Download Epidemiology, Pathophysiology, and Diagnosis of Pulmonary

Updates in PAH and what's on
the Horizon
Abubakr A Bajwa. MD, FCCP
Associate Professor of Medicine
Associate Chair of Operation, Department of Medicine
Division Chief, Pulmonary, Critical Care and Sleep Medicine
Medical Director Respiratory Therapy
Director Pulmonary Hypertension and Interstitial Lung Disease Clinic
University of Florida College of Medicine/Jacksonville
Mark Rumbak .MD
Professor of Medicine, Pulmonary and Critical Care Medicine
Division Director, Pulmonary, Critical Care and Sleep Medicine
Director, Bronchoscopy and Interventional Pulmonology
Section Chief, Tampa General Hospital
Disclosure
Consultant: United Therapeutics
Grants: UT, James and Esther King
Biomedical Foundation, UF
Research: UT, Gilead, Actelion, Bayer, AZ,
GSK, Intermune, BI
2
Objectives
 Learn about how your physician determines the right




treatment for you
Learn about the goals of your PAH treatment
Learn about new treatment targets being studied in
patients with PAH
Gain knowledge on the advances of clinical trials in PAH
Understand the benefits and risks of participating in
clinical trials
3
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
4
Where We Are
Survival (%)
100
0
Years From Time of Diagnosis
Adapted from Benza RL Chest 2012
5
Normal Pulmonary artery
6
PAH
7
PAH: Therapeutic Targets
8
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
9
Endothelin Pathway
1. Bosentan (Tracleer®)
2. Ambrisentan (Letaris®)
3. Macitentan (Opsimut®)
Endothelial
cell
Endothelin
production
Endothelin
receptor A
Endothelin
receptor B
Endothelin receptor
antagonists (ERAs)
Smooth
muscle cell
10
Adapted from Humbert et al. NEJM 2004
Nitric Oxide (NO) Pathway
1. Sildenafil (Revatio®)
2. Tadalafil (Adcirca®)
3. Riociguat (Adempas®)
Endothelial
cell
NO
production
NO
Guanylate
cyclase
NO
cGMP
Smooth
muscle cell
Vasodilation
11
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®)
Endothelial
cell
PGI2
production
Prostacyclin
Prostacyclin
receptor receptor
agonists
Smooth
muscle cell
Prostacyclin
derivatives
Vasodilation
12
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
13
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
14
AMBITION: Initial Combination Therapy With
Ambrisentan-Tadalafil Compared With Monotherapy
Primary Endpoint: Time to First Clinical Failure Event
Primary Analysis Set
100
1 year 88.9%
2 year 79.7%
Event-Free (%)
75
3 year 67.6%
1 year 75.5%
50
2 year 63.2%
3 year 56.1%
25
HR: 0.502
95% CI: 0.348-0.724
P=0.0002
Combination therapy
Pooled monotherapy
0
0
24
48
72
96
120
144
168
192
Time (weeks)
Number at Risk:
Combination
253
229
186
145
106
71
36
4
Pooled monotherapy
247
209
155
108
77
49
25
5
Galie N, et al. N Engl J Med. 2015;373:834-844
15
GRIPHON: Selexipag for PAH
Primary Endpoint: Time to First Event
Patients without an event (KM)%
100
80
60
Selexipag
40
Placebo
20
Selexipag vs placebo: Risk reduction 40%
HR = 0.60; 99% CI, 0.46-0.78; P<0.0001
0
0
6
12
Selexipag
24
30
36
149
171
88
101
28
40
Months
No. at Risk:
Placebo
18
582
574
433
455
Sitbon O, et al. N Engl J Med. 2015:373:2522-2533.
347
361
220
246
16
SERAPHIN: Effect of Macitentan 10 mg on
All-Cause Hospitalization
100%
80%
60%
46.8%
41.6%*
40%
37.2% †
20%
0%
Placebo (n=249)
Macitentan 3 mg (n=250)
Macitentan 10 mg (n=242)
*Risk of all-cause hospitalization reduced by 18.9% compared with placebo. HR: 0.811 (95% CI: 0.623 to 1.057);
P=0.1208.
† Risk of all-cause hospitalization reduced by 32.3% compared with placebo. HR: 0.677 (95% CI: 0.514 to 0.891);
P=0.0005.
Channick RN, et al. JACC Heart Fail. 2015;3:1-8.
17
COMPERA Registry: Anticoagulation Effect on
Survival in IPAH and APAH
IPAH Survival
APAH Survival
100%
100%
P=0.017
P=0.28
80%
Survival of Patients
Survival of Patients
80%
60%
40%
20%
No anticoagulation
Anticoagulation
0%
0
1
2
3
Disease Duration Since IPAH Diagnosis (years)
N=168 patients with newly diagnosed IPAH receiving
anticoagulation versus matched pairs never receiving
anticoagulation.
Olsson KM, et al. Circulation. 2014;129:57-65.
60%
40%
20%
No anticoagulation
Anticoagulation
0%
0
1
2
3
Disease Duration Since APAH Diagnosis (years)
N=210 patients with APAH receiving anticoagulation and
N=273 patients without anticoagulation.
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REVEAL: Use of Warfarin in IPAH
Survival Through 36
Months
100
P=0.17
81.1 ± 3.6%
Survival (%)
90
80
70
77.2 ± 3.7%
Started warfarin on study (n=144)
Never on warfarin (n=144)
60
Hazard
Ratio
95% Confidence
Interval
P value
Unadjusted
1.42
0.86, 2.32
0.17
REVEAL risk score adjusted
1.37
0.84, 2.25
0.21
50
40
0
0
6
12
18
24
30
36
Time From Warfarin Start/Match (months)
No. at risk
Warfarin
Never warfarin
144
144
124
135
119
110
108
110
93
95
83
81
77
67
N=144 patients with IPAH who initiated warfarin while enrolled in REVEAL, compared with
144 matched patients never receiving warfarin.
