Download Selexipag for the treatment of pulmonary arterial hypertension

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CLINICAL REVIEW
SELEXIPAG
Selexipag for the treatment of pulmonary arterial
hypertension
Zachary R. Noel, Pharm.D., BCPS,
Department of Pharmacy Practice and
Science, University of Maryland School of
Pharmacy, Baltimore, MD.
Kazuhiko Kido, Pharm.D., M.S.,
Department of Pharmacy Practice, South
Dakota State University, Sioux Falls, SD,
and Department of Pharmacy, Avera
McKennan Hospital, Sioux Falls, SD.
Tracy E. Macaulay, Pharm.D.,
AACC, BCPS-AQ Cardiology,
Department of Pharmacy Practice
and Science, University of Kentucky
College of Pharmacy, Lexington, KY, and
UKHealthCare Jack and Linda Gill Heart
Institute, Lexington, KY.
Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety
and tolerability, dosing and administration, and place in therapy of selexipag, an orally administered selective prostacyclin receptor agonist for the
treatment of pulmonary arterial hypertension (PAH), are reviewed.
Summary. The first-in-class oral prostacyclin IP receptor agonist selexipag (Uptravi, Actelion Pharmaceuticals) was approved by the Food and
Drug Administration in December 2015. Selexipag is rapidly hydrolyzed
to a long-acting metabolite that binds with high selectivity to IP receptors, resulting in vasodilation, inhibition of platelet aggregation, and antiinflammatory effects. Results of a long-term, placebo-controlled, clinical outcomes–driven trial showed that selexipag significantly reduced the
occurrence of the composite primary outcome (all-cause mortality and
development of PAH-related complications). Selexipag is indicated for use
in patients with World Health Organization functional class (FC) II or III
disease. The recommended initial selexipag dosage is 200 mg twice daily.
Like prostanoid analogs, selexipag has a dose-dependent adverse-effect
profile that includes nausea, vomiting, diarrhea, headache, and musculoskeletal pain. Although selexipag offers distinct pharmacologic advantages over other agents for the treatment of PAH, important issues of cost
and access must be considered.
Conclusion. Selexipag is an oral prostacyclin IP receptor agonist approved for use as monotherapy or in combination with other therapies to
slow PAH progression and reduce the risk of hospitalization in patients
with FC II or III symptoms. Its stability and relatively long half-life offer
conveniences over conventional prostanoid therapies.
Keywords: ACT-293987, MRE-269, prostacyclin, prostaglandin I2, pulmonary arterial hypertension, selexipag
Am J Health-Syst Pharm. 2017; 74:e360-6
P
Address correspondence to Dr. Noel
([email protected]).
This article will appear in the August 1,
2017, issue of AJHP.
Copyright © 2017, American Society of
Health-System Pharmacists, Inc. All rights
reserved. 1079-2082/17/0000-e360.
DOI 10.2146/ajhp160798
e360 ulmonary arterial hypertension
(PAH) is a rare disease characterized by increases in pulmonary
vascular resistance. PAH most commonly refers to elevated pulmonary
pressures secondary to precapillary
causes and not attributable to chronic
lung, heart, or thromboembolic disease.1-3 In the 5-group pulmonary hypertension classification system of the
World Health Organization (WHO),
group 1 comprises PAH of various etiologies, which include heritable conditions (e.g., mutation of BMPR2, the
gene coding for bone morphogenetic
AM J HEALTH-SYST PHARM | VOLUME 74 | 2017
protein receptor type 2), exposure to
toxins or drugs (e.g., stimulants such
as fenfluramine), connective tissue
disorders, human immunodeficiency
virus infection, and congenital heart
disease.4 The incidence of PAH is approximately 2.4 cases per million annually, and the disease is 2–4 times
more common in women than in
men.1,2 Morbidity from PAH stems
from elevated right heart pressures
that, ultimately, lead to right-sided
heart failure, a need for lung transplantation, and death. Patients with
PAH are categorized into 4 WHO func-
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CLINICAL REVIEW
SELEXIPAG
tional class (FCs) according to the
frequency and severity of symptoms,
with WHO FC IV disease being the
most severe (Table 1).5 Annual mortality in patients with PAH overall is 15%,
and 3-year mortality ranges from 35%
to 77%, depending on the underlying
cause, the treatments pursued (i.e.,
lung transplantation), and FC status.2
There is no cure for PAH, and available
therapies only slow disease progression or provide symptomatic relief.
