Download Oral Prostacylins

1
THE GREAT DEBATE
Oral Prostacyclins
Disclosures
• Kelly Chin, MD
• Participant discloses the following financial or non-financial relationships:
• Participated in clinical trials supported by Actelion, Bayer, Gilead, GlaxoSmithKline,
Novartis, United Therapeutics, GeNO and the NIH
• Advisory Boards or consulting: Actelion and Bayer
• Steering committee for GRIPHON
• Participant has indicated the following discussion of unapproved drug or product uses:
• Will discuss medications not yet approved for use
• R. James White, MD, PhD
• Participant discloses the following financial or non-financial relationships:
• United Therapeutics: Investigator, Consultant, Steering Committee (no personal
financial renumeration -- support only to University of Rochester)
• Gilead Sciences: Investigator, Consultant (personal renumeration, no equity)
• Bayer: Consultant (personal renumeration, no equity)
• Participant has indicated the following discussion of unapproved drug or product uses:
• broad use of oral treprostinil for PAH; similar to my use of other drugs for PAH, my use
of oral treprostinil is broader than that indicated on the label
• Melisa Wilson, ARNP, ACNP-BC
• Participant has no financial or non-financial arrangements or affiliations to disclose.
• Participant has indicated no discussion of unapproved drug or product uses.
Disclosures
This continuing education activity is managed and
accredited by Professional Education Services Group in
cooperation with the Pulmonary Hypertension
Association. Neither PESG, nor PHA, nor any accrediting
organization support or endorse any product or service
mentioned in the is activity.
PESG and PHA staff has no financial interest to disclose.
Commercial Support was not received for this activity.
Learning Objectives
• To understand the study results for the oral prostacyclin
registration trials (FREEDOM M, C and C2 and GRIPHON)
including both primary and secondary endpoints.
• To understand the most common oral prostacyclin side
effects and to list options for reducing side effect severity.
• To identify patients who are appropriate (and especially
those not appropriate) to consider using oral treprostinil in
place of parenteral prostacyclin therapy (the Freedom-205
study).
5
Disclaimers
• The views of the expressed in this debate are not those of
PHA or any affiliates of the PHA. They are the views of the
debaters who are experts in the field of PAH.
6
How many patients or research subjects
have you started on oral prostacyclin?
A. 0
B. 1-10
C. 11-20
D. 20-30
E. > 30
7
Is your center currently participating in a
research study utilizing oral prostacyclin?
A. Yes
B. No
What is the max total daily dose of your
current patients on oral treprostinil?
A. I don't have any patients on oral treprostinil
B. 0.025 - 3mg
C. 3.125 - 9mg
D. 9.125 - 15mg
E. 15.125 - 21 mg
F. > 21 mg daily
Jim White, MD
9
Prostacyclin in PAH: a brief history
• 1976 Moncada…Vane: an unstable “PGX” compound could relax vessel
preparations and inhibit platelet aggregation (Nature)
• 1982 Rubin, Groves, Reeves: acute pulmonary vasodilation in 7 severe PPH patients
with 50% reduction in PVR (Circ)
• 1984 Higenbottam: chronic therapy in a “bedbound” woman (Lancet)
• 1995 FDA approval of synthetic prostacyclin for chronic use in the US
• 1996 Barst et al: 12 weeks of randomized, open-label epoprostenol therapy with
robustly improved 6MWT, hemodynamics, quality of life (NEJM)
• 2002 FDA approval of subcutaneous treprostinil
• 2004 FDA approval of intravenous treprostinil and inhaled iloprost
• 2008 FDA approval of thermostable epoprostenol (Veletri)
• 2013 FDA approval of oral treprostinil
• 2015 Likely introduction of oral selexipag
Consistent results: data and experience
Pulmonary Vascular
Resistance
(Woods units)
30
25
20
15
10
5
0
At Baseline
After Adenosine
Challenge
After Epoprostenol
Therapy
McLaughlin VV, et al. N Engl J Med. 1998;338:273-277.
Consistent challenge for our patients
• IV: indwelling catheter care; thrombosis;
catheter infection; sepsis; endocarditis;
• SQ: Moderate-severe site pain at the time of
new infusions sites is pretty much the rule;
anxiety about site dislodgement
• For everyone: sex, showering, sleep, and
swimming will never be the same
C and C2: important mistakes
• Dose matters, and we didn’t get anywhere close:
suggests that this behaves similarly to parenteral
prostacyclins that we already know/love
• BID and TID: might as well be different drugs
– AE tolerance
– Dose titration
• If you only have experience with BID, then
you don’t know TID oral TRE
C: Median Change in 6MWD by Dose
Achieved at Week 16
6MWD Median Change
from Baseline (m)
40.
