THE SOUTHPAW STUDY - United Therapeutics · 2018. 9. 26. · This presentation and any related discussions or statements are intended to educate ... » The c-index for the final model

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

2

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


4

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


5

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


6

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


9

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%!


10

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


13

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?


17

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


20

SOUTHPAW STUDY

» Prostacyclins may be beneficial in PH associated with RV dysfunction in HFpEF

» Target the PH HFpEF-RV phenotype


21

SOUTHPAW STUDY DESIGN OVERVIEW

24-WEEKtreatment period

N=310WHO GROUP 2 PH

85 CLINICAL SITES

RANDOMIZE 1:1

NCT03037580


22


PLACEBO

ORAL TREPROSTINIL


N=310WHO GROUP 2 PH

85 CLINICAL SITES

RANDOMIZE 1:1

NCT03037580


23


PLACEBO

ORAL TREPROSTINIL

KEY CLINICAL ASSESSMENTS


N=310WHO GROUP 2 PH

85 CLINICAL SITES

RANDOMIZE 1:1

NCT03037580


24


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


25


ORAL TREPROSTINIL

PLACEBO

INTERIM SAFETY REVIEWS BY DMCKEY CLINICAL

ASSESSMENTS24-WEEKtreatment period

N=310WHO GROUP 2 PH

85 CLINICAL SITES

RANDOMIZE 1:1

NCT03037580


26


INTERIM SAFETY REVIEWS BY DMC

Interim safety reviews at N=10, 30, 60, 100, and 200

Allows increasing total daily dose of oral treprostinil


27

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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THE SOUTHPAW STUDY - United Therapeutics · 2018. 9. 26. · This presentation and any related discussions or statements are intended to educate ... » The c-index for the final model