Efficacy and Safety of a Novel Antihypertensive Pharmacotherapeutic - - PowerPoint PPT Presentation

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Efficacy and Safety of a Novel Antihypertensive Pharmacotherapeutic - - PowerPoint PPT Presentation

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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,

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Efficacy and Safety of a Novel Antihypertensive Pharmacotherapeutic Approach in a High-Risk, Diverse Population

Novel Evaluation With QGC001 in Hypertensive Overweight Patients of Multiple Ethnic origins

K.C. Ferdinand, F. Balavoine, B. Besse, H.R. Black,

  • S. Desbrandes, H.C. Dittrich, S.D. Nesbitt.
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SLIDE 2

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

Balavoine, Bruno Besse, Stephanie Desbrandes are full-time employees of Quantum Genomics

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SLIDE 3

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; 2Carey R. et al., Hypertension. 2018;72:0000; 3Helmer A et al., Annals of

Pharmacology 2018 1-9; 4The State of Obesity 2018; 5Jordan J, et al., J Hypertens 2007, 25(4):897–900;

6Bramlage P, et al., Am J Hypertens 2004, 17(10):904–910

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SLIDE 4

Firibastat: Mechanism of Action

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1Bodineau et al., Hypertension, 2008. 2 Marc et al., Hypertension, 2012. 3Huang et al., Cardiovascular Research, 2013

  • 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

Vasopressin release Sympathetic nerve activity Baroreflex activation Blood pressure

firibastat

2 x EC33

Brain reductases

APA

x Angio II Angio III

APA = Aminopeptidase A Angio II = Angiotensin II Angio III = Angiotensin III

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SLIDE 5

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)

1Bodineau et al., Hypertension, 2008; 2 Marc et al., Hypertension, 2012; 3Balavoine

et al., Clin. Pharmacokinet., 2014; 4Azizi et al., Hypertension (submitted)

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Main Entry Criteria

T1D: type 1 diabetes mellitus; T2D: type 2 diabetes mellitus

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/1.73m2
  • T1D or T2D with A1C>8% or treated with short-acting insulin or

sodium-glucose cotransporter 2 inhibitors

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Phase 2b NEW-HOPE Study design U.S. Multicenter open-label trial

Clinicaltrials.gov : NCT03198793

AOBP: Automated Office Blood Pressure

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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

1 NEW-HOPE Protocol QGC001/2QG02; 2 Myers MG, Matangi M, Kaczorowski J., J Clin

  • Hypertens. 2018;00:1–7.

*ABP: Ambulatory Blood Pressure

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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

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SLIDE 10

816 subjects screened 254 subjects Intent-to-treat* population

36 (14.1%) subjects withdrew

  • 17 (6.6%) adverse events
  • 5 (2.0%) consent withdrawn
  • 5 (2.0%) lost to follow-up
  • 2 (0.8%) non-compliance
  • 2 (0.8%) severe hypertension

560 subjects ineligible

(Mainly due to BP level)

256 subjects enrolled 218 subjects completed study on treatment (per-protocol)

250mg BID: 37 subjects (14%) 500mg BID: 178 subjects (70%) 500mg BID+HCTZ: 39 subjects (15%)

* All patients who took at least one capsule and with at least one post- baseline blood pressure assessment

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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

Baseline characteristics N=254

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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%)

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Primary Endpoint: change to week 8 in systolic AOBP

Change at day 56 P value*

  • 9.7 mmHg

<0.0001 95% CI [-10.9 , -7.4 ]

153.9±7.2 144.3*±14.2

7 14 28 56

N=254

*ITT population-LOCF LOCF: Last observation carried forward 95% CI : 95% confidence interval

N=254

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SLIDE 14

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

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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.

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Systolic AOBP change across sub-groups

  • 7

p value for interaction

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Firibastat effectiveness in black and non-black patients

7 14 28 56

days N=96 N=158

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Firibastat effectiveness in black and non-black patients

Black N= 96 Non-Black 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)

p<0.0001

  • 9.1 (14.2)

p<0.0001

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SLIDE 19

Safety

Events Patients (%) N= 255 Treatment-emergent adverse events (TEAE) 107 (42%) Related TEAEs

  • Headache
  • Skin reaction

61 11 9 35 (14%) 10 (4%) 7 (3%) Adverse event leading to discontinuation

  • Skin reaction
  • Headache
  • Hypertension
  • Dizziness
  • Diarrhea
  • Others

25 3 4 3 5 3 7 19 (7.5%) Serious adverse event 5 5 (2%) Serious related Adverse event

  • Erythema multiforme

1 1 1 (0.4%)

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SLIDE 20

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

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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.

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SLIDE 22

Discussion

  • Both ESC/ESH 2018 and ACC/AHA 2017 guidelines recommend a combination
  • f 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

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SLIDE 23

Conclusion

  • Firibastat (85% monotherapy), significantly (p<0.0001) decreased systolic

AOBP (by 9.7 mmHg) in a diverse (53.5% minorities) high-risk (65% obese) hypertensive population

  • Consistent results were found for diastolic AOBP
  • Efficacy similar in black/non black subjects and in overweight/obese subjects
  • No angioedema was reported in this cohort of 8 week-treatment-period
  • Skin

reactions (4%) and headaches (3%) were the most common side-effects,

  • Otherwise firibastat was well tolerated

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SLIDE 24

Conclusion

The NEW-HOPE results, in a high-risk diverse population, where monotherapy with ACE-i/ARB may be less effective, support the strategy to further investigate firibastat, the first brain-aminopeptidase A inhibitor, in subjects with difficult-to-treat or resistant hypertension.

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SLIDE 25

Aknowledgments

  • Investigators : B. Mc Lean, A. White, Y. Khronusova, S. Lynd, S. Arora, N. Andrawis, J.

Neutel, A. Ahmed, D. Vega, M. Butcher, T. Isakov, J. Agaiby, O. Akinboboye, P. Toth, A. Feldman, J. Frias, V. Conrad, C. Strout, M. Guice, A. Murillo, V. Bland, P. Pemu, H. Williams, A. Lacour, W. Farris, N. Smith, S. Nesbitt, E. Miel, B. Gatto, E. Grasso, R. Strzinek, S. Randhawa,

  • F. Sogade, A. Ryan, B. Hutchinson, J. Flack, R. Broker, C. Johnson, Y. Goldberg, D. De Atkine
  • Subjects enrolled into the study
  • Association of Black Cardiologists
  • Inside Edge Consulting Group
  • Medpace

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SLIDE 26

THANK YOU!

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Background

  • In blacks, HTN occurs earlier, is more severe, controlled less often and has a

higher morbidity and mortality rate than in whites1

  • Blacks compared to whites may have reduced BP response to ACEis or

ARBs as monotherapy2

  • Limited HTN studies have been conducted in similar high-risk diverse

populations, at risk of resistant HTN, a high unmet need

1 NCHS data brief N°289 , Oct 2017 2Helmer A & Al. Annals of pharmacology 2018 1-9

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