UT-15C SR
34
30.
20.
18
10.
3.8
0.
N (active)
AE D/C or dose < or = 1 mg
1.25 mg to 3.25 mg
58
Tapson, VF… Galie, N. Chest 142: 1383-1390 (2012)
49
3.5 mg to 16 mg
52
C2: Median Change in 6MWD by Dose
Achieved at Week 16
6MWD Median Change
from Baseline (m)
50
UT-15C SR
44
40
30
20
12
10
0
8
AE D/C or dose < or = 1 mg
N (active)
UT Unpublished Data on File
33
1.25 mg to 3.25 mg
73
3.5 mg to 16 mg
41
BID  TID @ U of R
• Initial conversion instructions were to divide the total daily
BID dose by 3 (a dose reduction for each individual dose)
• Titration continued over 2-6 weeks based on tolerability
• Average time from 2nd PK visit to exit from open label study
was 9 months (range 6 to 12 months)
Regimen
Average Total Daily
Dose (mg)
16
Range
(mg)
4 to 35
TID (PK visit)
19
4 to 43
TID (exit from OL study)
24
3 to 60
BID
Pharmacokinetic Profile
10 mg BID
AUC 32
Cmin .3.5
10 mg TID
AUC 56
Cmin 1.5
55 yo, 130 kg IPAH male
15/16 AE impression of change (much improved)
Pharmacokinetic Parameters
Parameter
BID
TID
Total Daily Dose mg
mean (range)
16
(4-35)
19
(3.75-43)
Cmax ng/mL
mean (SD)
8.6
(4.2)
8.9
(4.2)
AUC h*ng/mL
mean (SD)
47.8
(21.2)
58.0
(29.4)
Pharmacokinetics –
Trough Increases
p = 0.013, paired t
p = 0.013, paired t
• Cmin increased by ~2-fold
with TID dosing
• Peak/trough ratio reduced
by ~ 2-fold with TID
dosing
• AE profile improved in
12/13
Oral Treprostinil:
we are learning how to give our patients a new
choice… and CHOICES are GOOD.
• Freedom EV: a longer trial to determine meaningful doses
(> 12 mg daily) and demonstrate meaningful outcomes
– Reduction in clinical events
– Improvement in exercise tolerance
• Developing better post-trial experience with new drugs
(especially prostacyclins) has always been the rule in PAH
– Site pain with SQ
– High output failure with EPO
Oral Prostanoids as Add-on Therapy in the
Treatment of PAH
Presented by
Kelly Chin, MD
Director, PH Program
UT Southwestern
Oral Prostanoids should NOT routinely be used in
the treatment of PAH
• Evidence for benefit too limited
• Dosing issues are prohibitive
▫ Peak / trough and po admin limit dose
▫ Dose response suggests lower dose ineffective
(hemodynamics and sc tre data)
▫ Peak / trough effects not fully explored – walk data
• Strong evidence iv/ sc and inhaled PGI2 work
▫ Why not just try po?
 Delays may causes clinical worsening and death
 Unless very cautious - will be used in the wrong patients
Prostacyclin – IV / SC
FC: functional class, QOL: quality of life, CW: clinical worsening.  = primary endpoint
Prostacyclin Meds: Half Lives
•
Epo: IV only, 3-5 min
•
Iloprost: 20-30 min; inh vasodil for 1-2 hr
•
Beraprost: 0.5 to 1 hr
•
Treprostinil: 2-4 hrs
•
Selexipag: 8-14 hours
Barst RJ et al. NEJM 1996;334:296
Badesch DB Annals of IM 2000;132:425
Simonneau G. AJRCCM 2002;165:800
McLaughlin VV et al. Circulation. 2002;106:1477-1482.
Sitbon O et al. Upfront triple combination therapy in PAH: a pilot study. Eur Respir J 2014;43:1691
Beraprost: 12 week and 12 month studies
12 Week (ALPHABET) Study
• 6MWD: 24 m, p=0.04
• Cath – no improvement
▫ Beraprost -6% PVR
▫ Placebo +1% PVR
12 Month (Barst) Study; stopped early
• 1: no improvement disease
progression (p=0.25)
• 2: no improvement 6MWD, peak VO2,
QOL, hemodynamics (PVR +1% vs + 2.5%)
Galie et al. Effects of beraprost, an oral prostacyclin analog… JACC 2002;39:1496-1502.
