Tadalafil (Cialis) or Sildenafil (Viagra) to Protect Muscles in DMD?

Tadalafil (Cialis) or Sildenafil
(Viagra) to Protect Muscles in DMD?
Ron Victor, M.D.
Burns & Allen Chair
Associate Director, Cedars-Sinai Heart Institute
Professor of Medicine, UCLA (Center for DMD)
Outline
•  Premise
-why Cialis or Viagra for DMD?
•  Promise
-benefits in children with pulmonary HTN
-benefits in mdx mice and zebrafish
model of DMD
•  Preview
-our PPMD study in boys with DMD
Premise
Neuronal nitric oxide synthase
(nNOS) is a dystrophinassociated protein in skeletal
muscle.
Muscle cell
Lai, Thomas et al., JCI 2009; commentary by Heydermann & McNally
Healthy muscles make nitric oxide
working muscle
Nitric
Oxide
nNOS
blood
vessels
enlarge
oxygen delivery
Dystrophin-deficient muscles make
only tiny amounts of nitric oxide
nNOS
Nitric
Oxide
DMD muscle
oxygen deficit
blood vessels
clamp down
Victor, Thomas et al.
  mdx mouse
  nNOS knock out mouse
  boys with DMD
Cialis and Viagra boost cGMP
… in blood vessels that feed muscles
DMD muscle
Nitric
Oxide
nNOS
Less hurt?
cGMP
oxygen
restored?
blood
vessels
enlarge?
Promise
Cialis and Viagra prevent postexercise fatigue in mdx mice
mdx mice
untreated
“fatigue”
Kobayashi et al., Nature 2008
Blood vessels
clamped down
Cialis
Blood vessels
enlarged
The clinical translation gap
# research papers per year
60
50
mdx mice
40
30
20
10
dystrophin
gene
discovered
DMD
BMD
0
1980 1985 1990 1995 2000 2005 2010
Acute Cialis for BMD?
Cialis or Viagra for
DMD?
Preview (study starts next week)….
Objec&ves To plan for a multicenter clinical outcomes
trial, we first designed a dose-finding study
comparing open-label Cialis and Viagra on:
  Muscle
oxygen delivery
  Safety and tolerability
  Clinically meaningful outcomes
Cialis or Viagra?
Cialis
• Long acting (1 /day)
• Less costly
• Well absorbed
• No drop in BP
• Specific cGMP
Viagra
• Short acting (4 /day)
• More costly
• Less well absorbed
• Small drops in BP
• “Off target” cAMP
Enrollment
Target enrollment
30 patients
Inclusion criteria
-Proven DMD
-Ages 7-15
-Ambulatory (6 MWT)
-Normal echocardiogram
(standard measures)
Exclusion criteria
-Heart failure
-Very high blood pressure
-Irregular heart rhythm
-Other risk factors
-Severe attention deficit
Participation
Duration of participation
6 research clinic visits in 8 weeks
Study protocol
-Baseline visits- weeks 1 and 2
-Randomize patients to Cialis or Viagra
target week
enrollment
30 dose-week
boys
-First drug: low dose3, high
4
-Washout- weeks 5 and 6
-Second drug: low dose- week 7, high dose week 8
Research Clinic Tests
  Muscle
  Six
oxygen and blood flow—handgrip test
target enrollment 30 boys
minute walk test (2 in a row: fatigability?)
  Special
Echocardiogram (early abnormalities)
Other Measures
  Home
-Accelerometer
-Holter monitor
  Patient
reported outcomes
-Quality of life
target enrollment 30 boys
-Perceived effort and perceived hurt (6MWT)
Safety Monitoring
How
-Questionnaires
-Nurse phone calls
-Holter monitoring
-Blood pressure checks
Side-effects
-Indigestion
-Headaches
-Dizziness
Adverse events
-Prolonged erection
-Loss of vision
-Loss of hearing
-Irregular heart rhythm
-Low blood pressure
Closing comments
Cialis and Viagra
•  will not cure DMD
•  may permit more exercise with less
muscle injury (skeletal & heart muscle)
•  may slow disease progression
•  no new drug development is needed
•  adjunct to gene therapy for DMD
Hypertension & Vascular Biology
Clinical Research Center
Many thanks!
Gail Thomas
UPenn-CHOP
Lee Sweeney
Rick Finkel
U of Florida
Barry Byrne
Krista Vandendborne
Glenn Walter
Melissa Spencer, R. Elashoff,
Stan Nelson, Carrie Miceli
Parent Advisors
Stan Nelson and Carrie Miceli
Mindy Cameron
Ariane Salvatori
Amy Martin
Cathy and Scott Jones
Debra Miller
Pat Furlong
Sharon Hesterlee