In PAH, levels of prostacyclin
(also referred to as prostaglandin I2,
or PGI2) and nitric oxide, both potent
vasodilators and inhibitors of platelet aggregation, are decreased, while
the level of thromboxane A2, a potent vasoconstrictor and promotor of
platelet aggregation, is increased.3 In
addition, endothelin-1 activity is increased, enhancing vasoconstriction
and smooth muscle cell proliferation
within the pulmonary arteries. Current Food and Drug Administration
(FDA)–approved therapies for PAH
include endothelin receptor antagonists (ERAs), phosphodiesterase type
5 (PDE5) inhibitors, a soluble guanylate cyclase stimulator, prostacyclin analogs, and the most recently
approved therapy, an agonist of the
prostacyclin IP receptor (1 of 9 types
of prostanoid receptor).5,6 IP receptor agonists are designed to modulate
pulmonary vasoconstriction, platelet
aggregation, and smooth muscle cell
proliferation that result from alterations in the balance of endothelin,
nitric oxide, and prostacyclin.3 The
choice of therapy is based on a variety
of patient-specific factors and largely
guided by the WHO FC.5-7 In addition
to the aforementioned medications,
supportive treatments include diuretics for symptomatic relief and anticoagulation for prevention of thromboembolic events.
Although patients often require
combinations of therapies, targeting prostacyclin has been consistently proven to be an effective strategy for reducing morbidity in PAH.5,6
Epoprostenol is the synthetic form
of prostacyclin, and other analogs,
KEY POINTS
• Selexipag is the only Food and
Drug Administration–approved
oral prostacyclin IP receptor
agonist for the treatment of
pulmonary arterial hypertension (PAH).
• Selexipag reduces the risks
of hospitalization and disease
progression in patients with
PAH and World Health Organization functional class II or III
symptoms, as compared with
patients not receiving selexipag, but has not been shown
to reduce mortality.
• Selexipag has predictable,
dose-dependent adverse effects consistent with those of
other prostanoid therapies, including musculoskeletal pain,
flushing, nausea, vomiting,
and headache.
on the pharmacology, pharmacokinetics and pharmacodynamics, dosage and administration, and clinical
efficacy and safety of selexipag; cost
considerations and place in therapy
are also discussed.
Pharmacology
Selexipag (formerly known as NS304) is an orally administered prodrug that is rapidly hydrolyzed to a
long-acting metabolite that is a highly
selective prostacyclin IP receptor
agonist. The prostacyclin IP receptor
is coupled to a Gs protein and, when
activated by a prostacyclin modulator
such as selexipag, causes stimulation
of adenylate cyclase and an increase
in cytosolic calcium concentrations.10
Ultimately, activity on this receptor
results in vasodilation, an antiproliferation effect on pulmonary artery
smooth muscle cells, inhibition of
platelet aggregation, and antiinflammatory effects.11
Pharmacokinetics and
pharmacodynamics
such as treprostinil and iloprost, are
also available. However, these agents
have significant drawbacks due to
their pharmacologic instability and
short biological half-life, which create
challenges with drug administration,
including a need for continuous infusion or administration as often as 9
times per day in some instances.8 Limitations of available drug entities have
led to the ongoing development of
pharmaceuticals targeting prostacyclin and the prostacyclin IP receptor.