Barst RJ et al. Beraprost Therapy for PAH. JACC 2003; 41: 2119-2125
Beraprost Modified Release: Open
label bid dosing
- BPS-314d / BPS-MR
• Japan (N=46): Rx naive
▫ Cath improved (PVR 12%, p<0.05)
▫ 6MWD improved 33m (p<0.05)
• US and Europe (N=36): ERA / PDE5 OK
▫ Max and fixed dosing groups
▫ Endpoints: walk, FC, cath
Kuneida T. Effects of long-acting beraprost sodium in Japanese patients with
PAH. Int Heart J. 2009;50:513-529
FREEDOM STUDIES: 12 to 16 Week RCT:
FREEDOM M
• PEAK: 6MWD 23 m p<0.05
• TROUGH: 6MWD 13 m p<0.05
• No change: FC, TTCW
FREEDOM C
FREEDOM C (Figure)
• 6MWD 11 m, p=0.07
• No change: FC, TTCW
• DFI improved
Walk Distance
FREEDOM C2
• 6MWD 10 m, p=0.09
• No change: FC, TTCW, QOL, NTBNP
Jing ZC et al. [FREEDOM M]. Circulation 2013;127:624.
Tapson VF et al. [FREEDOM-C]. Chest 2012; 142:1383.
Tapson VF et al. [FREEDOM-C2]. Chest 2013;144:952.
Results
 = primary endpoint
2 = hemodynamic improvement in phase 2 study
Results – Background Rx Trials and po PGI2 Trials
 = primary endpoint
2 = hemodynamic improvement in phase 2 study
Dosing and tolerability
• FREEDOM RCT
▫ M: 3.6  2.2 mg bid
▫ C: 3 mg bid (median)
▫ C2: 3.1  1.9 mg bid
UT Southwestern: Dosing
(7.2 mg/24 hr)
(6 mg / 24 hr)
(6.2 mg / 24 hr)
• FREEDOM Extension
• 12 months: 8.4 mg / 24 hr
• UT Southwestern: 8.6 mg / 24 hr
• Side effects
• Nausea
• Headache
• Diarrhea
White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
Baseline Demographics
Characteristic
Age in Years: mean (range)
Gender: male : female
PAH Etiology: n (%)
Idiopathic/heritable/appetite suppressant/stimulant use
Collagen vascular disease
Other (porto-pulm, HIV)
Congenital systemic-to-pulmonary shunt
Baseline 6MWD (meters): median (range)
Baseline Remodulin Dose (ng/kg/min): median (range)
Remodulin Route of Administration: (SC:IV)
Time on Remodulin (years): median (range)
PAH Background Therapy: n (%)
ERA + PDE-5 I
PDE-5 I only
ERA only
n = 33
50 (18 - 80)
8 : 25
23 (70)
7 (21)
2 (6)
1 (3)
446.5 (279-705)
57 (25 - 111)
28 : 5
3.5 (0.6-9.3)
9 (27)
21 (64)
3 (9)
Oral Tre Dosing
Mean ± SD
Median (range)
Baseline Remodulin Dose
(ng/kg/min)
Total Daily Dose of Oral
Treprostinil (mg) At Transition*
Week 24 Total Daily
Oral Treprostinil Dose (mg)***
TID
(n=23)
63 ± 21
60 (27-111)
34 ± 12
33 (11-60)
40 ± 14
39 (17-82)
Pharmacokinetic Parameters
Median Six Minute Walk Distance
447
• Median change in 6MWD from Baseline to Week 24 was +16.7 meters
463
Hemodynamics and Echocardiography
Mean
Change
from
Baseline
Baseline
Week 24
mean ± SD
(range)
mean ± SD
(range)
PAPm
(mmHg)
38 ± 13
(12 – 69)
40 ± 16
(13 – 73)
+2.2 + 8.6
(-12 –26)
CO†*
(L/min)
5.6 ± 1.5
(3 – 10)
5.3 ± 1.2
(3 - 8)
-0.3 + 1.3
(-3 – 2)
CI†*
(L/min/m2)
3.0 ± 0.5
(2 – 4)
2.8 ± 0.6
(2 – 4)
-0.1 + 0.7
(-1 – 1)
PCWP
(mmHg)
10 ± 2
(5 – 14)
11 ± 4
(4 – 17)
+0.6 ± 4.6
(-8 - 11)
PVR†
(mmHg*min/L)
5.2 ± 2.4
(1 - 9)
5.8 ± 3.5
(1 – 14)
+0.8 + 2.4
(-3 - 8)
RAPm
(mmHg)
6±2
(2 – 8)
6±3
(1 – 12)
+0.5 + 3.7
(-7 – 8)
TAPSE‡
(cm)
2.0 ± 0.4
(1.1 – 3.0)
2.0 ± 0.4
(1.1 – 3.0)
+0.3 + 0.3
(-0.6 – 0.6)
Assessment
N = 30 except where †N = 29 and ‡n=33
Only the Fick method was used for CO and in the CI calculation above for the purposes of this analysis
Late failures were not a surprise…
Transition study: optimal parenteral patients
