THE SOUTHPAW STUDY - United Therapeutics · 2018. 9. 26. · This presentation and any related...
Transcript of THE SOUTHPAW STUDY - United Therapeutics · 2018. 9. 26. · This presentation and any related...
HEART FAILURE AND PRESERVED EJECTION FRACTION: CLINICAL STUDY DESIGN AND TREATMENT
THE SOUTHPAW STUDY
Mardi Gomberg-Maitland, MD, MSc Professor of Medicine, Inova Heart and Vascular Institute, VA USA
UTHR Science Day 2018 / SOUTHPAW/ Mardi Gomberg-Maitland
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SAFE HARBOR STATEMENT
Remarks today concerning United Therapeutics may include forward-looking statements which represent United Therapeutics’ expectations or beliefs regarding future events. We caution that such statements involve risks and uncertainties that may cause actual results to differ materially from those in the forward-looking statements. Consequently, all such forward-looking statements are qualified by the cautionary language and risk factors set forth in United Therapeutics’ periodic and other reports filed with the SEC.
There can be no assurance that the actual results, events or developments referenced in such forward-looking statements will occur or be realized. United Therapeutics assumes no obligation to update these forward-looking statements to reflect actual results, changes in assumptions or changes in factors affecting such forward-looking statements.
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WHAT IS WHO GROUP 2 PH?WHO Classification of Pulmonary Hypertension (PH) 21-23
PULMONARY HYPERTENSION (PH)
GROUP 1Pulmonary Arterial
Hypertension (PAH)
GROUP 2PH Due to
Left Heart Disease
GROUP 3PH Due to
Lung Disease
GROUP 4PH Due to Chronic
Thromboembolism
GROUP 5PH Due to
Unclear Multifactorial Mechanisms
Systolic dysfunction Diastolic dysfunction Valvular disease Complex Congenital Heart Disease/Myopathy
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THE UNDERLYING PROBLEM1
» The heart can fail to eject blood normally and can fail because it does not relax normally (refills with blood) or both
» Success in heart failure therapeutics has been in HFrEF not HFpEF
One method to phenotype/
classify patients
EJECTION FRACTION % (EF) =Amount of blood pumped out of the ventricle
Total amount of blood in ventricle
½ of the cohort have a
“preserved” EF, HFpEF
½ have “reduced“ EF,
HFrEF
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SCOPE OF THE PROBLEM
~5.7 MIL
50% ~2.85 MIL
36-83% 1-2.4 MIL
5-13% 67-350 K
HEART FAILURE2-5
HFpEF6
PH HFpEF7-9
Combined PRE-AND-POST CAPILLARY PH HFpEF - SOUTHPAW10-13
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PH HFpEF PATIENTS HAVE WORSE PROGNOSIS VS PAH
PAH REGISTRY 1 YEAR SURVIVAL PROGNOSIS15-17
84-88%
» 1 yr survival / incident cases = 85%
REGISTRY 1 / CHICAGO
» 1 yr survival model cohort = 91% » 1 yr survival incident cohort = 84.6%
100
80
60
40
20
0
Perc
enta
ge S
urvi
val
RISK SCORES
NUMBER AT RISK
0
0 (N=163)
1 (N=120)
2-3 (N=57)
Time from Baseline Diagnosis (Months)
1
2-3
0 2 4 6 8 10 12 14 16 18 20 22 24
163 156 145 62 56 52 50 47 45 41 39 38 38
120 106 102 42 37 34 33 31 30 28 27 24 23
57 45 41 21 17 17 15 14 14 12 11 10 8
10
30
50
70
90
100
80
60
40
20
0
Perc
enta
ge S
urvi
val
RISK SCORES
NUMBER AT RISK
0
0 (N=163)
1 (N=120)
2-3 (N=57)
Time from Baseline Diagnosis (Months)
1
2-3
0 2 4 6 8 10 12 14 16 18 20 22 24
163 156 145 62 56 52 50 47 45 41 39 38 38
120 106 102 42 37 34 33 31 30 28 27 24 23
57 45 41 21 17 17 15 14 14 12 11 10 8
10
30
50
70
90
» 90% if no risk scores
» 80% for 1 risk score
» 60% for 2-3 risk scores
PH HFpEF 1 YEAR SURVIVAL PROGNOSISFOR 0,1,2-3 RISK SCORES14
60-90%
REGISTRY 2 / USA
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PH-LHD PREDICTORS OF MORTALITY14
» This analysis was performed using 340 WHO Group 2 Pulmonary Hypertension patients with any follow-up from baseline diagnosis
» The c-index for the final model is .709 and c-index for the risk score is .708
Variable HR (95% CI) P value
Systolic Blood Pressure ≤ 113 mmHg 2.6 (1.7,4.0) <.001
PA SAT ≤ 48 % 2.3 (1.3,4.3) .006
Enlarged LA size 2.1 (1.1,3.8) .023
HGB < 11 2.2 (1.3,3.6) .002
RV Hypertrophy 2.1 (1.1,4.0) .021
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HFpEF IS NOT AS SIMPLE AS WE THOUGHT
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To determine that LVEF is “Preserved” (whatever that means!)
