REVatio for hEaRt diSease in Duchenne Muscular Dystrophy: REVERSE-DMD

Kathryn R. Wagner, M.D., Ph.D. The Kennedy Krieger Institute Johns Hopkins School of Medicine June 26, 2010



Men with DMD in industrialized countries are living longer with each passing decade since the 1960s.



Dilated cardiomyopathy increases with age in DMD



Lack of dystrophin is required but not sufficient to cause pathology

PDE5 inhibitor: increases cGMP specifically  Vasorelaxant properties first studied for hypertension and angina pectoralis  Side effect of penile erections led to FDA approval for erectile dysfunction  Safe in treatment of pediatric pulmonary hypertension  Brand names: Revatio, Viagra 



PDE5a is upregulated in dilated cardiomyopathy

ď ˝â€Ż

Sildenafil inhibits cardiac hypertrophy induced by constriction of the thoracic aorta B 3wk 9 wk

-Sil

+Sil

Takimoto et al., Nat Med 2005



PDE5 inhibition reverses established hypertrophy LVMass (mg)

Wall thickness (mm)

Fractional Shortening (%) 80

200 1.2

160

60

120

.8

40

80 40 0



.4

p<0.001 TAC -7d

+ Sil (1wk)

+ Sil (2wk)

0

p<0.001 TAC -7d

+ Sil (1wk)

20

+ Sil (2wk)

0

p<0.01 TAC -7d

+ Sil (1wk)

+ Sil (2wk)

Current NIH-funded multicenter trial of sildenafil in the treatment of diastolic heart failure (RELAX trial)

Enhancing cGMP signaling via genetic or pharmacological means (sildenafil) improves contractile function and sarcolemmal integrity in mdx (Khairallah et al. 2008)  Treatment of mdx with sildenafil prevented cardiac functional decline and fibrosis and reversed cardiac dysfunction when begun at later stages (Parchen et al., 2009) 

Hypothesis: PDE5 inhibition with sildenafil (Revatio) will improve cardiac function in adolescents and adults with Duchenne muscular dystrophy

Randomized, Double-Blind, Placebo-Controlled  Duration: 12 months 

◦ 6 months placebo controlled ◦ 6 months open label 

Single dose of sildenafil will be tested ◦ 20 mg three times a day ◦ Prior randomized dose-escalation studies have determined this dose is both safe and efficacious for the treatment of pulmonary hypertension and preeclampsia

To determine whether a 6 month trial of oral sildenafil compared to placebo improves cardiac contractile function in DMD as determined by > 10% decline in end-systolic volume as detected by cardiac magnetic resonance (CMR) imagining  Left ventricular end-systolic volume (LVESV) 

◦ Change from baseline in LVESV after 6 months on sildenafil vs placebo ◦ Change from baseline in LVESV after 6 months vs 12 months on sildenafil



Safety



Cardiac



Skeletal muscle function



Quality of Life

◦ Frequency and grade of adverse events ◦ Systolic and diastolic LV function by MRI ◦ Differences in LV mass and fibrosis by MRI ◦ Brachial flow-mediated vasodilation ◦ Forced vital capacity ◦ Pincher strength ◦ Grip strength ◦ InQol ◦ SF36



Inclusion criteria (selected) ◦ DMD by absence of dystrophin protein or mutation in dystrophin gene predictive of DMD ◦ Male ◦ Age > 15 years ◦ Cardiac dysfunction with ejection fraction < 45% ◦ A stable dose of ACE-inhibitor or ARB for at least 3 months ◦ Use of beta-adrenergic receptor blockers or glucocortico-steroids are neither required or excluded but must be stable for past 3 months



Exclusion criteria (selected) ◦ Use of nitrates or alpha-adrenergic receptor blockers ◦ History of priapism or conditions that may predispose to ◦ Factors that would preclude obtaining an MRI ◦ Systolic blood pressure < 85 mm Hg at baseline ◦ Chronic kidney disease stages 4 and 5 as determine by cystatin C ◦ Current use of sildenafil ◦ Active tobacco use

Month Week: Day:

0

Informed Consent

X

Inclusion/Exclusion

X

0 0 1

1 2

2

3

6 26 180

181

182

7

8

9

12 52

Safety measures:

Vital signs

X

Q 6hr

Q 6hr

X

X

X

Q 6hr

Q 6hr

Q 6hr

X

X

X

X

Physical Exam

X

X

X

X

X

X

X

X

X

X

X

X

X

Hematology/chemistries

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Adverse Events Efficacy measures: Cardiac MRI

X

X

X

Flow-mediated vasodilation (FMD)

X

X

Electrocardiogram

X

X

Forced vital capacity

X

X

X

X

X

INQoL & SF-36

X

X

X

X

X

Pincher and grip test

X

X

X

X

X

X

Drug dosing: Inpatient administration Dispense 1 months’ supply Dispense 3 months’ supply

X

X X

X X

X

X

X X

X

X

X X

Acknowledgements Muscle Clinical Research Team: Geni Bibat, MD Michael Munchel, RN Courtney Broadley, PT Diana Escolar, MD

Collaborators : Daniel Judge, MD, Department of Cardiology, Johns Hopkins David Kass, MD, Department of Cardiology, Johns Hopkins Al Lardo, MD, Department of Radiology, Johns Hopkins George Vella, Director of Research, Charleyâ&#x20AC;&#x2122;s Fund, Inc. Men with Duchenne

Pfizer Funding: Charley's Fund Inc. Cure Duchenne Nash Avery Foundation

wagnerk@kennedykrieger.org