may succeed with oral
• Careful patient selection: impressive clinical response
to parenteral drug with good hemodynamics and RV
function
• Meticulous followup to guard against late
deterioration
Treprostinil: utility in iv / sc to po transitions
• Declines any dose (2)
• Unable to uptitrate at
>12 mos (6)
• Other (3)
• Start IV Rx (17)
• Death (3)
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
Hemodynamics: UTSW cohort (N=34)
*Follow-up catheterization at 117 months of therapy
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
Transition to IV
therapy: N=13
Dosing and tolerability
• FREEDOM RCT
▫ M: 3.6  2.2 mg bid
▫ C: 3 mg bid (median)
▫ C2: 3.1  1.9 mg bid
UT Southwestern: Dosing
(7.2 mg/24 hr)
(6 mg / 24 hr)
(6.2 mg / 24 hr)
• FREEDOM Extension
• 12 months: 8.4 mg / 24 hr
• UT Southwestern: 8.6 mg / 24 hr
• Side effects
• Nausea
• Headache
• Diarrhea
White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
Typical dosing: intravenous prostacyclins vs po tre
• PK Study
▫ 12 mg / 24 hr  20 ng/kg/min iv
UTSW Dosing: Rationale
• Clinical experience
• SC treprostinil mortality data:
▫ 10 ng/kg/min increase in dose
▫ Dose >40 ng/kg/min
• Other centers (survey, below)
White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481
Oudiz RJ. Dosing considerations… Am Heart J 2009;157:625-35
Benza RL et al. Prognostic factors associated with increased survival…sc treprostinil. J Heart Lung Transplant. 2011;30:982.
Jim White, MD
45
Treprostinil: Add on therapy
• Declines any dose (2)
• Unable to uptitrate at
>12 mos (6)
• Other (3)
• Start IV Rx (17)
• Death (3)
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
Hemodynamics: UTSW cohort (N=34)
*Follow-up catheterization at 117 months of therapy
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224.
UTSW Cohort: Walk and Hemodynamics
Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, epub ahead of print. Avail at http://www.jstor.org/stable/10.1086/682224.
Oral Therapy: Change in PVR vs. Dose
Oral Treprostinil – tid dosing option
In God We Trust, All
Others Bring Data
- W. Edwards Deming
Jones A et al. Pharmacokinetics of 3 times a day dosing… J Cardiovasc Pharmacol. 2014;63:227-232.
Conclusions
• Oral treprostinil, the only currently approved oral prostacyclin, should
not be utilized as add-on therapy in PAH patients who are
▫ Responding adequately to therapy
▫ Not responding adequately to therapy
▫ Currently doing well on iv/sc therapy
• IV/SC and inhaled therapy remain better proven therapies
• Increased dosing frequency is an interesting idea
▫ Further study is needed
53
CASE STUDY
History
• 50-year-old female admitted with complaints of chest pain
and shortness of breath. She states for the last 3 months,
has been having progressively worsening shortness of
breath, chest heaviness off and on with and without activity,
and overall joint pain. Has no swelling in the ankles,
orthopnea. No palpitations, syncope or near syncope
Past Medical History
• SLE follows with rheumatology
• No history of MI or CAD.
• stress test in 2009, negative for ischemia
• echo in 2009 which showed EF 60%, no pulmonary hypertension.
• Childhood asthma
• Scleroderma
ER admission
•
•
•
•
On arrival to the emergency room, her BNP was found to
be 800.