WHAT IS THE EF IN HFpEF? 40%, 45%, 50%?18
CHARM ASE “normal”
Low Ejection Fraction
Preserved Ejection Fraction
10% 20% 30% 40% 50% 60% 70% 80%
HFrEF
TOPCAT, IPreserve, PARAGON
CAVEATS
» Assessment of LVEF is a ±7 measurement
» All Cutoffs are arbitrary
» There is no therapy for Heart Failure with LVEF > 40%!
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MANY PROCESSES LEAD TO HFpEF9
Stiff arteries
Longitudinal pumping problems Autonomic dysfunction
Ventricles and atria not working in coordinated fashion
Non-heart causesof volume overload
Inability for heart rate to respond appropriately Inflammation
Skeletal muscle abnormalities
The membrane that lines the inside of the heart and blood vessels that control relaxation and contraction doesn’t work
High pressure in the lungs with right pump failureRelaxation of the heart abnormalities
HFpEF
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HFpEF PHENOTYPES19
RHF/PH HFpEF1
CAD-HFpEF2
HCM like HFpEF4
Rare causes of HFpEF5What everyone sees in clinic
“typical” HFpEF (HTN, NIDDM obesity, CKD)
3
High output HFpEF8 Unclear HFpEF- what is a mix
of phenotypes and super sick (MG clinic patient)
9
A-fib predominant HFpEF6
Valvular HFpEF (multiple 2+ lesions)
7
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HYPOTHESIS
MAYBE WE CAN USE PROSTACYCLINS IN PH ASSOCIATED WITH RV
DYSFUNCTION IN HFpEF
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OVERLAP OF GENETICS ISOLATED/MIXED PH-LHD AND PAH20
PAH SNPs
Ipc-PH SNPs
Cpc-PH SNPs
Cpc-PH Similar to PH:
» Younger age» Severe pulmonary
vascular disease
Cpc-PH Similar to Ipc-PH:
» Medical comorbidities» Severity and
chronicity of LV disease
CLINICAL ANALYSIS GENETIC ANALYSIS
141 SNPs with ↑ lung expression
» Actin Binding » Extracellular Matrix » Basement Membrane » MHC II Proteins
Ipc-PH = isolated post-capillary pulmonary hypertension; Cpc-PH = combined post-capillary and pre-capillary pulmonary hypertension; SNPs = single-nucleotide polymorphisms; PAH = pulmonary arterial hypertension; MHC = major histocompatibility complex; LV = left ventricular.
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VIRTUAL REALITY EXPERIENCE
VR INSTRUCTIONS
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TREATING PH IN HFpEF24,25
» HFpEF patients are different than HFrEF patients; increasing as more people are “elderly”
» HFpEF patients experience greater BP reduction, less increase in CO and a greater likelihood of stroke volume drop with vasodilators
» PAH therapies may have a different effect in patients with HFpEF
» RV dysfunction in HFpEF is a possible target
» Therapies will need to be targeted more based on hemodynamics or other endpoints not previously usedRX
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WHAT DO WE KNOW SO FAR?
