Download ajrccm - Pulmonary Hypertension Association

PHA Thanks the Medical
Education Fund Sponsors!
PHA Thanks the Washington, DC Planning
Committee and Presenters!
•
Christopher Barnett, M.D., MPH; Co-chair
•
Grant Farr, D.O.
•
Oksana A. Shlobin, M.D., FCCP; Co-chair
•
Mardi Gomberg-Maitland, M.D., MSc
•
Janet Arp
•
Hunter Groninger, M.D., FACP, FAAHPM
•
Daniel C. Grinnan, M.D.
•
Shilpa Johri, M.D.
•
Denise Lewis, RN, BSN
•
Todd M. Kolb, M.D., Ph.D.
•
Stephen Mathai, M.D., MHS
•
Katherine Kroner
•
Betsie Miklos
•
Tunay Kuru, M.D.
•
Gerilynn Connors, B.S., RRT,MAACVPR,
FAARC
•
Janet Pinson, MSN, ACNP
•
Gautam Ramani, M.D.
•
Virginia Steen, M.D.
•
Nargues Weir, M.D.
•
•
•
Rachel Damico, M.D., Ph.D.
Jason M. Elinoff, M.D.
Karen Fagan, M.D.
PH Patients and Families Education Forum
A Program of the Pulmonary Hypertension Association Medical
Education Fund
Washington, D.C.
October 1, 2016
Where We Are,
Where We Are Going,
and How Do We Get There?
Jason M. Elinoff, MD
Critical Care Medicine Department
Mark O. Hatfield Clinical Center
National Institutes of Health
Disclosure
I have no relevant financial disclosures
Disclaimer
The content of this presentation does not
necessarily reflect the views or policies of
the U.S. Department of Health and Human
Services, nor does mention of trade
names, commercial products, or
organizations imply endorsement by the
U.S. government.
Where We Began
•
•
Survival (%)
100
No treatment available
Less than 50% of people with
PAH lived more than 3 years
from the time of diagnosis
0
Years From Time of Diagnosis
Adapted from D’Alonzo GE Ann Intern Med 1991
Where We Are
Survival (%)
100
0
Years From Time of Diagnosis
Adapted from Benza RL Chest 2012
Where We Are
Survival (%)
100
More People Are
Living Longer
With PAH
0
Years From Time of Diagnosis
Adapted from Benza RL Chest 2012
Timeline of PAH Drug Development
Treprostinil
intravenous
Ambrisentan Room temperature
stable epoprostenol
Treprostinil
subcutaneous
Macitentan
Riociguat
Sildenafil
Bosentan
Tadalafil
Epoprostenol
1995
2001
2002
2004 2005
Iloprost
Courtesy of Dr. Harold I. Palevsky
2007
2009
Treprostinil
inhaled
2010
2013
Selexipag
2014
2015
Treprostinil oral
PAH: Therapeutic Targets
PAH: Therapeutic Targets
PAH: Therapeutic Targets
PAH: Therapeutic Targets
Adapted from Humbert et al. NEJM 2004
PAH: Therapeutic Targets
Pulmonary artery
endothelial cells
Adapted from Humbert et al. NEJM 2004
PAH: Therapeutic Targets
Pulmonary artery
endothelial cells
Pulmonary artery
smooth muscle cells
Adapted from Humbert et al. NEJM 2004
Endothelin Pathway
Endothelial
cell
Endothelin
production
Endothelin
receptor A
Smooth
muscle cell
Endothelin
receptor B
Vasoconstriction
Adapted from Humbert et al. NEJM 2004
Endothelin Pathway
Endothelial
cell
Endothelin
production
Endothelin
receptor A
Endothelin
receptor B
Endothelin receptor
antagonists (ERAs)
Smooth
muscle cell
Adapted from Humbert et al. NEJM 2004