In late 2015, selexipag (Uptiva,
Actelion Pharmaceuticals, South San
Francisco, CA) was approved by FDA
and granted the orphan drug designation as the first-in-class oral selective prostacyclin IP receptor agonist.9
Selexipag is approved for treatment of
PAH to delay disease progression and
reduce the risk of hospitalization and
offers therapeutic conveniences over
the aforementioned prostacyclintargeted therapies. This article focuses
Following oral administration,
selexipag is rapidly hydrolyzed to the
primary active metabolite ACT-333679
(formerly known as MRE-269). The affinity of ACT-333679 for the prostacyclin IP receptor is 10-fold higher than
that of selexipag and more than 130
times more specific for the IP receptor
than for other prostaglandin receptor subtypes.10,12,13 In addition to being more potent than selexipag, ACT333679 produces overall exposure, as
measured by the area under the concentration–time curve (AUC), 3 times
higher than selexipag exposure.14,15
The mean half-lives of selexipag and
ACT-333679 are 0.7–2.3 and 9.4–14.2
hours, respectively. When taken on an
empty stomach, the maximum concentration (Cmax) of ACT-333679 occurs
at approximately 4 hours. With administration with food, the Cmax is reduced
and the time to Cmax is delayed considerably, with overall ACT-333679 exposure modestly reduced (by 25%).10,12,16
After selexipag metabolism, elimination is predominately through the
AM J HEALTH-SYST PHARM | VOLUME 74 | 2017 e361
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CLINICAL REVIEW
feces, with negligible excretion in the
urine.16 Selexipag and ACT-333679 are
greater than 99% protein bound and
are extensively metabolized by the
liver. Both selexipag and ACT-333679
undergo metabolism by cytochrome
P-450 (CYP) isozymes 3A4 and 2C8
and are substrates for organic anion
transporting polypeptide (OATP) 1B1
and OATP1B3. Selexipag is also a substrate for P-glycoprotein (P-gp).9
A pharmacokinetic study involving 20 healthy men taking selexipag concomitantly with lopinavir–
ritonavir, an inhibitor of CYP3A4, P-gp,
OATP1B1, and OATP1B3, resulted in a
more than 2-fold increase in the AUC
of selexipag but only an 8% increase in
the ACT-333679 AUC.15 These changes
in ACT-333679 pharmacokinetic values were not considered to be clinically relevant,15 and selexipag dose
adjustment is not required with concomitant use of lopinavir–ritonavir.9
Another pharmacokinetic study, involving 19 healthy men and designed
to measure the effects of selexipag
administration on warfarin pharmacodynamics, was recently conducted.17
After multiple oral doses of selexipag
400 mg, a single dose of warfarin 20 mg
was administered. Concentrations of
selexipag and ACT-333679 were unaffected by concurrent warfarin administration. Likewise, relative to values observed with placebo use, International
Normalized Ratio values and R- and
S-warfarin concentrations were unaffected by selexipag administration.
In a prospective Phase I study,
selexipag and ACT-333679 concentrations were assessed in 18 individuals
with varying degrees of hepatic impairment.18 Selexipag concentrations
increased 2.1- and 4.5-fold in individuals with Child–Pugh class A and
class B liver impairment, respectively.
In addition, ACT-333679 concentrations increased 1.2-, 2.2-, and 2.9-fold
in those with classes A, B, and C liver
impairment, respectively. A second
Phase I trial enrolled patients with
an estimated glomerular filtration
rate (eGFR) of 15–30 mL/min per 1.73
m2 of body surface area and a con-
e362 SELEXIPAG
Table 1. World Health Organization Functional Class Descriptions for
PAH5,a
Class
Description
I
Patients with PAH but without resulting limitation of physical activity.
Ordinary physical activity does not cause undue dyspnea or fatigue,
chest pain, or near syncope.
II
Patients with PAH resulting in slight limitation of physical activity. They
are comfortable at rest. Ordinary physical activity causes undue
dyspnea or fatigue, chest pain, or near syncope.
III
Patients with PAH resulting in marked limitation of physical activity.
They are comfortable at rest. Less than ordinary activity causes
undue dyspnea or fatigue, chest pain, or near syncope.