Preston I, et al. Circulation, 2015;132:2403-2411.
19
REVEAL: Survival by 1-year Change in 6MWD
100%
95%
90%
85%
80%
75%
70%
65%
60%
55%
50%
Newly Diagnosed Patients
Patients with change in 6MWD
within 10 percentage points
-45 -35 -25 -15 -5
5 15 25
Percent Change in 6MWD
35
45
One-year Survival
One-year Survival
All Patients
100%
95%
90%
85%
80%
75%
70%
65%
60%
55%
50%
Patients with change in 6MWD
within 10 percentage points
-45 -35 -25 -15 -5
5 15 25
Percent Change in 6MWD
35
45
N=1,798 patients enrolled in REVEAL registry with baseline and 1-year follow-up 6MWD.
Farber HW, et al. J Heart Lung Transplant. 2015;34:362-368.
20
Figure 1. Implantation location of the drug delivery system.
Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular
Delivery System : Results of the DelIVery for PAH Trial
Robert C. Bourge, Aaron B. Waxman, Mardi Gomberg-Maitland, Shelley M. Shapiro, James H. Tarver III, Dianne L. Zwicke,
Jeremy P. Feldman, Murali M. Chakinala, Robert P. Frantz, Fernando Torres, Jeffrey Cerkvenik, Marty Morris, Melissa Thalin,
Leigh Peterson, Lewis J. Rubin
Chest, Volume 150, Issue 1, 2016, 27–34
http://dx.doi.org/10.1016/j.chest.2015.11.005
21
PAH Therapy: Experimental Therapy
Drug Repurposing:
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
23
Drug Repurposing:
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
24
Drug Repurposing:
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
25
Drug Repurposing:
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
26
Drug Repurposing:
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
27
Drug Repurposing:
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
28
Drug Repurposing:
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
29
Drug Repurposing:
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
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AJRCCM 2016
LARIAT: Bardoxolone Methyl for PAH
Study Design
Abstract
Bardoxolone methyl
• Nrf2 activator and NF-κB suppressor, targets dysfunctional
inflammatory, metabolic, and bioenergetic pathways
• US-only Phase II double-blind, randomized, placebo-controlled trial
• WHO Group I patients required to be on 1-2 background PAH-specific
therapies
• Part 1: Dose-ranging (2.5, 5, 10, 20 mg – n=8 per dose group)
once daily
• Part 2: Open-label extension
Primary Study Endpoints
• Change in 6MWD from baseline through 16 weeks
• Safety and tolerability
• Determine the dose range for further clinical trials
Oudiz R, et al. Chest. 2015;148(4_MeetingAbstracts):639A.
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Abstract
LARIAT: Bardoxolone Methyl in PAH
Primary Endpoint Mean Change in 6MWD
Primary Study Endpoint
25
21.4 †
21.6 *
Change in 6MWD, m
20
15
10
5
0.2
0
Absolute Change 6MWD
Placebo-corrected treatment effect
Placebo
Phase 2, placebo-controlled dose-ranging study. Combined efficacy analysis. No dose response noted.
*P<0.001. †P=0.037
Oudiz R, et al. Chest. 2015;148(4_MeetingAbstracts):639A.
32
Group 4 PH: Balloon Percutaneous Angioplasty
(BPA) in CTEPH
• Organized thrombi is forced on one side of the vessel enlarging the lumen
• BPA causes local dissection of the media with thinning (arrowheads) of the
vascular wall leading to the expansion of the luminal diameter over time
• Experience using this technique is largely confined to Japan
• Experts suggest that this technique may be appropriate for patients with
residual PH following PEA
• Risk of dissection if PEA follows BPA
Kitani, et al. Circ Cardiovasc Interv. 2014;7:857-859.
33
Abstract
Efficacy of Balloon Pulmonary Angioplasty in Patients
with Inoperable CTEPH
CI
25
Before
PVR
After
6
7.0
3.7
0
Before
After
BNP (pg/ml)
PVR (WU)
8
2
2.7
2.4
350
300
250
200
150
100
50
0
90
80
70
88
92
Before
After
60
BNP
P<0.01
P<0.01
100
Before
10
4
3.5
3
2.5
2
1.5
1
0.5
0
SaO2 (mmHg)
38
CI (l/min/m2)
mPAP (mmHg)
60
50
40
30
20
10
0
SaO2
P<0.01
P<0.01
After
6MWD
P<0.01
6MWD (m)
mPAP
156
41
Before
After
700
600
500
400
300
200
100
0
P<0.01
488
383
Before
After
N=72 inoperable CTEPH patients undergoing BPA.
Mean follow-up period = 21 months.
Aoiki T, et al. American Thoracic Society. San Francisco CA. May 13-18, 2016. A1229.
34
Types of Clinical Trials
Observational Study
• Choose a convenient
study population
• Collect data over time
or review data from
prior records
• Look for patterns or
associations
• Generate new
hypotheses
Interventional Study
• Carefully selected
participants
• Participants and the
researchers may be
“blinded”
• Typically includes a
control group to
compare to the
intervention group
35
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
36
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
37
How Do I Learn More About Current PH
Studies?
Ask your PH health care team!
38
https://clinicaltrials.gov/ or ask your PH specialist!
39
https://clinicaltrials.gov/ or ask your PH specialist!
40
Questions??
Abubakr Bajwa, MD
Mark Rumbak, MD
41