Endothelin Pathway
1. Bosentan (Tracleer®)
2. Ambrisentan (Letaris®)
3. Macitentan (Opsimut®)
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
Endothelial
cell
NO
production
NO
Guanylate
cyclase
NO
cGMP
Smooth
muscle cell
Vasodilation
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
Endothelial
cell
NO
production
NO
Guanylate
cyclase
NO
cGMP
Smooth
muscle cell
Phosphodiesterase
type 5
PDE5
Inhibitors
Vasodilation
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
Endothelial
cell
NO
production
NO
GuanylateGuanylate
cyclase
cyclase
stimulators
NO
Phosphodiesterase
type 5
cGMP
Smooth
muscle cell
PDE5
inhibitors
Vasodilation
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
Endothelial
cell
NO
production
NO
GuanylateGuanylate
cyclase
cyclase
stimulators
NO
Phosphodiesterase
type 5
cGMP
Smooth
muscle cell
PDE5
inhibitors
Vasodilation
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
1. Sildenafil (Revatio®)
2. Tadalafil (Adcirca®)
3. Riociguat (Adempas®)
Adapted from Humbert et al. NEJM 2004
Prostacyclin (PGI2) Pathway
Endothelial
cell
PGI2
production
Prostacyclin
receptor
Smooth
muscle cell
PGI2
Vasodilation
Adapted from Humbert et al. NEJM 2004
Prostacyclin (PGI2) Pathway
Endothelial
cell
PGI2
production
Prostacyclin
Prostacyclin
receptor receptor
agonists
Smooth
muscle cell
Prostacyclin
derivatives
Vasodilation
Adapted from Humbert et al. NEJM 2004
Prostacyclin (PGI2) Pathway
1. Epoprostenol (Flolan®, Veletri®)
2. Treprostinil (Remodulin®, Tyvaso®, Orenitram®)
3. Iloprost (Ventavis®)
4. Selexipag (Uptravi®)
Adapted from Humbert et al. NEJM 2004
Goals of PAH Treatment
• Improve survival
• Maintain or improve quality of life
• Decrease symptoms
• Improve exercise capacity
• Minimize side-effects of treatment
Patients without an Event (%)
Advances In Clinical Trials
100
90
80
70
60
50
40
30
12-16 weeks
20
10
0
0
6
12
18
Months
24
30
36
• Hospitalization for
worsening PAH
• Decreased 6 MWD
AND worse
symptoms needing
additional treatment
• Need for continuous
prostacyclin treatment
• Lung transplant
• Death
Advances In Clinical Trials
Patients without an Event (%)
Macitentan (Opsimut®)
N=242, 10 mg
N=250, 3 mg
100
90
80
70
60
Placebo
N=250
50
40
30
100
90
80
70
60
50
40
30
20
10
0
20
10
0
0
6
12
Selexipag (Uptravi®)
N=582
18
Months
24
30
36
Placebo
N=574
0
6
12
18
24
30
36
Months
N Engl J Med 2013 and 2015.
Advances In Clinical Trials
Patients without an Event (%)
Macitentan (Opsimut®)
N=242, 10 mg
N=250, 3 mg
100
90
80
70
60
Placebo
N=250
50
40
30
20
10
0
100
90
80
70
60
Over 700 Patients Participated
0
6
12
18
Months
24
30
Selexipag (Uptravi®)
N=582
36
50
40
30
20
10
0
Placebo
N=574
Over 1000 Patients Participated
0
6
12
18
24
30
36
Months
N Engl J Med 2013 and 2015.
Participants with No Event (%)
Advances In Clinical Trials
100
80
60
40
20
0
0
24
48
72
96
120 144 168 192
Weeks
Participants with No Event (%)
Is Initial Combination Therapy
Superior To Either Drug Alone?