D-dimer was elevated 2.21
CTA chest showed the following:
• No evidence of pulmonary embolism
• Cardiomegaly with congestive heart failure signs
• Prominent pulmonary arteries
• Probable pulmonary artery hypertension. She was
admitted for evaluation.
She was given 1 dose of IV Lasix
Pertinent History
• PAST SURGICAL HISTORY: C-section x 2
• ALLERGIES: NONE
• SOCIAL HISTORY: The patient denies any tobacco or
alcohol use. No caffeine use, is a homemaker, is divorced.
• HOME MEDICATIONS: Gabapentin 100 mg TID
Echo Conclusion
1. Dilated right ventricle, which appears thickened, also somewhat
hypokinetic with evidence of paroxysmal motion of the interventricular
septum secondary to pressure overload, associated with a dilated
right atrium and severe pulmonary hypertension with pulmonary
artery systolic pressure estimated at 97 mmHg.
2. Normal left ventricular cavity size, thickness and contractility with
an ejection fraction in the 60% range.
3. Normal valvular structures.
4. No obvious masses, thrombus, vegetations or pericardial effusion.
5. Trace mitral insufficiency, mild to severe tricuspid insufficiency.
6. Trace small pericardial effusion.
7. Grade 1 diastolic impairment.
The Plan
• Treated with Diuretics and Steroids with some
improvement in symptoms.
• Transferred to the PH center for further evaluation.
The real story
• She presented with progressive dyspnea and near syncopal
symptoms. She has a diagnosis of SLE and Scleroderma made
about 5 years ago. That time she had DOE which was moderate.
She has had slowly progressive dyspnea and exercise
intolerance until the last 3 months, when she became unable to
walk up a flight of stairs without having to stop 3 times. Prior to
that time she was able to climb a flight of stairs without stopping,
but had to stop and rest at the top. She also had dizziness and
near syncopal episodes when bending over. She has lost 3 jobs
because of her limitations, and has not been able to follow up
regularly with any physicians because of loss of her insurance.
She recently established with a free clinic and is able to see a
Rheumatologist there.
Physical Exam Findings
General Appearance:
Awake; alert and oriented X 3; no acute distress.
Neck:
supple; no JVD; no carotid bruit; JVP normal.
Cardiovascular:
Regular rate and rhythm, pulses normal; no rubs 1/6 HSM; normal PMI, no RV heave.
Pulmonary:
Decreased BS bases, good air movement, no wheezes, no rales, no rhonchi.
Extremities:
No edema, cyanosis, clubbing; pedal pulses and DP intact.
Neurological:
alert, no motor deficits and memory normal.
Cath Data
Clinical Testing Condition Baseline 1
50 mcg/kg/min
100 mcg/kg/min 150 mcg/kg/min
SBP mmHg
DBP mmHg
MAP mmHg
Pulse
134
93
103
73
165
87
113
88
156
78
102
103
157
70
96
103
FA O2 Sat
PA O2 Sat
96
75
97
74
97
78
97
83
RA mean mmHg
PCWP mean mmHg
2
3
7
7
6
3
7
2
PAS mmHg
PAD mmHg
PAM mmHg
93
32
55
96
33
56
101
34
60
106
35
62
CO (Fick) l/min
CI (Fick) l/min/m2
3.58
2.1
3.34
2
4.06
2.4
5.74
3.4
PVR (dynes)
SVR (dynes)
1162
2257
1174
2539
1123
1892
836
1240
WHATCHAWANNA DO?
Which of the current therapies available today
would you select for this patient?
A.
B.
C.
D.
Hi ho! Hi ho! IV is the way to go.
Down with Hickmans, I love subQ.
Orentiram would be divine but not with wine.
A little bit of this a little of that. I am a oral combination
brat.
E. It is the i.n.h.a.l.e. Inhaled the drug is the one for me.
Social Situation
• Patient has 2 daughters
• One teenager
• One in early 20’s – has her own apartment
• Patient had mental status changes
• Work up negative for any acute process
• Psych evaluation- suspect Bipolar disorder, but family says this behavior
is new.
• Possible related to medications
• Patient now states she no longer wishes to be on parenteral therapy
• What prostacyclin would you now choose for the patient
and why?
66
QUESTIONS & ANSWERS
Thank you
67
Winner of the debate
A. Kelly Chin, MD
B. Jim White, MD
C. It is a tie!
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