J Clin Hypertens. 2018;00:1–7. 21
Discussion • Both ESC/ESH 2018 and ACC/AHA 2017 guidelines recommend a combination of 2 drugs as a first-line in black patients • Limited trial evidence of ACE-I/ARB effectiveness in a similar high risk diverse population for 8 weeks, in monotherapy • In both guidelines ACE-i/ARB are not recommended as first line monotherapy in black subjects • ALLHAT: blacks with metabolic syndrome (mean BMI 33.3 ± 6.5) had SBP/DBP 3 mmHg higher with lisinopril-based therapy vs. chlorthalidone (p<0.001) 1 ESC/ESH guidelines 2018; 2 ACC/AHA guidelines 2017; 3 Wright J. JAMA. 2005; 293:1595-1608 22
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