100
• Hospitalization for worsening PAH or
80 • Decreased 6 MWD AND severe
symptoms (class III/IV) or
60
• Lack of long term clinical improvement or
40 • Death
20
0
0
24
48
72
96
120 144 168 192
Weeks
N Engl J Med 2015
Participants with No Event (%)
Yes, Initial Combination Therapy Is
Better Than Either Drug Alone
Ambrisentan (Letaris®)
AND
Tadalafil (Adcirca®)
N=253
100
80
60
Ambrisentan (Letaris®)
or
Tadalafil (Adcirca®)
N=247
40
20
0
0
24
48
72
96
120 144 168 192
Weeks
N Engl J Med 2015
General Medical Management
• Prevent fluid retention (dietary
changes, monitoring your weight and
use of diuretics)
• Regular exercise if able (Pulmonary
Rehab)
• Prevent low oxygen levels (oxygen
therapy and/or nocturnal CPAP)
• Use of blood thinners
General Medical Management
• Immunizations (e.g. influenza and
Prevnar/Pneumvax)
• Avoidance of pregnancy
• Communication with your other
medical providers
How Does Your PH
Physician Determine The
Right Treatment For You?
• More options = more decisions
• Treatment decisions are individualized and
based largely on the severity of your PH
• Other considerations:




Patient preferences
Social support
Other medical conditions
Side effects
Determining Risk….
Part Science & Part Art
• Variables in the equation
- How severe are your symptoms?
We(i.e.
useyour
data
from
multiple
sources
to
functional classification)
make
final
judgments…a
key
is
the
- How is the right side of your heart
experience
of the healthcare provider!
performing?
- Are your symptoms worsening quickly?
- Six minute walk distance
- Laboratory blood tests
Courtesy of Dr. Harold I. Palevsky
“Because that’s where the
money is….”
In PAH – the major determinant of
symptom severity, risk of progression &
survival is right ventricular function
(NOT the pulmonary arterial pressures!)
Courtesy of Dr. Harold I. Palevsky
How Do We Know When
To Escalate PAH Therapy?
• Failure to improve with current therapy
• Improved, but not enough (symptoms,
exercise tolerance, quality of life, etc.)
• Improved for a period of time, but now
deteriorating
How Do We Know When
To Escalate PAH Therapy?
• Other mitigating factors?
Diet, abnormal heart rhythm, low blood
count (anemia), blood clot in the lung
(pulmonary embolism), worsening of
other medical conditions
• Go back to the variables in the equation….




Echocardiogram
6 minute walk test
Blood tests
Catheterization




Patient preferences
Social support
Other medical conditions
Side effects
Taking Aim At New
Targets
Treatment Targets
Pulmonary HTN
↑Pulmonary vascular resistance
↑Mean pulmonary artery pressure
Treatment Targets
Vasodilation
↓ Pulmonary artery pressure
↓ Pulmonary vascular resistance
Increased cell proliferaton
Altered cell metabolism
Inflammation
Estrogen
Right Ventricular Adaptation
Drug Repurposing:
“Old” Drugs For New Purposes
Tacrolimus (FK-506)
• Mutations in the BMPR2 gene are the most
common genetic cause of PAH
• Impaired BMPR2 signaling is very common
even in PAH patients who do not have a gene
mutation
• Identified by molecular techniques searching
for drugs that activate BMPR2 signaling
(“drug repurposing”)
JCI 2013 and AJRCCM 2015
Drug Repurposing:
“Old” Drugs For New Purposes
Tacrolimus (FK-506)
• Demonstrated promising effects in PH animal
models
• Phase II study – early clinical trial to determine
safety and efficacy
• Target enrollment = 40 patients
• Stopped early due to slow enrollment at a
single center but a multi-center study is
planned
JCI 2013 and AJRCCM 2015
Drug Repurposing:
“Old” Drugs For New Purposes
Anastrazole (Aromatase inhibitor)
• Used in the treatment of breast cancer
• Prevents conversion of androgens to
estrogens
• Rationale is to reduce estrogen levels that
may contribute to the harmful changes in
the pulmonary arteries associated with PAH
AJRCCM 2016
Drug Repurposing:
“Old” Drugs For New Purposes
Anastrazole (Aromatase inhibitor)
• Pilot randomized, placebo-controlled study
• Primary outcome was change in blood
levels of estradiol as well as effect on the