THERE IS SOME EVIDENCE TO SUPPORT THE TREATMENT OF THE PULMONARY VASCULAR DISEASE
COMPONENT OF PH HFpEFSHOULD WE TARGET THE RV AS WELL?
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1 YR. DBPC TRIAL SILDENAFIL HFpEF24
» Improvement in mPAP, PVR and vasomotility
» Improvement in RV fxn (TAPSE) and dimension, lower mRAP
» Improvement in LV relaxation and distensibility (structural changes and/or ventricular interdependence)
» Improved lung alveolar gas conductance
0
8
2
6
4
0
8
2
6
4
6 months 12 monthsBaseline 6 months 12 monthsBaseline
*
*° *°
Pulmonary ArteriolarResistance (wood units)
Pulmonary ArteriolarResistance (wood units)
PLACEBO SILDENAFIL
LEGEND Individual and mean (±SD) values. *P<0.01 vs baseline; §P<0.01 vs corresponding placebo value.
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DILATE-1 STUDY: PHASE IIB HEMODYNAMIC STUDY26
Time (hours)
Mean
chan
ge fr
om ba
selin
ein
cardi
ac in
dex (
L/min/
m²)
-1
1
1.5
-0.5
0.5
0
0 0.5 1 2 3 4 5 6Time (hours)
Mean
chan
ge fr
om ba
selin
ein
PAWP
(mm
Hg)
-10
24
-6-8
0-2-4
0 0.5 1 2 3 4 5 6
Time (hours)
Mean
chan
ge fr
om ba
selin
ein
SVR (
dyn-
sec-
c- 5)
-900
300
600
-600
0
-300
0 0.5 1 2 3 4 5 6Time (hours)
Mean
chan
ge fr
om ba
selin
ein
map (
mm Hg
)
-40
1020
-20-30
0-10
0 0.5 1 2 3 4 5 6
B
D
A
C
Placebo (n=11)
Riociguat 2mg (n=10)
» Did not change mPAP (p=0.6) in 6 hrs BUT most patients did not reach target dose
» CI, PVR, SVR improved
» Increased SV did not increase PCWP
» Riociguat is vasodilatory and may improve diastolic function
LEGEND
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WHY SOUTHPAW: RATIONALE 27-32
» Prostacyclins act as vasodilators to widen the blood vessels of the pulmonary and systemic arterial vascular beds. These drugs also inhibit platelet aggregation, and smooth muscle cell proliferation
1
» No treatments approved to treat WHO Group 2 PH (PH HFpEF)
2 3
» Although PH HFpEF is typically thought of as a disease of the left heart, there are also significant abnormalities in the right heart (RV remodeling, both adaptive and maladaptive) in PH HFpEF
» Similar to how oral treprostinil treats PAH, it is thought that these components of PH HFpEF might be amenable to treatments with prostanoids
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SOUTHPAW STUDY
» Prostacyclins may be beneficial in PH associated with RV dysfunction in HFpEF
» Target the PH HFpEF-RV phenotype
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SOUTHPAW STUDY DESIGN OVERVIEW
24-WEEKtreatment period
N=310WHO GROUP 2 PH
85 CLINICAL SITES
RANDOMIZE 1:1
NCT03037580
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SOUTHPAW STUDY DESIGN OVERVIEW
PLACEBO
ORAL TREPROSTINIL
24-WEEKtreatment period
N=310WHO GROUP 2 PH
85 CLINICAL SITES
RANDOMIZE 1:1
NCT03037580
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SOUTHPAW STUDY DESIGN OVERVIEW
PLACEBO
ORAL TREPROSTINIL
KEY CLINICAL ASSESSMENTS
24-WEEKtreatment period
N=310WHO GROUP 2 PH
85 CLINICAL SITES
RANDOMIZE 1:1
NCT03037580
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SOUTHPAW STUDY DESIGN OVERVIEW
PRIMARY OBJECTIVE
CHANGE IN 6MWD from baseline to week 24
Clinical worsening, NT-pro-BNP
Safety, change in WHO Functional Class, patient-reported outcomes, biomarkers and genomics
SECONDARY OBJECTIVES
TERTIARY OBJECTIVES
KEY CLINICAL ASSESSMENTS
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SOUTHPAW STUDY DESIGN OVERVIEW
ORAL TREPROSTINIL
PLACEBO