IV
Patients with PAH with inability to carry out any physical activity
without symptoms. These patients manifest signs of right-sided
heart failure. Dyspnea and/or fatigue may even be present at rest.
Discomfort is increased by any physical activity.
PAH = pulmonary arterial hypertension.
a
trol group of individuals with normal
eGFR values (>90 mL/min/1.73 m2).18
Mean selexipag and ACT-333679 AUC
values were increased 1.7- and 1.6fold, respectively, in patients with
renal impairment relative to AUC
values in subjects with normal renal
function.
Dosage and administration
As with other prostanoid therapies,
the target dose of selexipag is the highest dose tolerated before dose-limiting
adverse effects such as headache, jaw
pain, flushing, and nausea.9 The starting dose of selexipag is 200 mg, to be administered orally twice daily. As soon
as 1 week after initiation of selexipag
therapy, the twice-daily dose may be
adjusted in increments of 200 mg to a
maximum of 1,600 mg or until unmanageable or intolerable adverse effects
occur. If the threshold for intolerable
adverse effects is breached, the twicedaily dose is reduced by 200 mg, and
this is considered the maximum tolerated dose. To help with dosage adjustment, selexipag tablets are available in
200-mg increments of strength ranging
from 200 to 1,600 mg. In clinical trials,
the median twice-daily dose tolerated was 800–1,000 mg.19,20 In the event
doses are missed for 3 days or more,
it is recommended that treatment be
resumed at a nonspecified lower dose,
AM J HEALTH-SYST PHARM | VOLUME 74 | 2017
with subsequent adjustment to the
maximum tolerated dose.9
Formal recommendations on se­
lex­ipag dosing in the context of renal
or hepatic impairment are lacking.
Based on the aforementioned pharmacokinetic studies, no adjustment
is necessary for patients with mild hepatic impairment (Child–Pugh class
A) or mild-to-moderate renal impairment.18 By contrast, the initial dosing
for patients with moderate hepatic
impairment (Child–Pugh class B)
should be decreased to 200 mg daily
and adjusted in weekly increments of
200 mg once daily.9 Selexipag use in
patients with severe hepatic impairment or severe renal impairment (an
eGFR of <15 mL/min/1.73 m2) has not
been studied adequately, and current
recommendations are to avoid use of
selexipag in these patients.9
Clinical efficacy
Selexipag has been studied in 2
randomized, multinational, doubleblind, placebo-controlled trials.19,20
In both trials the use of selexipag was
evaluated in patients with symptomatic PAH, including PAH due to idiopathic or hereditary causes, connective tissue disease, congenital heart
disease, or drug or toxin exposure. In
addition to patients who were receiving no background therapy for PAH,
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SELEXIPAG
the trials included patients receiving
an ERA or a PDE5 inhibitor (or both)
provided that they had been taking a
stable dose of these medications for
at least 12 weeks. Patients receiving
prostacyclin analogs were excluded;
thus, FC IV patients were largely unrepresented. One of the 2 trials evaluated the effects of selexipag on pulmonary hemodynamics in 43 patients
randomly assigned in a 3:1 fashion to
treatment with selexipag or placebo
use, with the selexipag dosage adjusted to a maximum of 800 mg twice
daily or until intolerable adverse effects were experienced.19 Mean ± S.D.
pulmonary vascular resistance (PVR)
values at baseline were 948.6 ± 428.0
and 867.2 ± 379.38 dyn · s · cm–5 in the
selexipag (n = 32) and placebo (n = 10)
groups, respectively. At 17 weeks, the
mean ± S.D. change from baseline in
PVR was –129.8 ± 309.7 dyn · s · cm–5 in
patients treated with selexipag versus
223.6 ± 355.4 dyn · s · cm–5 in placebo
users (p = 0.0022). The mean ± S.D.
cardiac index values at baseline were
2.5 ± 0.5 and 2.4 ± 0.6 L/min/m2 in
the selexipag and placebo groups,
respectively. The treatment effect of
selexipag resulted in an increase in
the mean cardiac index value of 0.5
L/min/m2 (95% confidence interval
[CI], 0.13–0.83 L/min/m2; p = 0.01).