right ventricle
• 12 PAH patients treated with anastrazole
and 6 treated with placebo
• Duration was 3 months
AJRCCM 2016
Drug Repurposing:
“Old” Drugs For New Purposes
Anastrazole (Aromatase inhibitor)
• Anastrazole reduced blood estrogen levels,
increased 6 MWD and did not change
measures of right heart function by echo
• There were no serious side effects and no
differences in side effects between the two
groups
AJRCCM 2016
Drug Repurposing:
“Old” Drugs For New Purposes
Spironolactone (Aldactone)
• In patients with left heart failure,
spironolactone improves blood vessel
function, inflammation and survival
• Spironolactone treatment is beneficial
in PH animal models
Trials 2013
Drug Repurposing:
“Old” Drugs For New Purposes
Spironolactone (Aldactone)
 Baylor University: Effect of spironolactone on blood
levels of collagen/fibrosis markers as well as safety and
tolerability
 Brigham and Women’s Hospital: Effect of ambrisentan
(Letaris®) + spironolactone on exercise capacity
 NIH Clinical Center: Effect of spironolactone on
exercise capacity, clinical worsening and inflammation
NCT01468571, NCT02253394 and NCT01712620
Drug Repurposing:
“Old” Drugs For New Purposes
Rituximab
• Depletes immune cells that make antibodies
• Phase II study in patients with Scleroderma
associated PAH
• Primary outcome is change in pulmonary
vascular resistance
• A subset of patients will undergo cardiac MRI
to determine effects on the right ventricle
NCT01086540
AJRCCM 2016
New Drugs Targeting
New Pathways
ASK1 Inhibitor (GS-4997; ARROW Trial)
• Suppresses of inflammation and cell
proliferation
• Phase II study assessing change in
pulmonary vascular resistance
• Long-term extension study planned
NCT02234141
AJRCCM 2016
New Drugs Targeting
New Pathways
Bardoxolone Methyl (LARIAT Trial)
• Suppresses inflammation and cell
proliferation
• Phase II, dose finding study assessing
change in 6MWD
• PAH, PH due to interstitial lung disease
and PH due to sarcoidosis
• Long-term extension study planned
NCT02036970
AJRCCM 2016
New Drugs Targeting
New Pathways
Ubenimex (Bestatin™; LIBERTY Study)
• Inhibits the inflammatory mediator LTB4
• Used in Japan to treat patients with
leukemia
• Phase II study assessing change in
pulmonary vascular resistance
• Long term extension study is planned
NCT01086540
AJRCCM 2016
Participating In
Clinical Research
Where We Want To Be
Survival (%)
100
0
Years From Time of Diagnosis
Adapted from Benza RL Chest 2012
What Is A Clinical Trial?
• Research involving human volunteers
with the goal of adding to medical
knowledge
• A clinical research study that follows a
specific protocol
• Two general types of clinical trials:
• Observational study
• Interventional study
Types of Clinical Trials
Observational Study
Interventional Study
• Choose a convenient
study population
• Carefully selected
participants
• Collect data over time
or review data from
prior records
• Participants and the
researchers may be
“blinded”
• Look for patterns or
associations
• Typically includes a
control group to
compare to the
intervention group
• Generate new
hypotheses
What Are The Benefits Of
Participating In A Clinical Trial?
• Generate knowledge that will help us
understand, diagnose and/or treat PH now
or in the future
• Without clinical research we are unable to
improve our understanding of human
disease
• Early access to new tests or treatments
• Frequent contact with health care providers
What Are The Risks Of
Participating In A Clinical Trial?
• Early access to new tests or treatments
• Side effects from medications or adverse effects
from study procedures
• Frequent contact with health care
providers
• Time investment
• The test or treatment may be ineffective
or even harmful
How Do I Learn More
About Current PH Studies?
Ask your PH health care team!
How Do I Learn More
About Current PH Studies?
How Do I Learn More
About Current PH Studies?
Thank You!
Questions?
Jason M. Elinoff, MD
Oksana Shlobin, MD
Stephen C. Mathai, MD, MHS