INTERIM SAFETY REVIEWS BY DMCKEY CLINICAL
ASSESSMENTS24-WEEKtreatment period
N=310WHO GROUP 2 PH
85 CLINICAL SITES
RANDOMIZE 1:1
NCT03037580
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SOUTHPAW STUDY DESIGN OVERVIEW
INTERIM SAFETY REVIEWS BY DMC
Interim safety reviews at N=10, 30, 60, 100, and 200
Allows increasing total daily dose of oral treprostinil
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ADAPTIVE DESIGN: STUDY DRUG & DOSING CONSIDERATIONS
1-10
11-30
31 & above
2 mg TID
4 mg TID
6 mg TID
» Individual up titration to a maximum in each cohort
» Ability to down titrate
»May not reach dose of 6 mg tid for maximum dose
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SUMMARY AND PROGRESS TO DATE
Significant unmet medical need
THE FIRST DMC MEETING NOTED NO SAFETY CONCERNS
After a slow start and some refining to the protocol, significant progress has been made in the past few months
» 14 in the past 2 months» 5 completed and enrolled into OLE» ~10% withdrawal rate
(consistent with historical oral treprostinil data)
27 RANDOMIZED
By enrolling patients with the correct phenotype (combined pre-and-post capillary PH HFpEF, RV dysfunction), and employing a cautious, adaptive design, Southpaw aims to safely treat these patients
3
4
1
2
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REFERENCES
1. Heidenreich PA. Circ Heart Failure 2013; 606-619.2. Mozzafarian et al 2016.3. Savarese 2017.4. Cogswell and Thenappan 2015.5. Pothineni et al 2018.6. Owan et al 2006.7. Lam et al 2009.8. Leung et al 2010.9. Shah et al 2014.10. Gerges 2015.11. Rosenkranz et al 2016.12. Dixon 2015 (abstract).13. Dixon, Trivedi and Shah 2016.14. Agarwal, Gomberg-Maitland. JHLT 2012.15. Humbert et al. AJRCCM 2006;173:1023-1030.16. Thenappan et al. Eur Resp J. 2007;30(6)1103-10.17. Badesch et al. Chest 2010; 137:376-387.18. Solomon SD HFpEF-TT. 2017.19. Oktay AA, Shah SJ. Curr Cardiol Rev 2014.20. Assad, Brittain. J Am Coll Cardiol 2016.
21. Simonneau G, et al. J Am Coll Cardiol. 2013;62(25):D34-41.22. Bourke SJ. Postgrad Med J. 2006;82:494-499.23. “Interstitial Lung Disease” www.erswhitebook.com – accessed December 2015.24. Guazzi M, et al. Circulation 2011;124:164-74. 25. Schwartzenberg S, et al. J Am Coll Cardiol 2012; 59: 442-51.26. Bonderman D. Circ 2013 Jul 30; 128(5): 502-511.27. Moncada, S. et al. (1976) An enzyme isolated from arteries trans- forms prostaglandin
endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263, 663–665.
28. Koh, E., et al. (1993) Effects of beraprost sodium, a stable analogue of prostacyclin, on hy-perplasia, hypertrophy and glycosaminoglycan synthesis of rat aortic smooth muscle cells. Artery 20:242–252.
29. Grosser, T., et al. (1995) Iloprost-induced inhibition of proliferation of coronary artery smooth muscle cells is abolished by homologous desensitization. Agents Actions Suppl. 45:85–91.
30. Harada, M., et al. (1999) Prostacyclin synthase gene transfer inhibits neointimal formation in rat balloon-injured arteries without bleeding complications. Cardiovasc. Res. 43:481–491.
31. Urashima T, Zhao M, Wagner R, et al. Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol. 2008;295:H1351–68.
32. Grossman NL, Fiack CA, Weinberg JM, Rybin DV, Farber HW. Pulmonary hypertension as-sociated with heart failure with preserved ejection fraction: acute hemodynamic effects of inhaled iloprost. Pulm Circ. 2015;5:198–203.
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