Baseline mean ± S.D. values for mean
pulmonary arterial pressure (mPAP)
were 54.5 ± 15.3 and 54.6 ± 13.8 mm
Hg in the selexipag and placebo
groups, respectively. After 17 weeks,
the mean ± S.D. change from baseline in mPAP was –1.7 ± 11.0 mm Hg
in patients treated with selexipag versus 5.7 ± 13.3 mm Hg in the placebo
group (treatment effect, –7.4 mm Hg
[95% CI, –15.9 to 1.1 mm Hg]; p = 0.1).
The mean ± S.D. changes from baseline in 6-minute walk distance were
24.7 m (95% CI, –1.6 to 50.9 m) in the
selexipag group and 0.4 m (95% CI,
–19.7 to 20.5 m) in the placebo group
(treatment effect, 24.2 m; 95% CI,
–23.7 to 72.2 m). Adverse effects were
reported in almost all patients in both
the treatment and placebo groups.
The most common adverse effects
that emerged as a result of treatment
with selexipag were headache (67%),
jaw pain (36%), pain in an extremity
(30%), nausea (27%), and nasopharyngitis (24%). Although the study was
limited by a small sample size, the
positive hemodynamic effects observed supported further investigation of selexipag in the then-ongoing
Phase III Prostacyclin (PGI2) Receptor
Agonist in Pulmonary Arterial Hypertension (GRIPHON) study.20
The now-completed GRIPHON
study is considered the landmark
trial of selexipag use in PAH. Enrollment in this event-driven trial began
in 2009 and was completed in 2014.
A total of 1,156 patients were randomly assigned in a 1:1 fashion to either selexipag or placebo use; about
80% of all study participants (n = 920)
were receiving standard therapies for
PAH at baseline, with most continuing
those therapies during the study. PAH
among study enrollees was predominately idiopathic (56% of patients
overall) or associated with connective
tissue disease (29% of patients). The
primary outcome was a composite of
all-cause mortality and development
of a complication due to PAH (defined
as disease progression or worsening
of PAH resulting in initiation of parenteral prostanoid therapy or oxygen
supplementation, hospitalization for
worsening PAH, or a need for lung
transplantation or balloon atrial septostomy). Disease progression was
defined as a decrease in 6-minute
walk distance of at least 15% in combination with worsening in functional
class or (in FC III or IV patients only)
a need for additional therapy. Baseline
characteristics were similar between
the study groups. Overall (both groups
combined), approximately 45% and
52% of patients were classified as FC
II and FC III, respectively; 20% were
receiving no background treatment
for PAH, 32% were on PDE5 inhibitor
monotherapy, 14% were on endothelin receptor antagonist monotherapy,
and 32% were receiving both forms
of therapy. A total of 397 patients, 155
(27.0%) in the selexipag group and
242 (41.6%) in the placebo group, had
a primary-endpoint event (hazard
ratio [HR], 0.60; 99% CI, 0.46–0.78;
p < 0.001). The treatment effect favoring selexipag was consistent across
all prespecified selexipag dosing levels and primarily driven by relative
reductions in rates of hospitalization
(13.6% with selexipag versus 18.7%
with placebo use) and disease progression (6.6% versus 17.3%). The occurrence of the composite secondary
endpoint, comprising death due to
PAH and hospitalization for worsening PAH, was also significantly lower
in patients treated with selexipag than
in placebo recipients: 17.8% versus
23.5% (HR, 0.7; 99% CI, 0.54–0.91;
p = 0.003). There was no significant
difference between the selexipag and
placebo groups in the all-cause death
rate (17.4% versus 18.0%, p = 0.42) or
in the rate of death due to PAH during
the treatment period (12.2% versus
14.3%, p = 0.18). Relative to baseline
values, the median 6-minute walk distance at 26 weeks was reduced by 9 m
in the placebo group and increased by
4 m in the selexipag group (p = 0.003).
The percentages of patients with no
worsening of WHO FC status were
similar in the placebo and selexipag
groups (74.9% and 77.8%, respectively; p = 0.28). A prespecified subgroup
analysis indicated that background
PAH regimens, including monotherapy with an ERA or a PDE5 inhibitor
and combination therapy with both an
ERA and a PDE5 inhibitor, did not significantly affect outcomes (p = 0.95).
The rates of discontinuation due
to adverse effects were 7.1% (n = 41) in
the placebo group and 14.3% (n = 82)
in the treatment group (p < 0.001). The
most common adverse effects leading to discontinuation of selexipag
use were headache (3.3% of patients),
diarrhea (2.3%), and nausea (1.7%).
There was no significant difference
in rates of serious adverse effects in
the selexipag and placebo groups.
Although the high discontinuation
rate (18.9% for the study population
overall) was the most significant limitation of this study, the investigators
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CLINICAL REVIEW
noted that it was anticipated and accounted for in the sensitivity analyses.
A long-term, open-label extension of
the GRIPHON study is being conducted to further assess the safety and tolerability of selexipag and is expected
to conclude in 2018.21
Safety and adverse effects
The adverse-effect profile of selexipag is consistent with those of other
prostacyclin therapies, which produce
a unique, predictable set of dosedependent adverse effects. There is
considerable interpatient variability
in the doses at which these adverse effects occur, and tolerance can develop
with time.19,20 Table 2 details data on
common or noteworthy adverse effects from the GRIPHON study.20 Adverse effects more commonly occur
during dose adjustment, but with time
these often improve.19,20 Administering
se­lex­ipag with food decreases the Cmax
and helps to mitigate adverse effects
associated with peak concentrations.16
Few adverse cardiovascular and
hematologic effects have been observed with the use of selexipag.
Among clinical trial participants,
changes in blood pressure and rates of
symptomatic hypotension were similar between those treated with selexipag and placebo users.19,20 Changes
in cardiac repolarization were studied in 91 healthy patients receiving
escalating doses of selexipag, and no
significant change in the Q-Tc interval was observed.22 Although selexipag produces an inhibitory effect on
platelet aggregation in vitro, no effect
on platelet function was observed in
healthy individuals given selexipag
doses of up to 1,800 mg.23 No increase
in major bleeding events with selexipag use was observed in clinical trials,
although anemia was more common
in patients treated with selexipag. For
reasons not yet identified, hyperthyroidism occurred in approximately
1% of clinical trial particpants treated
with selexipag and no placebo recipients; however, this led to drug discontinuation in only 1 patient. Periodic
monitoring of thyroid function should
e364 SELEXIPAG
Table 2. Adverse Effects Observed During GRIPHON Trial20,a
No. (%) Patients
Placebo
Group
(n = 577)
Selexipag
Group
(n = 575)
p
Headache
189 (32.8)
375 (65.2)
<0.001
Diarrhea
110 (19.1)
244 (42.4)
<0.001
Nausea
107 (18.5)
193 (33.6)
<0.001
Adverse Effect
Jaw pain
36 (6.2)
148 (25.7)
<0.001
206 (35.7)
126 (21.9)
<0.001
Vomiting
49 (8.5)
104 (18.1)
<0.001
Dyspnea
121 (21.0)
92 (16.0)
0.03
Myalgia
34 (5.9)
92 (16.0)
<0.001
Flushing
29 (5.0)
70 (12.2)
<0.001
Anemia
31 (5.4)
48 (8.3)
0.05
Hypotension
18 (3.1)
29 (5.0)
0.1
Major bleeding event
12 (2.1)
14 (2.4)
0.7
Worsening PAH
Hyperthyroidism
Discontinuation due to adverse effects
0
41 (7.1)
8 (1.4)
0.004
82 (14.3)
<0.001
PAH = pulmonary arterial hypertension.
a
be considered in patients receiving
selexipag.23
Place in therapy
On the basis of available clinical
trial data, selexipag was approved by
FDA for use in the treatment of PAH
(either as monotherapy or in combination with an ERA, a PDE5 inhibitor,
or both) to reduce disease progression
and the risk of hospitalization.9 Patients with FC II or III disease should
be considered for treatment with
selexipag, and 2015 joint European
guidelines on treatment of PAH recommend its use in these patients; this
was a class I recommendation (i.e., use
is “recommended/indicated”) based
on level B evidence (data derived
from a single randomized clinical trial
or large nonrandomized studies).6
Guidelines from the American College of Chest Physicians on PAH have
not been updated since the approval
of selexipag and thus do not provide
recommendations for its use. Selexipag has not been adequately studied
in patients with FC IV symptoms, and
parenteral prostacyclin analogs re-
AM J HEALTH-SYST PHARM | VOLUME 74 | 2017
main the standard of care for patients
with advanced disease.5,6
Although selexipag is approved for
use in combination with other PAH
therapies, it is unknown at this time
whether adding selexipag to other
therapies, such as an ERA or a PDE5
inhibitor, provides additional benefit
relative to the use of selexipag alone.
Prior to the approval of selexipag, a
trial evaluating the combination of
ambrisentan (an ERA) and tadalafil
(a PDE5 inhibitor) showed that compared with use of either agent alone,
the combined use of these agents reduced the risk of hospitalization or
disease progression by 50%, with only
a moderate increase in nonserious adverse effects (e.g., edema, headache)
in the combination therapy group.24 To
date, there have been no trials directly
comparing selexipag with the combination of ambrisentan and tadalafil.
Because of the benefits of selexipag use
demonstrated in the GRIPHON trial,20
as well as the benefits associated with
combination therapy with ambrisentan and tadalafil,24 clinicians may
choose a combination of these agents
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CLINICAL REVIEW
SELEXIPAG
to maximize treatment benefits. Subgroup analysis in the GRIPHON trial
suggested that the benefits of selexipag use are consistent irrespective of
background therapy. There is an ongoing trial to evaluate changes in PVR
in patients with newly diagnosed PAH
treated with the ERA macitentan in
combination with tadalafil and selexipag or with selexipag plus either macitentan or tadalafil.25 Study completion
is not anticipated until 2018 but may
provide additional insight on the use
of selexipag in combination with other
PAH medications.
Until additional clinical trial data
are available, the poor prognosis and
limited treatment options for patients
with PAH may favor aggressive upfront
therapy combining selexipag with an
ERA, a PDE5 inhibitor, or both; however, the questionable benefit of such
treatment should be weighed against
the financial burden and higher rate
of adverse effects that may occur with
combination therapies.
Cost and access
considerations
Selexipag is only available through
Accredo (Accredo Health, Inc., Memphis, TN) and CVS (CVS Health,
Woonsocket, RI) specialty pharmacies. The average wholesale price for
a 1-month supply of selexipag 200 mg
is $11,208, with an average monthly
price of $17,424 for doses of 400 mg
and above.26 In comparison, ERAs cost
approximately $10,000 per month,
and the oral prostacyclin analogue
treprostinil diolamine costs upward of
$10,000 per month for a median dosage of 2.5–5 mg twice daily.26 Financial assistance programs for insured
or uninsured individuals are available
through Actelion Pharmaceuticals. At
this time, data regarding the comparative cost-effectiveness of se­lex­ipag and
other therapies for PAH are lacking.
Conclusion
Selexipag is an oral prostacyclin
IP receptor agonist approved for use
as monotherapy or in combination
with other therapies to slow PAH pro
gression and reduce the risk of hospitalization in patients with FC II or III
symptoms. Its stability and relatively
long half-life offer conveniences over
conventional prostanoid therapies.
Disclosures
The authors have declared no potential
conflicts of interest.
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concepts and experimental therapies.
Circulation. 2010; 121:2045-66.
3. Montani D, Gunther S, Dorfmuller P
et al. Pulmonary arterial hypertension. Orphanet J Rare Dis. 2013; 8:97.
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